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CME
Article
Embryonic Heart Rate as a
Prognostic Factor for
Chromosomal Abnormalities
Deniz Oztekin, MD, Ozgur Oztekin, MD, Fatma I. Aydal, MD,
Sivekar Tinar, MD, Zehra H. Adibelli, MD
Objective. The purpose of this study was to evaluate the role of a slow embryonic heart rate in
embryos before 7 weeks’ gestation as a marker in screening for chromosomal abnormalities.
Methods. Fifty-seven embryos before 7 weeks’ gestation with slow heart rates were compared with
1156 embryos of the same gestational period with normal heart rates. Embryos that showed an
increased risk of chromosomal abnormalities in the screening blood tests underwent invasive analysis
for abnormal karyotype detection. Results. The rates of first-trimester death were 15.8% for pregnancies with slow embryonic heart rates (9 of 57) and 2.5% for those with normal heart rates (29 of
1156). Because of the increased risk of chromosomal abnormalities, amniocentesis was performed on
6 with slow embryonic heart rates and 61 with normal embryonic heart rates. After karyotype analysis, there were 2 fetuses with trisomy 21 in each group, which represented significantly higher percentage of embryos with trisomy 21 in the slow–heart rate group compared with the normal–heart
rate group (P < .05). Conclusions. When a slow embryonic heart rate is detected before 7 weeks’ gestation, there is a higher likelihood of chromosomal abnormalities. Key words: embryo; fetus; first
trimester; heart rate.
Abbreviations
bpm, beats per minute; CRL, crown-rump length; CVS,
chorionic villus sampling; NT, nuchal translucency
Received December 29, 2008, from the Department
of Obstetrics and Gynecology, Aegean Obstetrics
and Gynecology Training and Research Hospital,
Izmir, Turkey (D.O., S.T.); Department of Radiology,
Bozyaka Training and Research Hospital, Izmir,
Turkey (O.O., Z.H.A.); and Department of Obstetrics
and Gynecology, Izmir Can Medical Centre, Izmir,
Turkey (F.I.A.). Revision requested January 7, 2009.
Revised manuscript accepted for publication
February 2, 2009.
Address correspondence and reprint requests to
Deniz Oztekin, MD, Albayrak Mavisehir Evleri, Yali
Mahallesi, 6525 Sokak 35, Daire 31, Karsiyaka,
Izmir, Turkey.
E-mail: [email protected]
CME
Article includes CME test
I
t is estimated that approximately 30% to 40% of
implanted pregnancies result in spontaneous abortion during the first trimester, most of which occur
in the very early stage.1 However, after demonstration of positive embryonic heart activity, the rate of spontaneous abortion declines to 2% to 5%.2 The embryonic
heartbeat can usually be identified by prenatal sonography at 6 weeks’ gestation with a transvaginal transducer,
and the heart rate can be evaluated via M-mode sonography, which normally measures about 100 to 200 beats per
minute (bpm).3,4
Previous studies have found associations between
severe embryonic bradycardia and fetal loss.5,6 In the first
trimester, chromosomal abnormalities are the most
common causes of fetal death. When a slow heart rate is
detected in the first trimester, this may be due to an
abnormal development of the heart or an arrest in the
development of the conductive system, where these are
most likely due to a chromosomal anomaly and predict
subsequent miscarriage.7,8 The association between ane-
© 2009 by the American Institute of Ultrasound in Medicine • J Ultrasound Med 2009; 28:609–614 • 0278-4297/09/$3.50
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Embryonic Heart Rate and Chromosomal Abnormalities
uploidy and a slow embryonic heart rate has
been evaluated in a previous study, and chromosomal abnormalities were reported to be more
than twice as frequent in cases with a slow embryonic heart rate.9
The aim of this study was to assess the relationship between the embryonic heart rate and
chromosomal abnormalities by evaluating the
frequency of aneuploidy among embryos with
slow versus normal heart rates.
Materials and Methods
We prospectively collected the data on all obstetric sonograms obtained between June 2007 and
June 2008 that showed cardiac activity in singleton pregnancies at or before 7 weeks’ gestational
age. Exclusion criteria were vaginal bleeding at
the time of sonographic examination and pregnancies with systemic disorders (eg, hyperthyroidism, hypothyroidism, and diabetes). If a
woman had more than 1 sonogram in her pregnancy at or before 7 weeks, only the first sonogram showing cardiac activity was included in
the study. Informed consent was obtained from
each participant, and the Ethics Committee of
the institution approved this study.
