wangjunhong@jsph.org.cn
Total word count: 2155
Abstract
Objective: To investigate the outcomes of fetuses or neonates of
pregnant women with premature ventricular contractions (PVCs).
Design: Prospective cohort study.
Setting: University-affiliated tertiary hospital.
Population: 6, 148 pregnant women with normal cardiac structure and
function and 103 with a PVC burden >0.5% among them.
Methods: 103 pregnant women with PVCs were divided into two groups based
on the presence or absence of adverse fetal or neonatal events. The
adverse outcomes were compared between the groups.
Main outcome measures: Adverse fetal and neonatal events: premature
birth (<37 weeks gestation), small-for-gestational-age birth
weight (<10th percentile for gestational age or
<2500 g), respiratory distress syndrome, intraventricular
hemorrhage and fetal death (after 20 weeks gestation and before birth).
Results: A total of 17 adverse events (12 cases) occurred among 103
pregnant women with PVCs, which was significantly higher than that among
women without PVCs (11.65% vs. 2.93%, p<0.01). Compared with
that of the women without adverse events, the median PVC burden of women
with adverse fetal or neonatal outcomes was significantly higher (9.02%
vs. 2.30%, p<0.01). Multivariate logistic regression analysis
demonstrated that PVC burden was associated with adverse fetal or
neonatal outcomes among pregnant women with PVCs (OR: 1.34, 95% CI
(1.11-1.61), p<0.01).
Conclusions: Frequent PVCs have adverse effects on pregnancy, and the
PVC burden might be an important factor associated with adverse fetal
and neonatal outcomes among pregnant women with PVCs. Our cohort study
indicated that the higher the PVC burden is, the higher the likelihood
of adverse events would be.
Key words: fetal/neonatal outcomes; pregnancy; premature ventricular
contractions (PVCs)
Tweetable abstract: The PVC burden might be the main factor associated
with adverse pregnancy outcomes.
Funding
This work was supported by the National Natural Science Foundation of
China (NSFC 81570328, Wang JH), the Jiangsu Province ”333” project
(BRA2018389, Wang JH), the Jiangsu Province’s Key Provincial Talents
Program (ZDRCB2016005, Wang JH), the Open Project of State Key
Laboratory of Natural Medicines (No. SKLNMKF201903, Wang JH) and the
International cooperation project of Jiangsu Province (BZ2018054, Ding
Q).
Introduction
Idiopathic PVCs are relatively benign in cases without structural heart
diseases but may signal an increased risk of sudden death in cases with
structural heart disease (SHD) and may be markers of underlying
pathology. An estimated prevalence of 1 to 4% is found in the general
population on standard 12-lead electrocardiography
(ECG)1. Frequent PVCs, defined as more than 10% of
all QRS complexes on standard 24-hour Holter monitoring, have been found
to be associated with subsequent development of left ventricular
dilatation and PVC-induced
cardiomyopathy.
Treatment of frequent PVCs in patients with impaired ventricular
function can reverse this pattern2-7. PVCs may
increase during pregnancy, which leads to an additional challenge, as
pregnancy outcome implications are not known for this already cardiac
overloaded state8,9. Relatively few studies have
evaluated the relationship between PVCs and the adverse outcomes of
fetuses or neonates10. Therefore, we aimed to
determine the relationship between the adverse outcomes of the fetus or
neonate among pregnant women with PVCs.
Methods
Study design and patient population
This is a single-center prospective cohort study of consecutive
pregnancies referred to the First Affiliated Hospital of Nanjing Medical
University from July 2017 to July 2019. The inclusion criteria were
pregnant women with normal cardiac structure and function based on
echocardiographic examination. Pregnant women with PVC burdens greater
than 0.5% on Holter examination each time during the whole pregnancy
period were classified as the PVC group. The exclusion criteria were as
follows: pregnant women with 1) hyperthyroidism, 2) hypothyroidism, 3)
gestational hypertension or pregnancy with hypertension, 4) type I or II
diabetes, 5) chronic nephritis or impaired renal function (creatinine
clearance rate, Ccr <60 ml/min), 6) autoimmune disease, 7)
congenital heart diseases, 8) pulmonary artery hypertension, 9)
cardiomyopathy, 10) alcohol abuse, 11) anemia (Hgb<110 g/l),
12) smoking, and 13) a family history of sudden cardiac death.
