Abstract
There are limited data on the relation between congenital heart disease (CHD) and preterm birth (PTB). We aimed to estimate the risk of PTB in newborns with CHD, to study associations and risk factors (modifiable and non-modifiable) as well as investigate postnatal outcomes. This was a retrospective cohort study of 336 pregnancies diagnosed with CHD between 2011 and 2016. Groups consisted of those delivered at or after 37 weeks, and those who delivered prior to 37 weeks. Collected data included maternal and fetal characteristics as well postnatal outcomes. Complete data were obtained from 237 singleton pregnancies. The overall proportion of PTB was 23.2% for all CHD, of which 38.2% were spontaneous PTB which was almost unchanged after excluding extracardiac anomalies and pathogenic chromosomal abnormalities. Significant non-modifiable risk factors were pregnancy-related HTN disorders (P<0.001), fetal growth restriction (P = 0.01), and pathogenic chromosomal abnormalities (P = 0.046). Significant PTB modifiable risk factors included prenatal marijuana use (P = 0.01). Pregnancies delivered at 37–38 weeks had significantly more newborns with birthweight<2500 g (P<0.001), required more pre-operative NICU support including intubation (P = 0.049), vasopressors (P = 0.04), prostaglandins (P = 0.003), antibiotics (P = 0.01), and had longer hospital stay (P = 0.001) than those delivered at ≥ 39 weeks. Prenatally diagnosed pregnancies with CHD had higher PTB rate compared to the general population, with spontaneous PTB comprising 38.2% of these preterm deliveries. Most PTB risk factors were non-modifiable, however, significant modifiable factors included marijuana use in pregnancy. Outcomes were favorable in neonates delivered at or beyond 39 weeks.
Keywords: Congenital heart defect, Gestational age, Preterm birth, Pregnancy
Introduction
Preterm birth (PTB) and congenital heart defects (CHD) are two of the major causes of morbidity, disability, and mortality of perinatal origin [1–3], with PTB rate estimates of 12.8% [4] and CHD prevalence of 8–9 per 1000 live births among newborns during their first year of life [5]. Adverse outcomes have been reported with both CHD and PTB, and these outcomes are more pronounced when both conditions were combined [3, 6]. It has also been suggested that adverse outcomes including infant death rate decrease as gestational age advances from less than 34 to 40 weeks of gestation [7] with the reported infant mortality rates for preterm newborns and CHD ranging from 20 [8] to 65% [9].
Although known associations exist between congenital anomalies including CHD and PTB [1, 10], few specific data exist regarding the risk of PTB for pregnancies with CHD. Most available data are hospital-based studies of the clinical management and outcomes of preterm infants with CHD [3, 11]. One previous population-based study reported a higher risk of PTB for newborns with CHD [8]. This study did not assess the role of associated anomalies or the extent to which risk of PTB for newborns with CHD may be due to spontaneous versus medically indicated PTB. Moreover, few data are available on the associations between specific categories of CHD and PTB. When it comes to optimal timing of delivery, it has been shown by several reports that the risk of adverse outcomes in low-risk pregnancies is greater for neonates delivered in the early-term period (37–38 weeks of gestation) compared with neonates delivered at 39 weeks of gestation [12–17], however, reports are limited in the presence of prenatally diagnosed CHD with the absence of medical and obstetrical indication for early delivery. By using data from this large cohort, we aimed to estimate the risk of PTB in newborns with CHD, to examine the nature of PTB (spontaneous versus medically indicated PTB), and to study associations between specific categories of CHD and PTB and postnatal outcomes.
