RECURRENT PREGNANCY LOSS

Diagnostic factors identified in 1020 women with two

versus three or more recurrent pregnancy losses
Carolyn R. Jaslow, Ph.D.,a Judi L. Carney, M.D.,b and William H. Kutteh, M.D., Ph.D.b,c
a
Department of Biology, Rhodes College, b Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology,
University of Tennessee, and c Fertility Associates of Memphis, Memphis, Tennessee

Objective: To determine whether the frequency of abnormal results for evidence-based diagnostic tests differed
among women with recurrent pregnancy loss (RPL) based on the number of prior losses (n ¼ 2, 3, or R4) and
to determine whether abnormal results for additional investigative diagnostic tests differed in prevalence among
women with different numbers of pregnancy losses.
Design: Single-center, retrospective study.
Setting: Patients with RPL at a private practice.
Patient(s): One thousand twenty women who had two or more consecutive spontaneous pregnancy losses with the
same partner.
Intervention(s): None.
Main Outcome Measure(s): Frequencies of abnormal results for evidence-based diagnostic tests considered def-
inite or probable causes of RPL (karyotyping for parental chromosomal abnormalities; pelvic sonohysterography,
hysterosalpingogram, or hysteroscopy for uterine anomalies; immunological tests for lupus anticoagulant and anti-
cardiolipin antibodies; thrombophilic tests for the factor V Leiden mutation; and blood tests for thyroid-stimulating
hormone [TSH] and fasting blood glucose). We also measured the frequency of abnormal results for nine additional
investigative tests in the same patients (antiphosphatidyl serine antibodies, microbial infection, midluteal P, PRL,
functional protein C activity, functional protein S activity, antithrombin activity, fasting homocysteine and meth-
ylenetetrahydrofolate reductase polymorphisms, and factor II mutation).
Result(s): The prevalence of abnormal results for evidence-based and investigative diagnostic tests did not differ
among women with different numbers of pregnancy losses.
Conclusion(s): Evaluation of all couples with two, three, or more consecutive miscarriages is recommended. (Fer-
til Steril 2010;93:1234–43. 2010 by American Society for Reproductive Medicine.)
Key Words: Recurrent pregnancy loss, miscarriages, antiphospholipid antibodies, thrombophilias, evidence-based

Recurrent pregnancy loss (RPL) is a devastating problem for
hopeful parents, and it can be a perplexing, often frustrating,
clinical challenge for their physicians. RPL is estimated to
occur in 2%–4% of reproductive-age couples (1). Various eti-
ologies, either alone or in combination, have been proposed
to contribute to pregnancy loss; these include chromosomal
translocations, uterine abnormalities, endocrine defects,
thrombophilias, autoimmune diseases, and infectious agents
Received September 18, 2008; revised January 14, 2009; accepted Jan-
uary 30, 2009; published online March 31, 2009.
C.R.J. has nothing to disclose. J.L.C. has nothing to disclose. W.H.K. has
nothing to disclose.
Supported by a Creative Advance Planning Sabbatical Grant from the An-
drew W. Mellon Foundation and by the Frank Ling Research Grant in
Obstetrics and Gynecology from the University of Tennessee Health
Science Center, Memphis, Tennessee.
Presented at the 62d Annual Meeting of the American Society for Rep-
roductive Medicine, which was held in New Orleans, Louisiana, on
October 21–25, 2006.
Reprint requests: William H. Kutteh, M.D., Ph.D., Fertility Associates of
Memphis, 80 Humphreys Center, No. 307, Memphis, Tennessee
38120 (FAX: 901-747-4446; E-mail: wkutteh@utmem.edu).
(1–7). A recent survey of randomized controlled trials and
meta-analyses, however, yielded a more limited list of evi-
dence-based factors that merit testing in women with RPL
(7). These recommended diagnostic tests, described as defi-
nite or probable causes of RPL, include karyotyping for
parental chromosomal abnormalities; pelvic sonohysterogra-
phy, hysterosalpingogram, or hysteroscopy for uterine anom-
alies; immunological tests for lupus anticoagulant and
anticardiolipin antibodies; thrombophilic tests for the factor
V Leiden mutation; and blood tests for thyroid-stimulating
hormone (TSH) and fasting blood glucose (2, 7). Many of
the diagnostic tests recommended for evaluation of RPL
can be expensive and time-consuming, raising the question
about when testing is warranted. For example, some practi-
tioners recommend testing if a patient has had two consecu-
tive losses, whereas others advise waiting until she has had
three or more. The goal of this study was to determine
whether abnormal test results for factors that are definite or
probable causes of RPL occur with equal frequency in
women with only two pregnancy losses versus those who
have had greater numbers of losses.