The study protocol was performed
in accordance with the ethical standards established in the 1964
Declaration of Helsinki and its later amendments and was approved by the
institutional ethics committee of the First Affiliated Hospital of
Nanjing Medical University (2019SR-503). Informed consent was obtained
from all pregnant women enrolled in the study.
Baseline characteristics
Clinical and 12-lead electrocardiogram (ECG) data were collected at the
time of the initial clinic visit or for routine obstetric examinations
during the first trimester of pregnancy. If the standard 12-lead ECG
recorded the PVC events, Holter monitoring was then performed and
reexamined in each subsequent trimester to assess the burden of
ventricular premature contractions and analyze the total number of QRS
complexes, total number of PVCs and total runs of nonsustained
ventricular tachycardia (NSVT) (run with >3 consecutive
PVCs but <30 s). Furthermore, if the women had self-reported
symptoms such as palpitation during pregnancy, the 12-lead ECG
examination was then performed. If no arrhythmia was recorded, a
wearable single-lead ECG recorder (Shuweikang company, Nanjing, China)
was then weared for 3 continuous days to record the possible PVC events
in those pregnant women. The single-lead wearable ECG recorder was
designed to recognize the arrhythmia based on the Convolutional Neural
Network (CNN) technology. It can easily identify the PVCs when it
happens. Here is the image of the wearable ECG recorder and the
representative PVC captured by the recorder (Figure S1). And if the PVCs
was documented by 12-lead ECG or the wearable single-lead ECG recorder
and confirmed by the ECG experts in our center (Lin J & Chen QS), the
Holter was examined thereafter once a trimester for the remainder of the
pregnancy period. The average PVC burden was determined by calculating
the total number of PVCs in the total QRS complexes. PVC morphological
patterns were analyzed to determine the PVC origin. PVCs with inferior
axis and left bundle branch block (LBBB) patterns were determined to
most likely originate from the right ventricular outflow tract (RVOT).
Specific diagnostic procedures were carried out with reference to
published diagnostic criteria11. Specifically, the
burden, morphology and the origin of PVCs were calculated not by the
wearable recorder but by the Holter and 12-lead ECG results due to its
single lead characteristics.
Echocardiography was performed in the first and third trimesters in all
pregnant women. Experienced echocardiographers performed
echocardiography to ensure that there was no evidence of SHD in the
pregnant women and to ensure that the cardiac function of the enrolled
pregnant women was within the normal range (left ventricular ejection
function (LVEF) >60%).
All pregnant women were followed, and the data on characteristics
including age, comorbid medical conditions and family history were
recorded. All women were followed from preconception to 1 week after
delivery. If the exclusion criteria were met, they were excluded from
the study.
Neonatal/fetal outcome events
Two physicians blinded to the women’s baseline characteristics
independently verified adverse events. Adverse fetal and neonatal events
were defined as previously described12: premature
birth (<37 weeks gestation), small-for-gestational-age birth
weight (<10th percentile for gestational age or
<2500 g), respiratory distress syndrome, intraventricular
hemorrhage and fetal death (after 20 weeks gestation and before birth).
Only one event was counted if multiple events occurred in the fetus or
newborn simultaneously.
Statistical analysis
Statistical analysis was performed using SPSS (Version 22.0). Data are
presented as the means ± SDs, medians (25th–75th percentiles), or
proportions. Student’s t-test or the Wilcoxon rank-sum test was used to
compare continuous variables between the women with and without adverse
fetal/neonatal events who had PVCs >0.5%. Possible risk
factors of adverse events were analyzed using univariable logistic
regression, followed by multivariable logistic regression. A P value
<0.05 was considered statistically significant.