Materials and Methods
This was a retrospective cohort study of single tertiary care center. The fetal cardiology database was reviewed to identify prenatally diagnosed CHD over a 5-year period between 2011 and 2016. A total of 336 fetuses diagnosed with CHD were identified, and details of maternal characteristics, obstetrical outcomes, and postnatal outcomes were obtained for those who delivered at our institution. We excluded pregnancies with multiple gestation, termination, fetal demise, and lethal chromosomal abnormalities such as trisomy 13 and 18. Following exclusion, 237 pregnancies were included in the final analysis. Our cohort was divided into two groups which consisted of those delivered at or after 37 weeks of gestation (term), and those who delivered prior to 37 weeks of gestation (preterm). The PTB group was divided according to WHO categories [18] into three categories which are extremely preterm (<28 weeks), very preterm (28–31 weeks), and late preterm (32–36 weeks). The term birth group was divided into early term (37–38 weeks) and full term (39–40 weeks) [19]. The main outcome measure was risk of PTB. We distinguished spontaneous from medically induced PTB. Risk of PTB and spontaneous PTB were examined in three situations (1) all cases, and (2) cases excluding other anomalies, and (3) cases excluding extracardiac anomalies and pathogenic chromosomal abnormalities. Pathogenic chromosomal abnormalities were defined according to American College of Medical Genetics and Genomics guidelines into numerical abnormalities or pathogenic copy number variants [20]. The estimated date of term delivery, and therefore the gestational age at delivery, is determined on the basis of either the results of a first-trimester ultrasound or the date of the first day of the mother’s last menstrual period with supporting information from an ultrasound at less than 20 weeks of gestation in concordance with the standard criteria recommended by American College of Obstetricians and Gynecologists (ACOG) [21]. Secondary objectives included assessing associations and outcomes of PTB, and identifying optimal time of delivery in those pregnancies. Multiple covariates that could confound the association between gestational age and the outcomes of interest were assessed.
CHD type was classified using a method described by Botto et al. [22] into nine groups which consisted of (1) ventricular septal defects (VSD); (2) conotruncal defects including truncus arteriosus, interrupted aortic arch (IAA), transposition of the great arteries (d-TGA), double-outlet right ventricle (DORV), and tetralogy of fallot (TOF); (3) left ventricular outflow tract (LVOT) defects including hypoplastic left heart syndrome (HLHS), coarctation of aorta (CoA), and aortic stenosis; (4) right ventricular outflow tract (RVOT) defects including pulmonary stenosis, pulmonary atresia, tricuspid atresia, and Ebstein’ s anomaly; (5) atrioventricular septal defects (AVSD); (6) heterotaxy; (7) cardiac tumor, (8) total anomalous pulmonary venous return (TAPVR); and (9) complex heart defects. The study was approved by the University of Minnesota Institutional Review Board Committee.
Statistical Analysis
Variables of interest were summarized using frequency and percentage for categorical variables, and mean and standard deviation, or median and range for continuous variables by the previously defined groups. To investigate the association between certain variables of interest and PTB status, χ2 tests or Fisher’s exact tests were used for categorical variables, and Student’s t-tests or Wilcoxon rank-sum tests for continuous variables. All reported P-values are two-sided and a significance level of 0.05 was used. All statistical analyses were performed using R version 3.4.2.
Results
Two hundred and thirty seven singleton gestations with CHDs were included in the cohort of which 23.2% had PTB (n = 55). The median and range of gestational age at birth was 39 weeks (37, 40) for term infants, and 34 weeks (26, 36) for preterm infants. The PTB group included 3.6% (n = 2) extremely preterm (< 28 weeks), 7.3% (n = 4) very preterm (28–31 weeks), and 89.1% (n = 49) late preterm (32–36 weeks) infants. The term group included 32.4% (n = 59) early-term (37–38 weeks) and 67.6% (n = 123) fullterm infants (39–40 weeks).
The overall proportion of PTB was 23.2% (55/237) for all CHD cases, 21.6% (40/185) for CHD cases excluding extracardiac anomalies, and 20.6% (33/160) for CHD cases excluding extracardiac anomalies and pathogenic chromosomal abnormalities.
Of those with delivery < 37 weeks, the proportion of spontaneous PTB was 38.2% (21/55) in all CHD cases, 42.5% (17/40) for CHD cases excluding extracardiac anomalies, and 39.4% (13/33) for CHD cases excluding extracardiac anomalies and pathogenic chromosomal abnormalities.
Medical indications for PTB included abnormal umbilical artery Doppler (21.8%, n = 12), pregnancy-related hypertension (HTN) disorders including preeclampsia, eclampsia, and HELLP (21.8%, n = 12), and non-reassuring fetal heart tracing during non-stress test evaluations (20%, n = 10).
Demographics and exposure variables are summarized in Table 1. Significant modifiable variables that were associated with PTB included prenatal marijuana use (P = 0.01). Significant non-modifiable variables included pregnancy-related HTN disorders (P < 0.001), FGR (P = 0.01), and pathogenic chromosomal abnormalities (P = 0.046) (Table 1).