1234 Fertility and Sterility Vol. 93, No. 4, March 1, 2010 0015-0282/10/$36.00
Copyright ª2010 American Society for Reproductive Medicine, Published by Elsevier Inc. doi:10.1016/j.fertnstert.2009.01.166
MATERIALS AND METHODS
Subjects and Criteria for Pregnancies and Recurrent
Losses
This retrospective cohort study was approved by the Institu-
tional Review Board at the University of Tennessee Health
Sciences Center for exempt status because the research in-
volved 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 though identifiers
linked to the subjects. Subjects included patients with RPL
referred to the University of Tennessee, Memphis, or to Fer-
tility Associates of Memphis from 1996 to 2006. All women
20–45 years of age were included, regardless of socioeco-
nomic status or race. This age range is similar to that of pre-
vious studies (8–11). For each patient, a thorough medical
and obstetric history was obtained, and a physical examina-
tion was performed by one of us (WHK). As part of an ongo-
ing investigation of the causes of RPL, all patients were
encouraged to have an evaluation consisting of karyotypes
on both partners; hysterosalpingogram, hysteroscopy, or so-
nohysterography; blood tests for PRL, TSH, fasting glucose,
and midluteal P; tests of lupus anticoagulant activity (dilute
Russell viper venom test and partial thromboplastin time-Lu-
pus anticoagulant (PTT-LA), confirmed by a hexagonal phase
phospholipid test) and IgG and IgM anticardiolipin and anti-
phosphatidyl serine antibodies; and cervical cultures for
Chlamydia, Mycoplasma, and Ureaplasma. In 2001, as part
of a research protocol, a thrombophilic workup was added
that included testing for protein C activity, protein S activity,
antithrombin activity, activated protein C resistance, factor V
Leiden mutation, factor II mutation, and fasting homocys-
teine. Women with elevated fasting homocysteine had reflex-
ive testing for methylenetetrahydrofolate reductase
(MTHFR) gene polymorphisms. All testing was performed
when women were nonpregnant and at least 6 weeks remote
from a miscarriage. Information from outside medical
records and test results from the workup listed above were
added to the patient charts.
Pregnancy was defined by multiple positive urine bhCGs
and/or ultrasound documentation. Pregnancy loss was de-
fined as any natural abortion occurring at or before 20 weeks
of gestation or with a fetal weight of %500 g. Stillbirths and
unexplained intrauterine fetal demises, although rare in this
cohort, were also counted in each patient’s pregnancy loss
total. Patients whose losses all occurred after 20 weeks were
excluded. Molar pregnancies, ectopic pregnancies, and preg-
nancy terminations were also excluded from analysis.
In this study, 1020 patients were included because they had
experienced at least two consecutive pregnancy losses with
the same partner. The maximum number of consecutive
losses with a single current partner was used to define the
number of pregnancy losses for each patient. Two or more
consecutive losses with the same partner without carrying
a fetus to viability were categorized as primary RPL. Second-
ary RPL was categorized as two or more consecutive losses
after at least one viable pregnancy with the same partner.
Fertility and Sterility
Evidence-Based Diagnostic Tests Performed and Criteria
for Abnormal Test Results
Based on current, critical reviews of the literature that identi-
fied definite or probable causes of RPL (2, 7), we evaluated the
results of the following evidence-based diagnostic tests. For
each diagnostic test performed, patients were categorized as
normal or abnormal according to the criteria described below.
Parental genetics Parental karyotypes were reviewed by
a geneticist, and significant rearrangements (e.g., balanced
translocations and mosaics) were considered abnormal. Nor-
mal variants were considered normal. This category was
ranked as abnormal if either a patient or her partner had an
abnormal karyotype; normal if the female karyotype was nor-
mal and the male karyotype was either normal or unknown;
or unknown if both karyotypes were unknown.
Uterine anatomy Uterine anatomic defects were identified
by hysterosalpingogram, hysteroscopy, or sonohysterogra-
phy. Considered abnormal were congenital uterine anomalies
(such as unicornuate and bicornuate uteri) and significant
fundal filling defects or intrauterine abnormalities in the up-
per two-thirds of the uterine cavity. These included fibroids
and polyps greater than 1.0 cm that were in the cavity, septa
greater than 1.0 cm wide and 1.0 cm deep, or Asherman’s
syndrome adhesions.
Lupus anticoagulant Serum levels of lupus anticoagulant
were evaluated using the dilute Russell viper venom test and
PTT-LA. Results greater than 42 seconds that were not cor-
rected with a 1:1 mix with normal serum were considered ab-
normal if confirmed by a hexagonal phase phospholipid test.
Anticardiolipin antibodies Serum levels of anticardiolipin
IgG and IgM were measured by enzyme-linked immunoassay,
with abnormal levels exceeding 20 phospholipid units. All pos-
itive tests were confirmed by repeat testing at least 6 weeks later.
Factor V Leiden mutation This category was considered
abnormal if the patient had an activated protein C resistance
ratio %2.0 and a heterozygous or homozygous factor V Leiden
G1691A mutation.
Thyroid function Serum levels of TSH less than 0.45 mU/mL
or greater than 4.5 mU/mL were considered abnormal.
Blood glucose level A patient’s serum glucose level was
considered abnormal if fasting blood glucose was greater
than 126 mg/dL.
Additional Investigative Diagnostic Tests Performed and
Criteria for Abnormal Test Results
In addition to the evidence-based tests described above, we
measured the frequency of abnormal results from the follow-
ing investigative diagnostic tests. Numerous studies have
found links between these factors and RPL (3, 6, 12–23),
however, there is no consensus on whether these tests should
routinely be recommended for patients with RPL.
Antiphosphatidyl serine antibodies Serum levels of anti-
phosphatidyl serine IgG and IgM were measured by
1235
