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Perinatal risk factors of symptomatic preterm patent ductus arteriosus and secondary ligation
Journal Pre-proof Perinatal Risk Factors of Symptomatic Preterm Patent Ductus Arteriosus and Secondary Ligation Jin A. Lee, MD, PhD, Jin A. Sohn, MD, PhD, Sohee Oh, PhD, Byung Min Choi, MD, PhD PII:
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DOI:
https://doi.org/10.1016/j.pedneo.2020.03.016
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Pediatrics & Neonatology
Received Date: 18 September 2019 Revised Date:
3 March 2020
Accepted Date: 31 March 2020
Please cite this article as: Lee JA, Sohn JA, Oh S, Choi BM, Perinatal Risk Factors of Symptomatic Preterm Patent Ductus Arteriosus and Secondary Ligation, Pediatrics and Neonatology, https:// doi.org/10.1016/j.pedneo.2020.03.016. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Copyright © 2020, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. All rights reserved.
PEDN-D-19-00105_After Eng edited_final
Perinatal Risk Factors of Symptomatic Preterm Patent Ductus Arteriosus and Secondary Ligation Jin A Lee1,2, MD, PhD, Jin A Sohn1,2 , MD, PhD, Sohee Oh3, PhD, Byung Min Choi4,5, MD, PhD 1
Department of Pediatrics, Seoul National University–Seoul Metropolitan Government
Boramae Medical Center, Seoul, Korea 2
Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
3
Department of Biostatistics, Seoul National University–Seoul Metropolitan Government
Boramae Medical Center, Seoul, Korea 4
Department of Pediatrics, Korea Ansan Hospital, Gyunggi-do, Korea
5
Department of Pediatrics, Korea University College of Medicine, Seoul, Korea
Running title: Perinatal Risk factor of preterm patent ductus arteriosus
Corresponding author Jin A Lee, M.D., Ph.D. Department of Pediatrics, Seoul National University–Seoul Metropolitan Government Boramae Medical Center, 20, Boramae-ro 5-gil, Dongjak-gu, Seoul 07061, South Korea Tel: +82-2-870-2364
Fax: +82-2-831-2826
E-mail: [email protected]
1
Perinatal Risk Factors of Symptomatic Preterm Patent Ductus Arteriosus and Secondary Ligation
Article category: Original article
Running title: Perinatal Risk factor of preterm patent ductus arteriosus
2
Abstract Background: There has been conflicting evidence for the association between antenatal factors and the development of symptomatic patent ductus arteriosus (PDA) or failure of pharmacologic treatment, especially for maternal pregnancy–induced hypertension (PIH) or chorioamnionitis. We assessed the perinatal risk factors of symptomatic PDA in preterm infants and those of secondary ligation in infants with pharmacologic treatment for symptomatic PDA using a national cohort. Methods: A total of 2,961 infants with 22–29 weeks of gestation with symptomatic PDA or no PDA were included from the Korean Neonatal Network database. To identify significant perinatal risk factors associated with symptomatic PDA or secondary ligation, all perinatal factors were included in the univariate and multivariate generalized estimating equation analysis and final model was selected using backward elimination method based on Quasilikelihood Information Criterion. Results: Lower gestational age (GA), female gender, maternal PIH and surfactant use were significant risk factors of symptomatic PDA. Antenatal corticosteroid use decreased the risk of symptomatic PDA. For secondary ligation, lower GA and cesarean section were significant risk factors. Adjusted odds ratio (aOR) of PIH as a risk factor of symptomatic PDA was 1.56 [95% confidence interval 1.17–2.08]. In the subgroup analysis according to the GA, lower GA, female gender, multiple pregnancy, maternal PIH and surfactant use increased the risk of symptomatic PDA, and histologic chorioamnionitis and antenatal corticosteroid use decreased the risk of symptomatic PDA only in GA 26–29 weeks group.
3
Conclusion: Lower GA increased the risk of symptomatic PDA and secondary ligation. Maternal PIH and surfactant use increased the risk of symptomatic PDA; however, antenatal corticosteroid use decreased it. Close observation of the clinical symptoms of PDA is needed in preterm infants with maternal PIH.