Table 1.
Demographics and exposure variables
| Delivery ≥ 37 Weeks (N = 182) | Delivery <37 weeks (N = 55) | P value | |
|---|---|---|---|
| n (percent) | |||
| Age, mean | 30.7 (6.0) | 32 (5.3) | 0.15 |
| Ethnicity/race | 0.16 | ||
| Caucasian | 138 (78.0) | 48 (87.3) | |
| Black | 20 (11.3) | 3 (5.5) | |
| Latina | 10 (5.6) | 0 (0.0) | |
| Asian | 7 (4.0) | 4 (7.3) | |
| Other | 2 (1.1) | 0 (0.0) | |
| Pre-pregnancy BMI (kg/cm2) | 0.05 | ||
| Underweight | 3 (2.4) | 0 (0.0) | |
| Normal | 50 (40.0) | 22(52.4) | |
| Overweight | 39 (31.2) | 5 (11.9) | |
| Obese | 33 (26.4) | 15 (35.7) | |
| Parity | 0.17 | ||
| Nulliparous | 65 (35.7) | 26 (47.3) | |
| Multiparous | 117 (64.3) | 29 (52.7) | |
| Tobacco use in pregnancy | 15 (8.9) | 6 (12.0) | 0.59 |
| Marijuana use in pregnancy | 1(0.5) | 4 (7.3) | 0.01 |
| IVF pregnancy | 9 (4.9) | 6 (10.9) | 0.12 |
| DM (TlDM, T2DM, pre-gestational DM) | 8 (4.4) | 4 (7.3) | 0.48 |
| Pregnancy-related HTN disordersa | 7 (3.8) | 12 (21.8) | <0.001 |
| FGR | 11 (6.0) | 10 (18.2) | <0.001 |
| Associated anomalies | |||
| Extracardiac | 37 (20.3) | 15 (27.3) | 0.37 |
| Pathogenic chromosomalb | 2 (26.0) | 17 (43.6) | 0.046 |
| Cesarean delivery | 82 (45.1) | 36 (65.5) | 0.01 |
BMI body mass index, DM diabetes mellitus, FGR fetal growth restriction
Pregnancy-related HTN disorders: preeclampsia, eclampsia, and HELLP syndrome (hemolysis, elevated liver enzymes and low platelet)
Pathogenic chromosomal abnormalities: include aneuploidy and pathogenic copy number variants
P value is χ2 test or Fisher’s exact test for categorical variables or Student’s t-tests or Wilcoxon rank-sum tests for continuous variables
Cesarean delivery (CD) was significantly more common in preterm birth group (P = 0.01).
CHD types were divided into nine categories as explained in the methods section. The incidence of these categories in the cohort can be seen in Table 2.
Table 2.
CHD type association with preterm birth
| CHD type | All CHD cases | CHD cases excluding extracardiac anomalies | CHD cases excluding extracardiac anomalies and pathogenic chromosomal abnormalities | ||||||
|---|---|---|---|---|---|---|---|---|---|
| CHD type | |||||||||
| ≥37 weeks (N = 182) | <37 weeks (N = 55) | P value | ≥37 weeks (N = 145) | <37 weeks (N = 40) | P value | ≥37 weeks (N = 127) | <37 weeks (N = 33) | P value | |
| n (percent) | |||||||||
| VSD | 56 (30.8) | 21 (38.2) | 0.39 | 41 (28.3) | 16 (40.0) | 0.22 | 41 (32.3) | 15 (45.5) | 0.23 |
| Conotruncal defects | 34 (18.7) | 13 (23.6) | 0.54 | 26 (17.9) | 8 (20.0) | 0.95 | 23 (18.1) | 5 (15.2) | 0.89>0.99 |
| Truncus arteriosus | 1 (0.5) | 0 (0.0) | >0.99 | 1 (0.7) | 0 (0.0) | >0.99 | 1 (0.8) | 0 (0.0) | 0.21 |
| IAA | 1 (0.5) | 4 (7.3) | 0.01 | 0 (0.0) | 2 (5) | 0.046 | 0 (0.0) | 1 (3.0) | 0.3 |