Results
Baseline characteristics and fetal or neonatal outcomes
6, 148 pregnant women who fulfilled the inclusion criteria were enrolled
consecutively, of which 103 had symptomatic or asymptomatic PVCs. A
total of 17 adverse events occurred in 103 pregnant women with PVCs,
including 5 cases of respiratory distress syndrome, 5 preterm births and
7 small-for-gestational-age births. Finally, only 12 women with adverse
events were counted, as multiple events occurred in some of them
simultaneously. The remaining defined adverse events did not occur. The
other 91 pregnant women with PVCs delivered safely without adverse
events. A total of 177 fetal and neonatal adverse cases were counted in
the cohort of 6,045 pregnant women without PVCs. The incidence of
adverse events was significantly higher in PVC cases (11.65%) than in
those without PVC (2.93%) (Figure 1).
Cardiac rhythm of pregnant women with PVCs
The pregnant women with PVCs were divided into two groups on the basis
of the presence or absence of adverse events. The baseline
characteristics are listed in Table 1. The proportion of bigeminy PVCs
was significantly higher in pregnant women with adverse fetal or
neonatal outcomes (50% vs. 19.8%, p<0.05), as was the median
PVC burden, than in women without adverse events (9.02% vs. 2.30%,
p<0.01). The median documented PVC burden was 2.84% (1.02%
to 6.10%). Eight pregnancies had a maximal PVC burden
>10%, and of these, 2 pregnancies had a PVC burden
>20%. Although the LVEF of the adverse outcome group was
within the normal range, it remained slightly lower than that of the
control group (64.16±1.56% vs. 65.69±2.54%, p<0.05). There
were no other significant differences in the remaining baseline data
between the two groups.
12-Lead ECG showed normal sinus rhythm with premature ventricular
complexes in the study. PVCs with an LBBB and inferior axis, most likely
originating from RVOT, were found in 41.75% of pregnancies with PVCs.
In contrast, PVCs with an RBBB and inferior axis, frequently associated
with the left ventricular outflow tract (LVOT), accounted for
approximately 11.65%, far less than PVCs associated with the RVOT.
According to the special morphology of PVCs reported in the previous
literature12-15, PVCs originating from the tricuspid
annulus account for approximately 12.62% and 20.39% of PVCs
originating from the papillary muscles or fascicle of the left
ventricle, respectively. A total of 9.71% of PVC origins could not be
determined from the ECG (Figure S2).
Predictors of fetal and neonatal outcomes
The baseline characteristics of the study cohort suggested that the
average burden of PVCs was related to adverse outcomes, so the burden of
PVCs was further divided into low (<33rd percentile), middle
(33rd-67th percentile) and high groups (>67th percentile)
according to the percentile of the average PVC burden (Figure 2). The
incidence of adverse events was significantly higher in the high-burden
PVC group than in the low and middle groups, indicating that the higher
the PVC burden, the higher the likelihood of adverse events would be.
Univariable logistic regression analysis demonstrated that the LVEF,
bigeminy and burden of PVCs were associated with adverse fetal or
neonatal outcomes among pregnant women with PVCs; however, statistical
significance was evident for PVC burden only in the multivariate
logistic regression analysis (OR: 1.34, 95% CI (1.11-1.61),
p<0.05, Table 2).
Discussion
Main Findings
It is widely recognized that idiopathic PVCs are relatively benign in
structurally normal hearts16; however, relatively few
studies have evaluated the relationship between PVCs and the adverse
outcomes of fetuses or neonates among pregnant women10,
17. In this study, we found that PVCs were associated with a higher
frequency fetal/neonatal adverse events among pregnant women with a
structurally normal heart. In fact, we further demonstrated that ‘high’
PVC burden is an important factor for predicting the incidence of
adverse fetal/neonatal outcomes.
Interpretation
In our study, the pregnant women had a structurally normal heart and
high PVC burden, and the rate of adverse fetal/neonatal cases was
11.65%. However, in the group of women without PVCs, the incidence rate
was only 2.93%, which was significantly lower than that previously
reported in the group of pregnant women with or without structural heart
disease10, 18. The reasons might be that comorbidities
that may cause adverse fetal/neonatal outcomes, such as diabetes,
hypertension or hyperthyroidism were excluded from our study. In fact,
when the pregnant women with PVCs were divided by outcome, a
significantly high PVC burden, a high rate of bigeminal PVCs and
slightly decreased LVEF were associated with a high incidence of
fetal/neonatal events. Further multivariate logistic analysis suggested
that a high PVC burden was the only predictor of adverse fetal/neonatal
outcomes among women with PVCs. In contrast to previous
reports10, our study revealed a close relationship
between PVCs and adverse fetal/neonatal outcomes among pregnant women,
suggesting that more active medication or even invasive strategies such
as radiofrequency ablation should be considered for women with a high
PVC burden before or during pregnancy19. Furthermore,
it is undeniable to say that some of pregnant women with PVCs would not
be captured through an intermittent screening 12-lead EKG, which may
cause misclassification of women with PVCs into those without PVCs. We,
therefore, use the wearable single-lead ECG recorder to identify the
possible PVC in those women with self-reported symptoms such as
palpitation to reduce the possible misclassification.