enzyme-linked immunoassay, with abnormal levels exceed-
ing 20 phospholipid units. All positive tests were confirmed
by repeat testing at least 6 weeks later. This test was indepen-
dently considered abnormal only if the patient’s anticardioli-
pin antibodies were normal.
Microbial infection Positive cervical cultures for Chlamydia
trachomatis, Mycoplasma hominis, or Ureaplasma urealyti-
cum during the period of recurrent pregnancy losses were
considered abnormal.
Midluteal P Serum levels of P were abnormal if they were
less than 3 ng/mL in the midluteal phase.
PRL Serum levels of PRL that were greater than 23 ng/mL
were considered abnormal.
Thrombophilic factors Serum levels of functional protein C
activity less than 74%, functional protein S activity less
than 60%, and antithrombin activity less than 70% were con-
sidered abnormal. An abnormal result was recorded if fasting
homocysteine was greater than 14 mmol/L or if the patient
was heterozygous or homozygous for the MTHFR C677T
and/or A1298C polymorphisms. Heterozygous or homozy-
gous mutations for the G20210A prothrombin (factor II)
gene were classified as abnormal. Each thrombophilic factor
was analyzed independently.
Statistical Analyses
The SPSS cross-tabs procedure with the two-tailed Pearson’s
c2-test for significance was used to determine whether the
likelihood of abnormal results for each diagnostic test dif-
fered among women who had experienced two losses, three
losses, or four or more losses. Because the c2 analysis was re-
peated for multiple tests, the Bonferroni correction of divid-
ing the 0.05 alpha value by the number of tests was applied
(24). To determine whether the patients’ ages differed among
the RPL cohorts, one-way analysis of variance (ANOVA) was
used with Levene’s test for homogeneity of variances and the
Student-Neuman-Keuls post hoc procedure for all pairwise
multiple comparisons. All statistical tests were performed us-
ing SPSS Windows, version 13 (2006; SPSS Inc., Chicago).
RESULTS
The mean age of patients at their initial visit was 32.6 years
(range, 20–45 years). One-way ANOVA with Student-Neu-
man-Keuls post hoc procedure for all pairwise multiple com-
parisons showed no differences in mean age among women
with different numbers of pregnancy losses (mean ages 
SD for two losses, 32.5  4.8 years; for three losses, 32.5
 5.0 years; for four or more losses, 33.1  5.1 years;
P>.05). For each cohort of pregnancy loss (n ¼ 2, 3, R4 los-
ses) and for all patients, the mean age of women with one or
more prior live births (34.1  4.6 years) was greater than that
for women who had no prior live births (31.9  4.9 years;
P<.001). The ethnic makeup of the RPL population was
72% white, 26% African-American, and 2% Asian and other.
The average body mass index (kg/m2) for all RPL patients
was 26.2  6.3 (SD).
1236 Jaslow et al. Diagnostic factors in 1020 women with RPL
There were 4305 pregnancies, with 3492 total losses, for an
average of 3.4 losses per patient. Spontaneous losses
occurred 3251 times, with 90% of the losses occurring in
the first trimester (<13 weeks). The estimated gestational
age at loss was 8.6  3.6 weeks. The overwhelming majority
of patients (96%) had pregnancy losses that occurred primar-
ily before 13 weeks or had losses that occurred with equal
frequency before or after 13 weeks. Of all spontaneous preg-
nancy losses, 3019 were considered consecutive spontaneous
losses with the same partner and were used for analysis.
Among the 1020 patients, the number of these consecutive
losses ranged from two to 14; 447 (44%) of the patients
had only two consecutive losses, 343 (34%) had three, and
230 (22%) had four or more (Table 1). Two-thirds of the
women had not had a live birth before their consecutive preg-
nancy losses (primary RPL), and one-third had at least one
live birth before the consecutive losses (secondary RPL).
These proportions of primary and secondary RPLs were con-
sistent within cohorts of patients who had experienced two,
three, or four or more losses (Table 1).
Evidence-Based Diagnostic Tests
The likelihood of abnormal results from each of the seven
evidence-based diagnostic tests (parental genetics, uterine
anatomy, lupus anticoagulant, anticardiolipin antibodies,
factor V Leiden, TSH, and blood glucose) was the same for
women with two, three, or four or more losses (Table 2). Ta-
ble 2 also shows the prevalence of abnormal results for these
evidence-based tests among representative control popula-
tions. Uterine anatomic defects and autoimmune abnormali-
ties (lupus anticoagulant and anticardiolipin antibodies) were
the most common abnormalities found among all patients
(both about 18%). Elevated blood glucose (0.3%) was the
least common.
Of the 1020 patients, 403 (40%) had at least one abnormal
evidence-based diagnostic test (Table 3). The prevalence of
patients with one or more abnormal results was the same
among women with two, three, or four or more losses as
well as between women who had experienced a prior live
birth and those who had not (Table 3). Fifty-two (12.9%)
of the 403 women had abnormal results for two evidence-
based tests, and two (0.5%) patients had abnormal results
for a combination of three tests (lupus anticoagulant, anti-
cardiolipin antibodies, and either parental genetics or uterine
anatomy).
Additional Investigative Diagnostic Tests
The frequency of abnormal results for each investigative diag-
nostic test (antiphosphatidyl serine antibodies, microbial
infection, midluteal P, PRL, functional protein C activity,
functional protein S activity, antithrombin activity, fasting
homocysteine or MTHFR polymorphisms, and factor II muta-
tion) did not differ among women who had two, three, or four
or more losses (Table 4). Table 4 also shows the prevalence of
abnormal results for these investigative tests among
Vol. 93, No. 4, March 1, 2010
 TABLE 1
Reproductive history of 1020 patients with RPL.
No. of consecutive pregnancy losses
Prior live
births 2 3 4 5 6 7 8 9 10 R11 Total
0 298 222 82 34 19 5 5 1 2 2 670
R1 149 121 58 15 4 2 1 0 0 0 350
Total 447 343 140 49 23 7 6 1 2 2 1020
Jaslow. Diagnostic factors in 1020 women with RPL. Fertil Steril 2010.