| d-TGA | 15 (8.2) | 1 (1.8) | 0.13 | 14 (9.7) | 1 (2.5) | 0.2 | 13 (10.2) | 1 (3.0) | 0.27 |
| DORV | 5 (2.7) | 2 (3.6) | 0.67 | 3 (2.1) | 2 (5.0) | 0.3 | 3 (2.4) | 2 (6.1) | >0.99 |
| TOF | 12 (6.6) | 6 (10.9) | 0.38 | 8 (5.5) | 3 (7.5) | 0.71 | 6(4.7) | 1 (3.0) | |
| LVOT | 34 (18.7) | 5 (9.1) | 0.14>0.99 | 31 (21.4) | 5 (12.5) | 0.3 | 29 (22.8) | 5 (15.2) | 0.47>0.99 |
| HLHS | 15 (8.2) | 4 (7.3) | 0.02 | 15 (10.3) | 4 (10.0) | >0.99 | 15 (11.8) | 4 (12.1) | 0.13 |
| CoA | 17 (9.3) | 0 (0.0) | 0.55 | 14 (9.7) | 0 (0.0) | 0.04 | 12 (9.4) | 0 (0.0) | 0.5 |
| Aortic stenosis | 2(1.1) | 1 (1.8) | 2 (1.4) | 1 (2.5) | 0.52 | 2(1.6) | 1 (3.0) | ||
| RVOT | 22 (12.1) | 5 (9.1) | 0.71 | 21 (14.5) | 4 (10.0) | 0.64 | 18 (14.2) | 4 (12.1) | >0.99 |
| Pulmonary atresia | 7 (3.8) | 3 (5.5) | 0.7>0.99 | 7 (4.8) | 2(5.0) | >0.99 | 5 (3.9) | 2 (6.1) | 0.63>0.99 |
| Pulmonary stenosis | 3 (1.6) | 0 (0.0) | >0.99 | 3 (2.1) | 0 (0.0) | >0.99 | 3 (2.4) | 0 (0.0) | >0.99 |
| Tricuspid atresia | 9 (4.9) | 2(3.6) | >0.99 | 8 (5.5) | 2(5.0) | >0.99 | 7(5.5) | 2(6.1) | >0.99 |
| Ebstein’s anomaly | 3 (1.6) | 0 (0.0) | 3 (2.1) | 0 (0.0) | >0.99 | 3 (2.4) | 0 (0.0) | ||
| AVSD | 20 (11) | 9 (16.4) | 0.41 | 16 (11.0) | 5 (12.5) | 0.78 | 7 (5.5) | 2 (6.1) | >0.99 |
| Heterotaxy | 6 (3.3) | 1 (1.8) | >0.99 | 2 (1.4) | 1 (2.5) | 0.52 | 2 (1.6) | 1 (3.0) | 0.5 |
| Cardiac tumor | 2 (1.1) | 0 (0.0) | >0.99 | 2 (1.4) | 0 (0.0) | >0.99 | 1 (0.8) | 0 (0.0) | >0.99 |
| TAPVR | 3 (1.6) | 0 (0.0) | >0.99 | 3 (2.1) | 0 (0.0) | >0.99 | 3 (2.4) | 0 (0.0) | >0.99 |
| Complex defects | 5 (2.7) | 1 (1.8) | >0.99 | 3 (2.1) | 1 (2.5) | >0.99 | 3 (2.4) | 1 (3.0) | >0.99 |
IAA interrupted aortic arch, d-TGA transposition of great arteries, DORV double-outlet left ventricle, TOF tetralogy of fallot, LVOT left ventricular outflow tract, HLHS hypoplastic left heart syndrome, CoA coarctation of aorta, RVOT right ventricular outflow tract, AVSD atrioventricular septal defect, TAPVR total anomalous pulmonary venous return
P value is for χ2 test or Fisher’s exact test for categorical variables
CHD categories incidence varied across groups (Table 2). For all CHD cases, defects that were associated with PTB were IAA (P = 0.01). After excluding extracardiac anomalies, IAA barely met statistical significance (P = 0.046), and after excluding both extracardiac anomalies and pathogenic chromosomal abnormalities, none of the CHO types met statistical significance (Table 2).
Postnatal outcomes during NICU stay in the PTB group were significant for more newborns with birthweight < 2500 g (P < 0.001), arterial cord pH < 7.1 (P = 0.001), and pre-operative NICU support including use of high-frequency oscillatory ventilation (HFOV) (P = 0.002), and antibiotics (P = 0.01) (Table 3).