Key Words: patent ductus arteriosus; premature infant; risk factor
4
1. INTRODUCTION
In preterm infants with gestational age (GA) < 30 weeks, about 60–70% of patients have persistently patent ductus arteriosus (PDA) after the first 3 postnatal days, which facilitates symptomatic PDA.1 Lower GA is the most potent risk factor of symptomatic PDA, and many perinatal variables such as respiratory distress syndrome (RDS) were also reported to be risk factors of symptomatic PDA and poor response to pharmacologic treatment; however, most studies were single–center study with a small number of participants and moderate to late preterm infants were also included.2–5 Hypertensive disorders of pregnancy (HDP) and chorioamnionitis (CA) are representative maternal diseases which can impact on neonatal outcomes in preterm infants. There are no reports on the association between maternal HDP and the development of symptomatic PDA and only a few reports on the association of the failure of the pharmacologic treatment about preterm PDA.6 For the association between clinical CA and preterm PDA, clinical CA was reported to decrease the risk of PDA.7 However, other meta-analyses8,9 showed conflicting evidence for CA on the development of PDA. For the association between histologic chorioamnionitis (HCA) and the response to PDA treatment, intrauterine inflammation was an independent risk factor of PDA after indomethacin therapy in extremely–low–birth– weight infants.10 However, another meta-analysis showed that CA did not increase the risk of surgical ligation.8 The aim of this study was to assess whether there are any significant perinatal risk factors of symptomatic PDA in preterm infants with a GA of 22–29 weeks using a nationwide large
5
cohort database. We also assessed whether the perinatal risk factors can affect the efficacy of the pharmacologic treatment of symptomatic PDA.
2. METHODS 2.1. Study design and data collection We identified a cohort of 3,865 preterm infants with GA 22–29 weeks born between 2013 and 2015 registered in the Korean Neonatal Network (KNN). Clinical data were prospectively recorded in the KNN database from 69 neonatal intensive care units (NICUs) as previously described11 and analyzed retrospectively for the purposes of this manuscript. We excluded 115 infants due to any major congenital anomaly, 71 infants of missing or mismatched information on the PDA treatment, 568 infants who received prophylactic or presymptomatic PDA treatment and 5 infants admitted for more than one year in the NICU. Additionally, 145 infants who died before 3 postnatal days were also excluded because confirmation of the presence of symptomatic PDA was impossible. A total of 2,961 infants were included in the final analysis (Figure 1). First, we compared the demographic and perinatal characteristics between symptomatic PDA and no PDA groups. We also assessed the independent perinatal risk factors of symptomatic PDA by multivaraite analysis. Second, we compared the demographic and perinatal characteristics according to the presence of secondary PDA ligation among preterm infants who received pharmacologic treatment due to symptomatic PDA to assess the failure of pharmacologic treatment for symptomatic PDA. Pharmacologic characteristics were also compared between secondary ligation and no secondary ligation groups. Finally we searched for perinatal risk factors of secondary ligation in preterm infants who received pharmacologic 6
treatment. Additionally, subgroup analysis was done dividing infants into two groups: GA 22–25 weeks and 26–29 weeks. The demographic and perinatal characteristics included GA, birthweight, gender, cesarean section (CS), multiple pregnancy, gestational diabetes mellitus, HCA, pregnancy–induced hypertension (PIH), small for gestational age (SGA), complete course of antenatal corticosteroid use (ACS), clinical risk index for babies (CRIB)–II score,12 Apgar score at 5 minutes, presence of delivery room resuscitation, surfactant use, early sepsis, inhaled nitric oxide use and hypotension within 7 days after birth, and pulmonary hemorrhage. The pharmacologic characteristics included the type and route of pharmacologic treatment and the first day of pharmacologic treatment.