representative control populations. An elevated homocysteine DISCUSSION

and/or MTHFR polymorphism was identified in 44 (14%) of
314 patients. Of these 44, 16 (36.4%) had both elevated homo-
cysteine and a polymorphism of the MTHFR gene, eight
(18.2%) had an elevated homocysteine alone, and 20
(45.4%) had only an MTHFR polymorphism. At least one ab-
normal investigative test result was found in 36% of the pa-
tients, with no differences in frequency associated with
different numbers of pregnancy losses (Table 5). Of the 617
patients who had completely normal workups for the evi-
dence-based tests, 209 (34%) had at least one abnormal result
for the investigative diagnostic tests.
In this large study of women with RPL, abnormal results for
all diagnostic tests occurred with equal frequency, regardless
of whether the women had experienced only two consecutive
losses, three losses, or four or more losses. Although the pres-
ence of a particular abnormal test result does not prove that it
caused the pregnancy losses in these patients, abnormalities
in parental genetics, uterine anatomy, lupus anticoagulant,
anticardiolipin antibodies, factor V Leiden mutation, TSH,
and fasting blood glucose are considered either probable or
definite causes of RPL (2, 7). Approximately 25%–51% of
miscarriages in women with RPL are associated with

TABLE 2
Prevalence of abnormal results for each evidence-based diagnostic test from 1020 patients with RPL.
No. of consecutive pregnancy losses
Total Control
Test 2 (n [ 447) 3 (n [ 343) R4 (n [ 230) P value (n [ 1020) populations
Parental genetics 2.8 (8/281) 5.4 (15/280) 5.2 (11/212) .28 4.4 (34/773) 0.4 (4/1000)a
Uterine anatomy 18.7 (75/401) 18.2 (55/303) 16.7 (34/203) .84 18.1 (164/907) 7.5 (148/1961)b
c
Lupus anticoagulant 5.0 (20/400) 2.9 (9/307) 1.9 (4/216) .10 3.6 (33/923)
Anticardiolipin 15.6 (64/409) 13.1 (42/320) 17.1 (37/217) .42 15.1 (143/946) 6.7 (7/104)d
Factor V Leiden 4.2 (6/144) 8.1 (8/99) 10.3 (7/68) .21 6.8 (21/311) 6.8 (25/366)e
TSH 8.1 (32/396) 6.5 (19/291) 6.2 (12/194) .62 7.2 (63/881) 3.9 (241/6182)f
g
Blood glucose 0 (0/193) 0.8 (1/124) 0 (0/73) .34 0.3 (1/390)
Note: Values are the percentage of patients with abnormal results for that test (number of patients with abnormal results/
number of patients evaluated for that test). The likelihood that a diagnostic test is abnormal did not change with greater
numbers of pregnancy losses based on two-tailed Pearson’s c2-tests. The lack of significant differences is unchanged
whether using an alpha level of 0.05 or a Bonferroni corrected alpha value of 0.007 (0.05 divided by the seven tests). All
P-values are not significant.
a
Prevalence rate of balanced abnormalities per 1000 live births (25).
b
Percentage of premenopausal women without a history of infertility or RPL who had congenital uterine abnormalities or
submucosal fibroids (10).
c
Lupus anticoagulant prevalence is usually reported together with antiphospholipid antibodies.
d
Percentage of normal, fertile women positive for IgG or IgM anticardiolipin antibodies (26).
e
Percentage of normal, fertile women heterozygous or homozygous for the factor V Leiden G1691A mutation (27, 28).
f
Percentage of normal females R12 years who are not pregnant or taking estrogen and who had abnormal levels of TSH (29).
g
Abnormal glucose levels are highly variable depending on the population tested.
Jaslow. Diagnostic factors in 1020 women with RPL. Fertil Steril 2010.