Table 3.
Postnatal outcomes
| Outcomes | <37 weeks (N = 55) | ≥37 weeks (N = 182) | P value | 37–38 weeks (N = 59) | 39–40 weeks (N = 123) | P value |
|---|---|---|---|---|---|---|
| n (percent) | ||||||
| Sex | ||||||
| Male | 26 (49.1) | 96 (53.0) | 0.72 | 30 (50.8) | 66 (54.1) | 0.8 |
| Female | 27 (50.9) | 85 (47.0) | 29 (49.2) | 56 (45.9) | ||
| Weight <2500 g | 38 (73.1) | 13 (7.2) | <0.001 | 12 (20.3) | 1 (0.8) | <0.001 |
| Cord arterial pH <7.10 | 5 (16.7) | 0 (0.0) | 0.001 | 0 (0.0) | 0 (0.0) | |
| NICU support | ||||||
| Intubation | 24 (45.3) | 66 (36.5) | 0.26 | 28 (47.5) | 38 (31.1) | 0.049 |
| HFOV | 11 (45.8) | 8 (12.1) | 0.002 | 5 (17.9) | 3(7.9) | 0.27 |
| Nitric osride | 6(11.3) | 14 (7.7) | 0.41 | 4 (6.8) | 10 (8.2) | 0.99 |
| Vasopressors | 16 (30.2) | 43 (23.8) | 0.37 | 20 (33.9) | 23 (18.9) | 0.04 |
| Prostaglandin | 18 (34.0) | 83 (45.9) | 0.16 | 37 (62.7) | 46 (37.7) | 0.003 |
| Antibiotics | 34 (64.2) | 79 (43.6) | 0.01 | 34 (57.6) | 45 (36.9) | 0.01 |
| ECMO | 2 (3.6) | 10 (5.5) | 0.74 | 2 (3.4) | 8 (6.5) | 0.5 |
| Hospital length of stay (days), median (range) | 18 (1,294) | 16 (1,630) | 0.56 | 24 (2, 630) | 13 (1, 173) | 0.001 |
| Age at 1st cardiac surgery (days), medias (range) | 29 (2,1095) | 7 (1,540) | 0.002 | 8 (1,510) | 7 (1,540) | 0.86 |
NICU neonatal intensive care unit, HFOV high-frequency oscillatory ventilation, ECMO extracorporeal membrane oxygenation
P value is for χ2 test or Fisher’s exact test for categorical variables or Student’s t-tests or Wilcoxon rank-sum tests for continuous variables
We also investigated postnatal outcomes in both term groups (early term and full term). Outcomes in pregnancies delivered at 37–38 weeks compared to those delivered ≥ 39 weeks were significant for more newborns with birthweight < 2500 g (P < 0.001), pre-operative NICU support including intubation (P = 0.049), vasopressors (P = 0.04), prostaglandins (P = 0.003), and antibiotics (P = 0.01). They also had longer hospital stay with median of 24 days in infants delivered at 37–38 weeks compared to median of 13 days in those delivered ≥ 39 weeks (P = 0.001) (Table 3).
Discussion
We performed a retrospective cohort study with primary aim of investigating PTB risk in pregnancies diagnosed with CHO. Our secondary aim was evaluating PTB associations and outcomes. We also aimed to identify the optimal time of delivery in this group. We found more than a twofold increase in the overall risk of PTB (23.2%) in pregnancies with CHO compared to the general population (12.1% national population risk [23] and 10.6% global risk [24].).
The risk was almost unchanged after excluding extracardiac anomalies and pathogenic chromosomal abnormalities. Spontaneous PTB contributed to 38.2% of those preterm deliveries, which was almost unchanged after excluding other anomalies and chromosomal changes. Marijuana use in pregnancy was a significant modifiable factor for PTB. Newborns delivered at < 37 weeks had lower birthweight and required more NICU support than those delivered at ≥37 weeks. Our study also found that newborns delivered at 37–38 weeks had lower birthweight, required more NICU support, and had. longer hospital stay than those delivered at ≥39 weeks which support other few reports with similar findings [16, 25, 26].
Prior reports have shown that PTB rate in pregnancies with fetal CHD have ranged between 11.5 and 28% [6, 8, 27]. In our study, rate was 23.2% in all CHD cases, and 20.6% after excluding extracardiac anomalies and chromosomal abnormalities.