Idiopathic PVCs are distributed mainly to specific cardiac structural
sites, of which the RVOT accounts for approximately 67%, and the rest
are mainly followed by the LVOT around the annulus, papillary muscles
and other special sites20. The distribution of the
origin of PVCs in all pregnant women was documented to investigate the
relationship between the origin of PVCs and adverse pregnancy outcomes.
Unlike the studies by Nakagawa et al9 and Tong et
al10, which reported that 73%~92% of
PVCs originated from RVOT in pregnant women, we found that approximately
57.28% of PVCs originated from the right ventricle, of which only
41.75% originated from the RVOT. In addition, PVCs of the left
ventricle accounted for approximately 32.04% in our study, which was
significantly higher than that in the normal population. The possible
mechanism may be the reason that the left ventricle is more sensitive to
volumetric load than the right ventricle. However, because the origin of
9.71% of PVCs could not be identified based on the 12-lead ECG in our
study, this may have an impact on classification of the true
distribution of PVCs in pregnant women.
Study limitations
Although this study is a prospective, single-center study, the number of
participants included is still relatively small; therefore, a
large-scale and multicenter study should be performed in the future.
Second, PVC origin was classified by a standard 12-lead ECG pattern in
the study. Undeniably, changes in diaphragm position during pregnancy
and cardiac rotation may cause misjudgment of the origin of PVCs. Third,
because the PVC burden may fluctuate throughout the day and throughout
stages of pregnancy, we applied the average PVC burden screened by
Holter in each trimester to represent the PVC burden during pregnancy.
It is therefore suggested to use long-term wearable monitoring equipment
to screen the PVC burden in the future. Finally, all patients underwent
only two-dimensional echocardiography in the study, and cardiac magnetic
resonance might be suitable for further study to eliminate the
possibility of latent cardiomyopathy.
Conclusions
In conclusion, our study revealed that the prevalence of PVCs in
pregnancy is higher than that in the normal population. Frequent PVCs
have adverse effects on pregnancy, and
the PVC burden might be the main
factor associated with adverse pregnancy outcomes.
Disclosure of interests
The authors have declared that no conflict of interest exists.
Contribution to authorship
WJH, WX: Designed, supervised the study and prepared the manuscript. LJ,
QYX, CQS: Data collection and analysis, writing original draft. CYX,
XRJ, CJX, SYK, YSX and LXY: Data collection and analysis. ZMM and ZJH:
Writing - Review and Editing. DQ: Project administration and data
analysis.
Details of ethics approval
The study protocol was performed in accordance with the ethical
standards established in the 1964 Declaration of Helsinki and its later
amendments and was approved by the institutional ethics committee of the
First Affiliated Hospital of Nanjing Medical University (2019SR-503).
Supporting Information
Additional supporting information may be found online in the Supporting
Information section at the end of the article.
Figure S1. The image of the wearable one-lead ECG recorder and
representative PVC recorded by the recorder. A&B: the cover and back
image of the recorder; C: the representative PVC recorded by the
recorder.
Figure S2. The origin of PVC in pregnant women. LVOT, left ventricular
outflow tract; RVOT, right ventricular outflow tract; TV, tricuspid
valve; LP, left posterior; LA, left anterior; others indicate 10
unidentified classifications, 1 from right ventricular inflow tract, 1
from right ventricular apex, 1 from His bundle and 1 from right
ventricular mid-septum.
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Table 1. Baseline characteristics of pregnant women with premature
ventricular contractions