Fertility and Sterility 1237

 TABLE 3
Prevalence of patients with one or more abnormal results for evidence-based tests among 1020
patients with RPL.
No. of consecutive pregnancy losses
Prior live births 2 3 R4 Total
0 41 (123/298) 40 (90/222) 42 (63/150) 41 (276/670)
R1 38 (56/149) 35 (42/121) 36 (29/80) 36 (127/350)
Total 40 (179/447) 38 (132/343) 40 (92/230) 40 (403/1020)
Note: Values are the percentage of patients with one or more abnormal test results (number of patients with at least one
abnormal result/number of patients evaluated). Two-tailed Pearson’s c2-tests determined that the likelihood of having at
least one abnormal test result was the same for patients with different numbers of pregnancy losses and whether or not
they had any prior live births (P>.05).
Jaslow. Diagnostic factors in 1020 women with RPL. Fertil Steril 2010.

a chromosomal abnormality in the conceptus (11, 33–35),
and karyotyping of abortuses should be performed to deter-
mine whether there is a cytogenetic reason for the loss (33).
These losses, however, can occur whether or not the patient
has any of the above abnormalities in addition. The occur-
rence of an embryonic aneuploidy does not exclude, for ex-
ample, the possibility the mother also has a uterine septum
or elevated TSH.
Although abortus aneuploidy is more likely to occur with
increased age, especially above age 35 (11), there were no
differences in age among our cohorts of patients with differ-
ent numbers of losses. The probability of euploid miscar-
riages in RPL patients younger than age 36 is significantly
greater than in age-matched patients without a history of
pregnancy losses (33), indicating that recurrent losses are
more likely caused by abnormal factors than are unprece-
dented or sporadic losses in the general population. Since
the probability of uncovering an evidence-based abnormal
factor (about 40%) was not higher in patients with RPL
with three or more pregnancy losses than in patients with
RPL with only two, deferring testing until after the third re-
current loss does not improve the odds of discovering an ab-
normal factor. It does, however, cause additional emotional
distress for the patient who incurs another loss, along with in-
creasing the age at which she attempts her next pregnancy.
For women in their 30s, increased maternal age increases
the risk of subsequent fetal loss (36).
The overwhelming majority of patients had pregnancy los-
ses that occurred primarily in the first trimester (<13 weeks),
and those with losses exclusively after 20 weeks were ex-
cluded. We chose to include women whose losses occurred
predominantly in the first trimester but who also had a later
loss. We believe it was appropriate to include all these pa-
tients in our database because the time of fetal loss is much
earlier than the estimated gestational age in many cases.
Several other investigators have examined the factors asso-
ciated with RPL. Our study is the largest comprehensive one
reported to date, and it extends the findings from earlier stud-
ies (Table 6). The percentage of abnormal parental karyo-
types that we measured (4.4%) is similar to the frequencies
recorded by others (8, 18, 37–40) and falls within the reported
range (2.5%–8%) for women with RPL (1). Similarly, the fre-
quency of uterine anatomic defects that we found (18.1%)
also lies within the reported range (15%–20%) (1) and is
close to the percentages noted by Stephenson (8) and Stray-
Pederson and Stray-Pedersen (37). Clifford et al. (38) de-
tected many fewer uterine anomalies, most likely because
they used ultrasound instead of more sensitive methods
such as sonohysterography. In contrast, Harger et al. (39),
who used hysterosalpingograms and hysteroscopy, docu-
mented 50% more uterine anomalies than we did. Without
a statement of the specific criteria used for their definition
of a uterine defect, it is possible that Harger et al. found
a higher frequency because they included all types of uterine
anomalies, including some, such as defects in the lower third
of the cavity, that were not considered abnormal in our study.
The prevalence of abnormal lupus anticoagulant and anti-
cardiolipin antibodies among our 1020 patients with RPL
(16.8%) is similar to that of the 197 patients (20.3%) reported
by Stephenson (8) and the 500 patients (14%) examined by
Clifford et al. (38). Our anticardiolipin abnormalities
(15.1%) were also roughly equal to the 17.3% frequency
found among 866 women with at least two losses (18) and
the 17.0% frequency among 147 women with three or more
losses (26). Rey et al.’s (40) meta-analysis of seven moderate
or high-quality studies determined that the prevalence of the
factor V Leiden mutation among 1403 patients with recurrent
early losses was 7.8%, similar to our finding of a rate of 6.8%
for mutations.
In our study, abnormal levels of TSH were recorded for
7.2% of the patients with RPL. This is more than double the
previously reported frequencies (8, 37, 39), most likely be-
cause the newer TSH assays used in our investigation are
more sensitive than those used in the earlier studies. Fasting
blood glucose levels high enough to indicate diabetes mellitus
(>126 mg/dL) were found in only 0.3% of the RPL patients.
Although uncontrolled diabetes has been associated with