In a population study done by Tanner et al. [8], they investigated the risk of PIB in pregnancies with CHD which was 28%. However, spontaneous and medically indicated PTB were not distinguished.
In a geographical cohort study in large region of the Netherlands by Velzen et al. [28], the authors aimed to study the prevalence of PTB in pregnancies with isolated CHD. Authors found that 49.5% of their PTB pregnancies had spontaneous PTB, and 38.4% were induced. Our study had higher rate for medically indicated preterm deliveries even after excluding extracardiac anomalies and chromosomal abnormalities. This could be explained by the fact that our center is a large tertiary referral center in the area which could have been resulted in even more obstetrically and medically complicated pregnancies. It is noteworthy that the presence of chromosomal abnormalities did not significantly affect the PIB rate in our cohort unlike what has been shown in prior reports [29]. This could be explained either by the fact that the study was not powered for this outcome, or due to the exclusion of pregnancies complicated with trisomy 13, and trisomy 18.
CHD types that were associated with PTB included IAA, which was possibly due to the association with other extracardiac anomalies or chromosomal abnormalities including 22q11 deletion syndrome. This was supported by the subgroup analysis that showed none of the CHD types were significantly more common in the PTB group after exclusion. This finding was in contrast to a study by Lass et al. [6] which reported that PTB was higher among infants with anomalies of atrioventricular septum (adjusted OR 2.4, 95% CI 1.4–4.2). When it comes to prenatal marijuana use and PTB, available literature has been conflicting for few reasons including studies’ sample size and the presence of other exposure cofounders like tobacco use during pregnancy. Most reports do not show an association between prenatal marijuana use and PTB [30–33] including a meta-analysis by Conner et al. [32] which showed that when marijuana use was stratified by concomitant tobacco use, marijuana use alone was not associated with increased PTB. However, a recent large population-based retrospective cohort study examining 661,617 women including 9427 self-reported marijuana use in pregnancy showed that it was associated with double the risk of PTB (6.1% among women who did not report marijuana use and 12.0% among those reporting use). They conducted subgroup analysis in women who reported use of tobacco, alcohol, opioids, or no other substances in pregnancy. Among women who reported use of marijuana but no other substances, the crude rate of PTB was 9.1% compared with 5.9% among women who reported no use of substances and the relative risk was 1.34 (95% CI, 1.27–1.42) [34].
Strengths of our study include large sample size, and ability to investigate different categories of CHD. Our study was characterized by prenatal diagnosis that was confirmed postnatally. We acknowledge the limitations of our study including that we did not investigate the mechanism by which spontaneous PTB occurs in those pregnancies, which could be directly or indirectly related to CHD type itself. Mechanisms could be related to individual risks for PTB, maternal medical conditions [35–39], and undiagnosed genetics that could be associated with PTB [29]. Although our study included a large number of cases of CHD, certain categories of CHD could not be studied because of limited sample size. Socioeconomic status, environmental factors including air pollution [40], physical activity [41], and stress [42] are all factors that have been shown to be associated with PTB, but unfortunately, we could not obtain all these variables which might have contributed directly or indirectly to PTB in this population.
Conclusion
Our study showed increased PTB rate among pregnancies prenatally diagnosed with CHD. The PTB rate was higher than the general population, with spontaneous preterm birth contributing to 38% of those deliveries. Aside from obstetrical/medical indicated preterm delivery, risk factors that were significantly associated with preterm birth were mostly non-modifiable, with modifiable factors included marijuana use in pregnancy. Outcomes were more favorable in newborns delivered at ≥39 weeks gestation compared to those delivered prior to 39 weeks. Future studies could investigate mechanisms of spontaneous PTB in pregnancies with CHD.
Acknowledgements
Research reported in this publication was supported by NIH Grant P30 CA77598 utilizing the Biostatistics and Bioinformatics Core shared resource of the Masonic Cancer Center, University of Minnesota and by the National Center for Advancing Translational Sciences of the National Institutes of Health Award Number UL1TR002494. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
This study was an oral presentation at the 9th Phoenix Fetal Cardiology Symposium, 2018.
Footnotes
Compliance with Ethical Standards
Conflict of interest The authors report no conflicts of interest.
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