In a study done by Doubilet and Benson,4
embryos at less than 7 weeks’ gestational age
were divided into 2 subgroups: less than 6 weeks
3 days and 6 weeks 3 days to 7 weeks, based on
crown-rump length (CRL). The gestational age
was determined by transvaginal sonographic
measurement of CRL in the B-mode as a single
measurement from the cranial to caudal ends of
the body with the embryos in a neutral position.
The use of a single CRL measurement instead of
averaging 3 measurements may have been a limitation of our study.
The embryonic heart rate was determined by
transvaginal sonographic analysis, which was
performed by watching the embryo for at least 3
minutes for embryonic heart rate patterns, and
an average of 10 cardiac cycles were recorded in
the M-mode. The calculation of the embryonic
heart rate was made by measuring the time interval for 3 heartbeat waves in sequence, and with
those data, the number of heartbeats per minute
was calculated.
610
In the same study referred to above,4 if the
embryo was less than 6 weeks 3 days, the heart
rate was classified as slow if it was less than 100
bpm, whereas, if the embryo was between 6
weeks 3 days and 7 weeks, then the heart rate
was classified as slow if it was less than 120
bpm. Embryonic heart rates below the lower
limits that persisted throughout the 3-minute
interval of observation were categorized in the
slow–heart rate group, whereas temporal
bradycardia that did not persist throughout the
3-minute interval was categorized in the normal–heart rate group.
Sonographic evaluations of all pregnancies
were done with a LOGIQ 5 real-time scanning
system with the capacity of simultaneous
B- and M-mode scanning (GE Healthcare,
Milwaukee, WI). Ongoing pregnancies received
a subsequent sonographic follow-up at 11 to 14
weeks, and all of the embryos were evaluated in
terms of CRL and nuchal translucency (NT) measurements and observation of the head, brain,
chest, heart, abdominal wall, and extremities for
anomalies. In addition to the sonographic evaluation and NT measurements performed in all of
the patients, a combined test was advised to all.
Among the patients who missed the appropriate time to give a blood sample for the combined test, a triple test in the second trimester
was performed.
An NT value above the 95th percentile was
considered as showing increased NT. Invasive
tests (chorionic villus sampling [CVS] and
amniocentesis) were suggested in patients
whose combined risk or triple risk was 1 per
250 or higher at term for either Down syndrome or trisomy 18/13.
Newborn examinations of all neonates delivered in our research group at our hospital were
conducted by neonatologists. Fetuses from terminated pregnancies and those with in utero
death underwent fetopsy.
All statistical analyses were performed with
SPSS version 13.0 software (SPSS Inc, Chicago,
IL). The Student t test and χ2 test were used for
comparison of groups. Results were considered
statistically significant at P < .05.
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Oztekin et al
Results
The study population included 1272 singleton
pregnancies of less than 7 weeks’ gestation that
showed embryonic cardiac activity. Of these
patients, 376 were at less than 6 weeks 3 days in
gestational age, and 896 were from 6 weeks 3
days to 7 weeks of gestational age. The mean
maternal age ± SD was 26.67 ± 5.11 years (range,
16–41 years), and the median gravida was 3
(range, 1–6). Pregnancies with slow embryonic
heart rates were compared with those having
normal embryonic heart rates with respect to
chromosomal abnormalities (Table 1).
A slow embryonic heart rate was detected in 68
pregnancies. In the remaining 1204 patients, the
embryonic heart rate was in the normal range for
the respective gestational age. In the slow–heart
rate group, 11 patients (16.1%) ceased their regular visits; therefore, their subsequent data were
not available. From the remaining 57 pregnancies in the slow–heart rate group, 9 embryos
(15.8%) died by the end of the first trimester.
Nuchal translucency was measured in all of the
remaining 48 patients, and a combined test was
performed in 12 of them. In 2 pregnancies, an elevated combined test because of an increased NT
was observed. For the 36 patients who missed the
combined test, a triple test was performed in the
second trimester, and of these 36 patients, 4
showed an increased risk for aneuploidy even
though the NT measurements were found to be
within normal limits.