2.2. Definitions The “no PDA group” was defined as the group of patients with a spontaneously closed PDA or without any significant left–to–right shunt through PDA by echocardiography and without any symptoms and treatment attributable to PDA during hospitalization.13 Symptomatic PDA was defined as the presence of more than 2 out of 5 following symptoms caused by PDA with a confirmation of a large left–to–right ductal flow by echocardiography: 1) a systolic or continuous murmur; 2) a bounding pulse or hyperactive precordial pulsation; 3) hypotension; 4) respiratory difficulty; and 5) pulmonary edema or cardiomegaly (cardiothoracic ratio > 60%) on a chest radiograph.14 Actually, KNN classified the cohort population according to the therapeutic strategies for PDA as follows; group 1, no PDA as described above; group 2, prophylactic treatment when PDA treatment was done without any clinical symptoms or 7
diagnostic abnormalities in the echocardiography or any increased brain natriuretic peptide; group 3, pre-symptomatic treatment, in which PDA was confirmed by echocardiography, and PDA treatment was done without any clinical symptoms due to PDA; group 4, symptomatic treatment as PDA treatment was done because there were clinical symptoms due to PDA; and group 5, conservative treatment applying only conservative and supportive treatment without any pharmacologic or surgical intervention for PDA although there were clinical symptoms due to PDA. We defined the symptomatic PDA group as both symptomatic treatment group and conservative treatment group. Secondary ligation was defined as a patient receiving PDA ligation after the pharmacological treatment failed to close the PDA. Primary ligation was defined as a receiving PDA ligation without any pharmacological treatment for preterm PDA. PIH was defined as any maternal diagnosis of gestational hypertension, eclampsia or preeclampsia. HCA was defined as a documented case of CA shown by a placental biopsy.15 In Korea, almost all of the hospitals with NICUs routinely perform placental biopsies in the case of preterm deliveries. In our cohort, 83% of the study population received histologic confirmation of HCA. SGA was defined as a Z-score of less than the 10th percentile based on the KNN cohort. Delivery room resuscitation was defined when cardiac compression was done or medication was administered in the delivery room. Surfactant use was defined as any surfactant use for prophylactic or rescue treatment of RDS. Early sepsis was defined as a positive blood culture less than 7 days from birth with antibiotics use for more than 5 days. Hypotension was defined as hypotension requiring any inotropic or hydrocortisone use within 7 days after birth. Postnatal day of the first day of treatment for preterm PDA was defined as the difference 8
between the date of the first day of treatment and the date of birth. In this study, 0 day means less than 24 hours from birth.
2.3. Statistical analysis All the continuous variables are expressed as median and interquartile range (IQR), and the categorical variables are expressed as numbers and proportions. For the univariate analysis comparing the factors between symptomatic PDA and no PDA groups or between the secondary ligation and no secondary ligation groups, a generalized estimating equation (GEE)16 was done to consider correlation between twins from the same mother. To identify the risk factors of symptomatic PDA or secondary ligation, we performed the univariable and multivariable GEEs with adjustment for only GA. After that, all antenatal risk factors were included in the multivariable GEE. The final model was selected using backward elimination based on Quasi-likelihood Information Criterion (QIC) to avoid the multicollinearity problem.17 For the chosen model, predictability was evaluated with the area under the receiver operating characteristic curve (AUC), and goodness of fit was assessed using the Hosmer–Lemeshow test.18 The same methods were repeated in the subgroup analysis according to the GA group. The statistical analysis was done with R version 3.5.3. (http://www.r-project.org). P values less than 0.05 were considered statistically significant.
2.4. Statement of Ethics The KNN registry was approved by the institutional review board (IRB) at each participating 9
hospital, and informed consent to collect and use the clinical data and outcome of very–low– birth–weight infants was obtained from the parents at enrollment by the NICUs participating in the KNN. This study was exempted for IRB approval from the IRB of Seoul National University Boramae Hospital (IRB exemption number 07–2017–11).
3. RESULTS A total of 2,961 infants were included with 1,451 infants (49.0%) of symptomatic PDA. Among the infants with symptomatic PDA, 1,063 infants (73.3%) received pharmacological treatment for symptomatic PDA, and 333 (31.3%) received secondary ligation among the infants who received pharmacological treatment (Figure 1).
3.1. Perinatal risk factors of symptomatic PDA In the univariate analysis, infants with symptomatic PDA were younger and lighter at birth. More infants were female and had a lower 5 minute Apgar score in the symptomatic PDA group. There were fewer infants who received a complete course of ACS and the CRIB score was higher in the symptomatic PDA group. More infants received surfactant treatment in the symptomatic PDA group (Table 1). Multivariable analysis adjusting for only GA revealed that lower GA, female gender, CS, PIH, and surfactant use were significant risk factors of symptomatic PDA. A complete course of ACS and HCA lowered it. For the best model, GA, gender, CS, multiple pregnancy, PIH, HCA, complete course of ACS, and surfactant use were chosen [AUC = 0.696, 95% 10
confidence interval (CI) 0.675–0.717, Hosemer–Lemeshow test P–value 0.077]. In the multivariate analysis adjusting for those variables, lower GA, female gender, PIH, and surfactant use were significant risk factors of symptomatic PDA and a complete course of ACS decreased it (Table 2).