1238 Jaslow et al. Diagnostic factors in 1020 women with RPL Vol. 93, No. 4, March 1, 2010
 TABLE 4
Prevalence of abnormal results for each investigative diagnostic test given to 1018a patients with RPL.
No. of consecutive pregnancy losses
Control
Test 2 3 R4 P value Total populations
Antiphosphatidyl 4.6 (18/391) 5.6 (16/288) 7.8 (15/193) .29 5.6 (49/872) 0.5 (2/392)c
serine antibodiesb
Microbial infection 16.5 (70/425) 13.6 (45/331) 16.2 (37/228) .52 15.4 (152/984) 20.0 (27/135)d
Midluteal P 16.7 (63/377) 16.7 (47/281) 16.1 (31/193) .98 16.6 (141/851) 9.4 (5/53)e
PRL 5.9 (21/358) 6.1 (16/264) 4.8 (9/186) .84 5.7 (46/808) 0.4 (40/10,000)f
Functional protein 0.9 (1/115) 0 (0/85) 3.3 (2/61) .17 1.1 (3/261) 2.0 (7/345)g
C activity
Functional protein 3.5 (4/115) 2.4 (2/85) 5.0 (3/60) .69 3.5 (9/260) 3.5 (9/254)g
S activity
Antithrombin activity 2.6 (3/115) 0 (0/85) 1.6 (1/61) .33 1.5 (4/261) 0.8 (2/264)g
Homocysteine/ 15.1 (22/146) 10.2 (10/98) 17.1 (12/70) .39 14.0 (44/314) 5.2 (13/249)h
MTHFR
Factor II mutation 2.7 (2/74) 4.8 (2/42) 3.7 (1/27) .84 3.5 (5/143) 1.7 (6/359)g
Note: Values are the percentage of patients with abnormal results for that test (number of patients with abnormal results/
number of patients evaluated for that test). The likelihood that a diagnostic test is abnormal did not change with greater
numbers of pregnancy losses based on two-tailed Pearson’s c2-tests. The lack of significant differences is unchanged
whether using an alpha level of 0.05 or a Bonferroni corrected alpha value of 0.006 (0.05 divided by the nine tests). All
P-values are not significant.
a
Of the original 1020 RPL patients, two refused to have any of these investigative tests performed.
b
Antiphosphatidyl serine antibodies.
c
Percentage of normal, nonpregnant, reproductive-age women who had normal anticardiolipin and abnormal antiphos-
phatidyl serine IgG or IgM (18, 26).
d
Percentage of women attending a male infertility clinic who had positive cervical cultures for Mycoplasma hominis or Ure-
aplasma urealyticum (30).
e
Percentage of ovulatory, infertile women who had abnormal midluteal P (31).
f
Percentage of a normal adult population with abnormally elevated PRL (32).
g
Percentage of normal women with abnormal protein C, protein S, or antithrombin activity, or with a factor II (prothrombin)
G20210A mutation (27, 28).
h
Percentage of healthy women who had hyperhomocysteinemia (21).
Jaslow. Diagnostic factors in 1020 women with RPL. Fertil Steril 2010.

recurrent pregnancy loss, it is a relatively rare condition
among patients with RPL in developed countries. Measure-
ments of blood glucose may be of little value in a workup of
RPL.
The investigative diagnostic tests for antiphosphatidyl ser-
ine antibodies, microbial infections, midluteal P, PRL, and
thrombophilic factors (functional protein C activity, func-
tional protein S activity, antithrombin activity, fasting homo-
cysteine or MTHFR polymorphisms, and factor II mutation)
were evaluated separately in this study because there is no
consensus about the role of these factors in RPL. There are
no studies showing that these factors directly cause preg-
nancy loss. Several investigations, however, have shown sig-
nificant associations with RPL (3, 6, 12–23) or evidence of
negative effects during pregnancy.
Antiphosphatidyl serine antibodies are known to inhibit
trophoblast development and invasion and the synthesis of
pregnancy hormones such as hCG (41). In a study of 866
patients with RPL who were negative for anticardiolipin an-
tibodies, 10.1% had positive levels of another phospholipid
antibody, including antiphosphatidyl serine (18). Both low
molecular weight heparin and unfractionated heparin reduce
the in vitro binding of antiphosphatidyl serine antibodies, as
well as anticardiolipin antibodies, on a per-unit basis (42). In
two prospective treatment trials, women with unexplained
RPL and positive antiphosphatidyl serine antibodies had suc-
cessful deliveries after treatment with unfractionated or low
molecular weight heparin (43, 44). Because of these findings,
we have continued to treat RPL patients who have positive
antiphosphatidyl serine antibodies using prophylactic hepa-
rin and low-dose aspirin.
Understanding the relationship among adverse pregnancy
outcomes, elevated homocysteine levels, and MTHFR poly-
morphisms is an evolving area of medicine. Initially, MTHFR
polymorphisms were considered potentially useful for