The overall results revealed that 6 of 48 patients
(12.5%) had an increased risk for chromosomal
abnormalities. The patients at risk were advised
to undergo further tests (CVS or amniocentesis)
for analysis according to the gestational ages of
the fetuses. None of the patients preferred the
CVS study, whereas all preferred amniocentesis
(some had to wait a few weeks for the right time
to have amniocentesis). In amniocentesis, trisomy 21 was detected in 2 fetuses (4.2%), 1 from
the abnormal combined test group and the
other from the abnormal triple test group.
Echocardiographic findings were normal in
both of these patients.
In the normal–heart rate group of 1204 patients,
48 (3.9%) were lost to follow-up, and their outcomes could not be obtained from the hospital
J Ultrasound Med 2009; 28:609–614
records. Of the remaining 1156, 29 embryos
(2.5%) died before the end of the first trimester.
The remaining 1127 were evaluated for chromosomal abnormalities; 278 had a combined test,
and 849 had a triple test. In 61 (5.4%), 13 from the
combined test group and 48 from the triple test
group, an increased risk for chromosomal abnormalities was observed. None of the patients
showed an increased NT measurement on
sonography.
Two patients volunteered for CVS. No chromosomal abnormality was found by CVS in these
patients. For the remaining 59 patients, amniocentesis was performed as an advanced study for
further evaluation of this increased risk group,
and trisomy 21 was found in 2 patients (0.2%).
All neonates from the study group were examined by neonatologist, and no marker for aneuploidy was reported. Fetopsy found that there
were no chromosomally abnormal fetuses other
than the fetuses that were terminated because of
diagnosed chromosomal abnormalities based
on invasive tests.
The frequency of chromosomal anomalies was
higher in embryos with a slow heart rate (2 of 48)
than those with a normal heart rate (2 of 1127;
P = .009).
Discussion
Strategies involving biochemical studies and
sonography are able to prenatally detect twothirds of affected fetuses while selecting 5% of
the chromosomally normal population for invasive testing. These are used at 15 to 18 weeks for
biochemical screening or at 11 to 14 weeks when
NT is assessed.10 However, new strategies are
desirable to raise the detection rates and to
Table 1. Comparison of Data for the Slow– and Normal–Heart
Rate Groups
Parameter
Slow
Mean age ± SD, y
27.57 ± 5.17
Gestational age <6 wk 3 d
Gestational age 6 wk 3 d–7 wk
20/48
Lost to follow-up
11/68
Miscarriage
9/57
Amniocentesis
6/48
Chromosomal abnormality
2/48
Normal
P
26.63 ± 5.11
.17
356/848
48/1204
29/1156
61/1127
2/1127
.1
.0002
<.001
.05
.009
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Embryonic Heart Rate and Chromosomal Abnormalities
decrease unnecessary invasive tests. Most pregnant women prefer screening in the first
trimester as early as possible. The data in our
study imply that measurement of the embryonic
heart rate before 7 weeks’ gestation may be an
early marker for chromosomal abnormalities
among offspring with subsequent positive combined or triple screening results.
Studies of the heart rate in chromosomally
abnormal fetuses have reported conflicting
results. In a previous longitudinal study involving
1 fetus with trisomy 21 at 6 to 9 weeks’ gestation,
the heart rate was consistently below the third
percentile of the normal range.11 In another
study of 5 affected fetuses at 7 to 13 weeks, the
heart rate was always within the normal range.12
On the other hand, in some previous studies, an
increase in the heart rate with trisomy 21 was
reported.13,14 Two different hypotheses have been
proposed for tachycardia in trisomy 21. There
may be a delay in the functional maturation of
the parasympathetic system and a consequent
delay in the physiologic decrease in the heart rate
with gestation after 9 weeks.15 Alternatively, the
cause of tachycardia may be a compensatory
mechanism to increase cardiac output in the
phase of left heart obstruction in atrioventricular
or ventricular septal defects associated with relative narrowing of the aortic isthmus.16 In previous studies in which fetal tachycardia was
detected in trisomy 21, the fetal cardiac rhythms
were measured at 11 to 14 weeks’ gestation as
part of the first-trimester screening. Data on the
cardiac activity before 7 weeks’ gestation were
unavailable in these studies.