3.2. Perinatal risk factors of secondary PDA ligation In the univariate analysis, infants with secondary PDA ligation were younger and lighter at birth. The 5 minute Apgar score was lower, and CRIB score was higher in secondary ligation group (Table 3). In pharamcologic characteristics, there were no significant differences in the type of medication and the time to the first pharmacologic treatment between secondary ligation and no secondary ligation groups (Supplement 1). The median postnatal days of secondary ligation were 16 days from birth (IQR 9–25 days from birth). More infants received pharmacologic treatment by intravenous route in the secondary ligation group (P = 0.013). According to the multivariate analysis adjusted for GA only, lower GA and CS increased the risk of secondary ligation. For the best model, the GA, CS, and 5 minute Apgar score were chosen (AUC = 0.664, 95% CI 0.624–0.704, Hosemer–Lemeshow test P–value 0.258). In the multivariate analysis adjusting for those variables, only lower GA and CS increased the risk of secondary ligation (Table 4).
3.3. Subgroup analysis according to the GA (GA 22–25 weeks versus 26–29 weeks)
11
In infants with a GA of 22–25 weeks, there were no significant risk factors of symptomatic PDA after the multivariate analysis adjusting for GA, gender, CS, multiple pregnancy, PIH, HCA, complete course of ACS use, and surfactant use. Multivariate analysis in infants with a GA of 26–29 weeks showed that a lower GA at birth, female gender, multiple pregnancy, PIH, and surfactant use increased the risk of symptomatic PDA; however, HCA and a complete course of ACS use decreased it [AUC = 0.663, 95% CI 0.637–0.689, Hosemer– Lemeshow test P–value 0.118, Supplement 2]. For secondary ligation, in infants with a GA of 22–25 weeks, there were no significant risk factors after the multivariate analysis adjusting for the GA, CS, and 5 minute Apgar score. In infants with a GA of 26–29 weeks, only a lower GA at birth increased the risk of secondary ligation after the multivariate analysis [AUC = 0.614, 95% CI 0.568–0.659, Hosemer– Lemeshow test P–value 0.485, Supplement 3].
4. DISCUSSION In our study, many perinatal factors were associated with the development of symptomatic PDA; however, only lower GA and CS were significant risk factors for the failure of the pharmacologic treatment of preterm PDA. We suggest that lower GA, female gender, maternal PIH, and surfactant use are significant risk factors of symptomatic PDA, and ACS use is protective against the development of symptomatic PDA. HCA decreased the risk of symptomatic PDA only in GA 26–29 weeks group. In the multivariate analysis, we included GA as a continous variable (groups) because there was no significant difference when we divided GA variable into two or three groups. 12
Furthermore, according to the QIC criterion, the model with GA as a continous variable was better than that with GA groups. We performed subgroup analysis according to the GA to compensate for the non-linear effect of GA. There have been many reports on the risk factors of preterm PDA with a small study population2–5 and lower GA and birthweight were the most powerful risk factors of symptomatic PDA. A recent large observational study suggested that maternal antepartum hemorrhage, RDS, birthweight, female gender, GA and 5 minute Apgar score were significant risk factors of preterm PDA.4 For risk factors of pharmacologic response, lower GA, ACS, respiratory distress, and race were independent risk factors for persistent PDA after indomethacin treatment.2 Although many large cohort studies have suggested the adverse effect of male gender on the mortality and major neonatal outcomes in preterm infants,19,20 female gender was a significant risk factor of symptomatic PDA in our study and in another report.4 However, in other studies,21, 22 sex was not a significant risk factor of preterm PDA. Pourarian S et al23 showed that male gender might affect the refractory drug response to preterm PDA. Further studies are needed to ascertain the effect of gender difference on preterm symptomatic PDA and pharmacologic response to PDA treatment. RDS and mechanical ventilation are known to be potent risk factors of PDA requiring treatment.22,24 Surfactant use in infants with RDS can decrease the pulmonary resistance rapidly, which can increase the left–to–right shunting through preterm PDA and the clinical symptoms due to PDA. Actually, KNN did not collect the initial respiratory status including ventilator care within the first several days; thus we could not judge the effect of mechanical
13