Fertility and Sterility 1239

 TABLE 5
Prevalence of patients with one or more abnormal results for investigative tests among 1018 patients
with RPL.
No. of consecutive pregnancy losses
Prior live births 2 3 R4 Total
0 38 (114/297) 38 (83/221) 43 (65/150) 39 (262/668)
R1 36 (53/149) 24 (29/121)a 28 (22/80)b 30 (104/350)
Total 37 (167/446) 33 (112/342) 38 (87/230) 36 (366/1018)
Note: Values are the percentage of patients with one or more abnormal test results (number of patients with at least one
abnormal result/number of patients evaluated). Two-tailed Pearson’s c2-tests determined that the likelihood of having at
least one abnormal test result was the same for patients with different numbers of pregnancy losses (P>.05).
a
Women with three losses were less likely to have an abnormal test result if they had a prior live birth (P ¼ .01).
b
Women with four or more losses were less likely to have an abnormal test result if they had a prior live birth (P ¼ .02).
Jaslow. Diagnostic factors in 1020 women with RPL. Fertil Steril 2010.

diagnosing women with RPL (45). Emphasis shifted to mea-
suring homocysteine, however, because numerous studies sug-
gested that hyperhomocysteinemia was associated with
increased risk of arterial occlusion (46) and because elevated
homocysteine in vitro caused detachment and death of tropho-
blast cells, along with decreased hCG secretion (47). Addi-
tionally, Nelen et al. found in a meta-analysis of over 400
women that fasting homocysteine was a more sensitive test
than MTHFR genotyping for determining the risk of RPL (21).
In 2001, as a part of a research protocol, fasting homocys-
teine was added to our investigational panel in women with
RPL. To counsel siblings and parents of RPL patients who
may have been at risk for vascular disease, we reflexively
obtained genetic testing of MTHFR polymorphisms in these
patients. At the same time, studies clearly indicated an in-
creased risk of neural tube defects in women who had homo-
zygous and heterozygous polymorphisms of MTHFR (48,
49). Recently, MTHFR polymorphisms C677T and A1298C
have been implicated in fetal nonviability (50). Callejon
et al. (50) compared MTHFR genotypes from tissues of spon-
taneously aborted fetuses with genotypes from their living
siblings. The homozygous and heterozygous MTHFR poly-
morphisms, alone or in combination, were found

TABLE 6
Frequencies of abnormal results for evidence-based diagnostic tests from 1020 RPL patients
compared to frequencies from other studies.
Stray-Pedersen
and Stray-
This study Stephenson Pedersen Clifford et al. Harger et al.
Test (n [ 1020) (8) (n [ 197) (37) (n [ 195) (38) (n [ 500) (39) (n [ 155) Others
Parental genetics 4.4 3.5 2.6 3.6 7.7 —
Uterine anatomy 18.1 15.7 15.4 1.8 27.0 —
Lupus anticoagulant 3.6 — — 9 — —
(LAC)
Anticardiolipin 15.1 — — 6 — 17.3a
(ACA)
LAC and/or ACA 16.8 20.3 — 14 — —
Factor V Leiden 6.8 — — — — 7.8b
TSH 7.2 3.0 2.1 — 1.7 —
Blood glucose 0.3 — — — — —
Note: Percentage of patients with abnormal results per all patients evaluated for that test. Data are shown for this study and
for other studies listed by author with reference number and sample size. Dash (—) means authors did not report fre-
quency of this factor.
a
Yetman and Kutteh (18); 866 patients.
b
Rey et al. (40); meta-analysis of seven studies totaling 1403 patients.
Jaslow. Diagnostic factors in 1020 women with RPL. Fertil Steril 2010.