In our study, we detected 4 fetuses (0.3%) with
Down syndrome; 2 (4.2%) were in the slow–heart
rate group, and the other 2 (0.2%) were in the
normal–heart rate group. A significantly higher
percentage of fetuses with trisomy 21 in the
slow–heart rate group compared with the normal–heart rate group was observed, although the
number of patients was relatively small in the
group with slow embryonic heart rates. Another
limitation of our study was that the rates of loss to
follow-up and embryonic death at the end of the
first trimester were substantially higher in the
slow–heart rate group, such that these factors
may have had a negative impact on the karyotype
analysis. The early pregnancy losses were likely
612
to have been treated at a local clinic rather than
be referred to our hospital, which is a tertiary
medical center; thus, the high rate of loss to followup in the slow–heart rate group was of concern. For
comparison, the incidence of Down syndrome was
0.6% in an unselected population.17
A physiologically slower heart rate may be due
to immaturity of the sinoatrial node in the early
stages of pregnancy, or the atrial pacemaker may
actually be slower during early gestation in the
normal heart.9 However, in some cases, a slow
embryonic heart rate may represent idioventricular rates of an abnormal heart.18
In a study by Russo et al,19 it was reported that
32% of congenital heart diseases diagnosed prenatally were associated with chromosomal
anomalies, whereas another study showed that
36% of congenital heart disease in live births had
chromosomal anomalies.20 An underlying cause
of a slow embryonic heart rate may be an indication of cardiac problems with chromosomal
abnormalities.
A major limitation of our study was the method
of diagnosing or excluding chromosomal defects,
which was based on antenatal sonographic
assessment and biochemical screening tests.
Ideally, all fetuses included in these kinds of
studies should undergo karyotype analysis;
however, this is not achievable in practice.
Genetic testing of the conceptus after spontaneous abortion is not generally done, mainly
because of technical difficulties in karyotyping
the aborted specimen. Collection of the specimen can be difficult because many women
abort at home or outside standard laboratory
hours. Moreover, standard cytogenetic techniques are associated with high culture failure
rates; thus, there are spontaneous abortions in
the first trimester.21 Autosomal trisomies (in
37% of the karyotyped samples) were the most
frequently detected anomalies, followed by
polyploidies (9%) and monosomy X (6%).22,23 It
has been the common consensus that early
embryonic losses are mostly associated with
chromosomal defects. Our study, on the other
hand, supports the idea that embryos before 7
weeks’ gestation with slow heart rates have a
greater risk of chromosomal anomalies than
embryos of the same gestational age with normal heart rates.
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Several studies have documented that a slow
embryonic heart rate at 6 to 7 weeks’ gestation is
associated with a high rate of first-trimester
pregnancy loss. This often occurs soon after the
slow heartbeat is detected.5,9,24 In our study,
15.9% of cases resulted in spontaneous pregnancy loss at the end of the first trimester, and the
frequency of spontaneous abortion in our study
was slightly higher than that reported by some
of the previous studies. As an exception,
Doubilet et al25 reported that 60.6% of embryos
with slow heart rates had died by the end of the
first trimester. The higher fetal loss rate in this
study may have been due to the heart rate’s being
classified as slow if it was less than 90 bpm before
6 weeks 3 days and less than 110 bpm at 6 weeks
3 days to 7 weeks, which were both lower than
the limits used in most of the other studies.25 It is
difficult to compare the results of different studies, mostly because of differences in the accepted cutoff values for the definition of bradycardia,
and these differences lead to a divergence in the
results for early fetal losses.
In conclusion, our study shows that a slow
heart rate before 7 weeks’ gestation may be an
early marker for chromosomal abnormalities.
This suggests that an early slow embryonic heart
rate is a promising diagnostic factor that might
be included as an additional parameter in the
screening tests for detection of chromosomal
abnormalities. The advantages of early embryonic heart rate detection as a screening test for
chromosomal abnormalities, as opposed to
combined and triple tests, are that it is a less
expensive, noninvasive, convenient, and fast test
that would be associated with more effective
patient cooperation. However, it cannot be a
substitute for the biochemical screening tests
because it is more of a complementary test.
Additional studies involving larger patient populations are needed before any recommendations
can be made.
2.
Mackenzie WE, Holmes DS, Newton JR. Spontaneous
abortion rate in ultrasonographically viable pregnancies.
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Leiva MC, Tolosa JE, Binotto CN, et al. Fetal cardiac development and hemodynamics in the first trimester. Ultrasound
Obstet Gynecol 1999; 14:169–174.
4.
Doubilet PM, Benson CB. Embryonic heart rate in the early
first trimester: what rate is normal? J Ultrasound Med 1995;
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rate in early pregnancy. J Clin Ultrasound 1998; 26:33–36.
6.
Hyett J, Moscoso G, Nicolaides K. Abnormalities of the heart
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