ventilation or initial respiratory status on symptomatic PDA and pharmacologic response to PDA treatment. There have been many studies showing that ACS use reduced the symptomatic preterm PDA.25–27 In the lamb model, glucocorticoid treatment decreased the incidence of PDA in premature infants by affecting the interaction of prostaglandin E2 with the ductal tissue.28 ACS also reduces RDS, which is a potent risk factor of preterm PDA. There are reports that preeclampsia is a risk factor of major morbidities associated with preterm birth including bronchopulmonary dysplasia (BPD),29,30 necrotizing enterocolitis (NEC),31,32 and retinopathy of prematurity33; however, there are no reports about the association between PIH or preeclampsia and preterm symptomatic PDA. Actually, PIH and preeclampsia do not coincide exactly, and only PIH, not SGA, was a statistically significant risk factor of symptomatic PDA in our study. Studies about the association between preeclampsia/eclampsia and preterm symptomatic PDA are needed. There are conflicting reports on the association between HCA and symptomatic PDA8,9 or the treatment failure of the pharmacologic treatment.10 In our study, HCA was a protective factor for the development of symptomatic PDA in GA 26–29 weeks group, and there was no association with the performance of secondary ligation. In fact, HCA has been known to be associated with reduced RDS,34,35 which is known to be a significant risk factor of preterm PDA,24 so this can be one of the reasons why HCA is a protective factor for symptomatic PDA in our study. In our study, only lower GA and CS were significant risk factors of a pharmacologic response. Although there were no reports on the association between CS and the 14
pharmacologic response to PDA treatment, both CS and the prophylactic use of antibiotics in preparation of the CS can affect the gut microbiome of infants, which can be a risk factor of NEC.36,37 We did not include NEC in the risk factor analysis because we could not know the order of events between NEC and symptomatic PDA or secondary ligation. Furthermore, reduced intrapartum exposure to mechanical forces and stress hormones during CS can skip the important physiologic stimuli provided by vaginal delivery.37 The strength of our study is its population–based cohort study design with a large patient number, which represents about 80% of very–low–birth–weight infants delivered in about 80% of all the NICUs in South Korea. Moreover, the KNN database offers data on symptomatic PDA defined according to a previously published article14 and a more detailed treatment policy (prophylactic, pre-symptomatic, symptomatic, and conservative treatment),13 which is different from other nationwide cohorts. Second, we could collect information on HCA from KNN using the known histopathologic definition.15 We also defined SGA using the Z-score based on our own study population. The clear definition of such important antenatal risk factors can make our study results more accurate. Our study has some limitations. First, our study could not show the detailed information of echocardiography from KNN cohort. Second, although data about PDA group by therapeutic strategies for PDA in KNN were collected according to the previously defined criteria, the possibility of misclassification due to the differences in the treatment strategies and the timing of echocardiographic follow–up in each hospital cannot be totally excluded. Third, although the missing value for PIH was 0 and we were able to get the placental biopsy results from 83% of the study population, a reporting bias may still exist. Fourth, we were only able to collect the information about PIH, but not about preelampsia/eclampsia or the degree/ 15
severity of preeclampsia. Fifth, we did not assess the association between such perinatal factors, symptomatic PDA, and long–term outcomes such as BPD or pulmonary hypertension. Sixth, we could not get more information including the duration of ductal opening, the date of ductal closure and reopening, and the number of courses/dosage of pharmacologic treatment. Further studies are needed focusing on the association between perinatal factors and the duration of ductal patency. Seventh, we tried to make an efficient model to predict symptomatic PDA or secondary ligation in our cohort; however, because the highest AUC value did not exceed 80, we did not suggest any model using our cohort. In our study using a nationwide population based cohort, lower GA, female gender, maternal PIH, and surfactant use were significant risk factors of symptomatic PDA. In contrast, ACS use decreased it. HCA decreased the risk of symptomatic PDA in more mature preterm infants. Only lower GA and CS increased the risk of secondary ligation. Close follow–up with clinical assessment of PDA symptoms should be done in preterm infants with maternal PIH.
Conflicts of Interest Statement All authors have no conflicts of interest to disclose
Acknowledgements This research was supported by a fund (2016–ER6307–00#) by Research of Korea Centers for Disease Control and Prevention.