1240 Jaslow et al. Diagnostic factors in 1020 women with RPL Vol. 93, No. 4, March 1, 2010
significantly more frequently in the spontaneously aborted
tissues. None of the living offspring had three or four
MTHFR polymorphisms; genetic combinations that appear
to be determinants of fetal nonviability. Moreover, the wild-
type MTHFR allele showed a strong protective effect against
abortion.
Because of these recent findings, we now test all patients
with RPL and all patients with a personal or family history
of neural tube defects for both fasting homocysteine and
MTHFR polymorphisms. We believe that fasting homocys-
teine alone may be an insensitive screen because the majority
of patients are already taking prenatal vitamins with folic
acid and vitamin B6. MTHFR allele testing alone may be in-
adequate because other enzyme anomalies or dietary defi-
ciencies may contribute to elevated homocysteine. We
currently recommend that all patients with either elevated ho-
mocysteine and/or MTHFR polymorphisms be treated with
supplemental folic acid in the same manner as if they had pre-
viously conceived a baby with a neural tube defect.
Elevated concentrations of serum PRL have been found in
women with unexplained RPL compared with concentrations
in control groups (13, 51). In addition, when patients with
RPL were given bromocriptine to normalize PRL levels,
this treatment significantly reduced their miscarriage rate
compared to that of control patients with RPL who had ele-
vated PRL and did not receive treatment (14). On the basis
of these findings, we normalize PRL levels in patients with
RPL with hyperprolactinemia before allowing them to con-
ceive.
Abnormal levels of PRL and antiphosphatidyl serine anti-
bodies were an order of magnitude more common in all co-
horts of patients with RPL in our study than they were in
normal control populations (Table 4). Table 4 also shows
that the prevalence of hyperhomocysteinemia in patients
with RPL (14.0%) was almost 3 times greater than that in
a control population (5.2%). Consequently, diagnostic tests
for abnormal antiphosphatidyl serine antibodies, PRL, and
homocysteine/MTHFR may be useful when evaluating pa-
tients with RPL, even after only two losses.
The roles of the other investigative diagnostic tests in rela-
tion to RPL are more ambiguous. Two meta-analyses of
women with RPL found that those who received P supple-
mentation were significantly less likely to miscarry than
women who did not receive P (12, 52). There was, however,
little difference in the prevalence of abnormal P in our pa-
tients with RPL compared with that in the normal controls.
Similarly, thromboprophylaxis during pregnancy for women
with hereditary deficiencies of antithrombin, protein C, or
protein S significantly improved pregnancy success com-
pared with that for deficient women who did not receive treat-
ment (53), yet the frequencies of abnormal antithrombin,
protein C, and protein S among our patients were similar to
those reported for control populations. Furthermore, recent
meta-analyses did not find associations between abnormal
protein C, protein S, and antithrombin levels and RPL (19,
Fertility and Sterility
40). Meta-analyses of the factor II (prothombin) G20210A
mutation demonstrate an association with RPL (20, 40), but
the prevalence of factor II gene mutation was similar between
our patients with RPL and the control population. The fre-
quency of cervical microbial infections among our patients
with RPL was also similar to that reported in a control pop-
ulation (Table 4). Whether or not the frequency of abnormal
results for the nine investigative tests was higher among pa-
tients with RPL in our study than in control populations re-
ported in the literature, the probability of abnormal results
was the same for all women whether they had experienced
only two losses or more than two. If future research finds
that any of these factors has causative effects on RPL, then
our data support the argument that testing should be recom-
mended after only two losses rather than requiring the patient
to wait until after a third loss.
No abnormal results were detected for evidence-based
tests in 617 (60%) of the 1020 patients with RPL (Table 3).
For some of these patients, pregnancy losses may be attrib-
uted to aneuploidy of the conceptus, which can reach fre-
quencies of 50% or more, as described above. If the
investigative tests were accepted as causative, then 209
(34%) of these 617 women with normal results for the evi-
dence-based tests would be diagnosed with a possible cause
of RPL. Including the results of both the evidence-based
and investigative tests would then raise the number of pa-
tients with abnormal results from 403 (40%) to 612 (60%).
It is also possible that factors not measured in this study
may be associated with the pregnancy losses of the women
who had normal evidence-based tests. For example, Wilcox
et al. (54) demonstrated that later implantation of the concep-
tus increases the risk of pregnancy loss. Different expression
of T-helper cell cytokines has been found in women with RPL
compared with control women who had normal pregnancies
(55). Other studies have indicated that tobacco, caffeine, and
drug use may increase RPL (56, 57). Although we obtained
this information, we did not include such factors because
they require self-reporting, and both the usage and dosage
cannot be verified.
In conclusion, equal frequencies of abnormal test results
found among patients with two, three, or four or more recur-
rent pregnancy losses suggest that a complete evaluation of
the following evidence-based factors, parental karyotyping,
uterine anatomy, lupus anticoagulant, anticardiolipin anti-
bodies, factor V Leiden, and TSH, should be recommended
to all couples with two or more consecutive pregnancy losses.
Caution must be exerted in the interpretation of an abnormal
screening result, as the factor identified may not be the caus-
ative factor for pregnancy loss. For example, a woman with
a balanced translocation has an increased risk of pregnancy
loss if the fetal karyotype is unbalanced, but she may also
have a normal delivery if the fetal karyotype is balanced or
normal. Our study also provides evidence that abnormal anti-
phosphatidyl serine antibodies, PRL, and homocysteine/
MTHFR polymorphisms may be factors that should be con-
sidered as part of a complete evaluation. If other data surface
1241
supporting the role of cervical microbial infections, midluteal
P, and various other thrombophilic factors in causing RPL,
then these tests should be recommended as well to couples
with two or more consecutive losses. These data confirm
and extend prior studies and support the guidelines published
by the American College of Obstetricians and Gynecologists
(58), which state, ‘‘ . . . patients with two or more consecutive
spontaneous abortions are candidates for an evaluation to
determine the etiology, if any, for their pregnancy losses.’’
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