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Table 1 Demographic, antenatal, and perinatal characteristics of the study population according to the presence of symptomatic patent ductus arteriosus. Symptomatic PDA
P–value
Yes
No
(N = 1,451, 49.0%)
(N = 1,510, 51.0%)
GA at birth (weeks)
26.6 [25.3, 28.1]
28.3 [26.7, 29.1]
<0.001
Birth weight (g)
900 [720, 1,090]
1,090 [880, 1,270]
<0.001
Male gender
712 (49.1%)
825 (54.6%)
0.002
Cesarean section
1,046 (72.1%)
1,068 (70.7%)
0.432
Multiple pregnancy
507 (34.9%)
472 (31.3%)
0.126
Gestational diabetes mellitus
87 (6.0%)
107 (7.1%)
0.076
Histologic chorioamnionitis
509 (42.5%)
555 (44.0%)
0.654
PIH
174 (12.0%)
157 (10.4%)
0.155
SGA
163 (11.2%)
167 (11.1%)
0.999
Complete course of ACS
613 (42.2%)
749 (49.6%)
<0.001
Delivery room resuscitation
97 (6.9%)
80 (5.6%)
0.115
5 minute Apgar score
<0.001
22
0–3
135 (9.4%)
93 (6.2%)
4–6
570 (39.6%)
489 (32.5%)
7–10
735 (51.0%)
923 (61.3%)
CRIB-II score
11 [9, 14]
9 [7, 11]
<0.001
Surfactant use
1,431 (98.6%)
1,421 (94.1%)
<0.001
Early sepsis (<7 postnatal days)
100 (6.9%)
78 (5.2%)
0.119
iNO use < 7 postnatal days
76 (5.2%)
30 (2.0%)
<0.001
Hypotension(< 7 postnatal days)
610 (42.0%)
322 (21.3%)
<0.001
GA; gestational age, PIH; pregnancy–induced hypertension, SGA; small for gestational age, ACS; antenatal corticosteroid use, CRIB; clinical risk index for babies, iNO; inhaled nitric oxide
23
Table 2 Perinatal risk factors of symptomatic patent ductus arteriosus by univariate and multivariate analyses. Symptomatic PDA Univariate analysis
Multivariate analysis 1*
Multivariate analysis 2†
uOR
95% CI
P–value
aOR
95% CI
P–value
aOR
95% CI
P–value
GA at birth (per week)
0.70
(0.67, 0.74)
<0.001
0.70
(0.67, 0.74)
<0.001
0.69
(0.65, 0.73)
<0.001
Male gender
0.80
(0.69, 0.92)
0.002
0.78
(0.67, 0.91)
0.001
0.77
(0.65, 0.91)
0.002
Ceserean section
1.07
(0.91, 1.26)
0.432
1.27
(1.07, 1.51)
0.006
1.17
(0.97, 1.42)
0.107
Multiple pregnancy
1.14
(0.96, 1.36)
0.126
1.13
(0.95, 1.36)
0.174
1.23
(0.99, 1.51)
0.052
Gestational diabetes mellitus
0.76
(0.56, 1.03)
0.076
0.99
(0.72, 1.35)
0.940
PIH
1.18
(0.94, 1.49)
0.155
1.59
(1.24, 2.04)
<0.001
1.56
(1.17, 2.08)
0.002
24
Histologic chorioamnionitis
0.96
(0.82, 1.14)
0.654
0.76
(0.63, 0.90)
0.002
SGA
1.00
(0.80, 1.26)
0.999
1.04
(0.81, 1.33)
0.754
Delivery room resuscitation
1.27
(0.94, 1.71)
0.115
0.92
(0.66, 1.27)
0.598
Complete course of ACS
0.76
(0.65, 0.88)
<0.001
0.79
(0.68, 0.93)
0.004
0–3 group
1.82
(1.37, 2.40)
<0.001
0.99
(0.72, 1.35)
0.951
4–6 group
1.43
(1.22, 1.67)
<0.001
1.09
(0.92, 1.29)
0.315
Surfactant use
4.51
(2.78, 7.34)
<0.001
2.85
(1.73, 4.71)
<0.001
0.83
(0.69, 1.00)
0.053
0.82
(0.69, 0.98)
0.030
2.62
(1.54, 4.46)
<0.001
5 minute Apgar score group (ref. 7–10 group)
*
adjusted for GA
25
†
adjusted for GA, male gender, cesarean section, multiple pregnancy, PIH, histologic chorioamnionitis, complete course of ACS use, and
surfactant use uOR: unadjusted odds ratio, aOR; adjusted odds ratio, GA; gestational age, PIH; pregnancy–induced hypertension, SGA; small for gestational age, ACS; antenatal corticosteroid use
26
Table 3 Demographic, antenatal, and perinatal characteristics of the preterm infants who received pharmacologic treatment for symptomatic patent ductus arteriosus according to the presence of secondary ligation. Secondary ligation
P–value
Yes
No
(N = 333, 31.3%)
(N = 730, 68.7%)
GA at birth (weeks)
26.1 [25, 27.4]
27.3 [26.0, 28.6]
<0.001
Birth weight (g)
840 [710, 1,000]
980 [810, 1,163]
<0.001
Male gender
151 (45.3%)
362 (49.6%)
0.254
Cesarean section
247 (74.2%)
520 (71.2%)
0.395
Multiple pregnancy
105 (31.5%)
254 (34.8%)
0.367
Gestational diabetes mellitus
16 (4.8%)
50 (6.8%)
0.271
Histologic chorioamnionitis
116 (45.3%)
251 (41.8%)
0.403
PIH
36 (10.8%)
93 (12.7%)
0.354
SGA
32 (9.6%)
73 (10.0%)
0.844
Complete course of ACS
142 (42.6%)
287 (39.3%)
0.389
Delivery room resuscitation
22 (6.9%)
39 (5.6%)
0.466
27
5 minute Apgar score
0.002
0–3
40 (12.1%)
46 (6.4%)
4–6
142 (42.9%)
281 (38.9%)
7–10
149 (45.0%)
149 (45.0%)
CRIB-II score
12 [10, 14]
10 [8, 12]
<0.001
Surfactant use
331 (99.4%)
714 (97.8%)
0.074
Early sepsis<7 postnatal days
28 (8.4%)
40 (5.5%)
0.087
iNO use < 7 postnatal days
11 (3.3%)
18 (2.5%)
0.405
Hypotension(< 7 postnatal days)
181 (54.4%)
235 (32.2%)
<0.001
Pulmonary hemorrhage
46 (13.8%)
70 (9.6%)
0.028
GA; gestational age, PIH; pregnancy–induced hypertension, SGA; small for gestational age, ACS; antenatal corticosteroid use, CRIB; clinical risk index for babies, iNO; inhaled nitric oxide
28
Table 4 Perinatal risk factors of secondary ligation in infants who received pharmacologic treatment for symptomatic patent ductus arteriosus by univariate and multivariate analyses. Secondary ligation Univariate analysis
Multivariate analysis 1*
Multivariate analysis 2†
uOR
95% CI
P–value
aOR
95% CI
P–value
aOR
95% CI
P–value
GA at birth (per week)
0.74
(0.68, 0.80)
<0.001
0.74
(0.68, 0.80)
<0.001
0.73
(0.67, 0.80)
<0.001
Male gender
0.86
(0.66, 1.12)
0.254
0.82
(0.63, 1.07)
0.151
Ceserean section
1.14
(0.85, 1.52)
0.395
1.42
(1.04, 1.93)
0.026
1.40
(1.03, 1.91)
0.033
Multiple pregnancy
0.87
(0.65, 1.17)
0.367
0.93
(0.68, 1.26)
0.631
Gestational diabetes mellitus
0.71
(0.39, 1.30)
0.271
0.89
(0.49, 1.64)
0.713
PIH
0.82
(0.54, 1.24)
0.354
1.15
(0.75, 1.76)
0.512
29
Histologic chorioamnionitis
1.14
(0.84, 1.54)
0.403
0.89
(0.64, 1.23)
0.470
SGA
0.96
(0.62, 1.48)
0.844
1.02
(0.64, 1.62)
0.942
Delivery room resuscitation
1.23
(0.71, 2.12)
0.466
0.95
(0.52, 1.73)
0.861
Complete course of ACS
1.13
(0.86, 1.48)
0.389
1.15
(0.87, 1.53)
0.334
0–3 group
2.26
(1.41, 3.61)
0.001
1.51
(0.91, 2.51)
0.110
1.51
(0.91, 2.53)
0.114
4–6 group
1.35
(1.02, 1.78)
0.037
1.11
(0.83, 1.49)
0.485
1.12
(0.84, 1.50)
0.450
Surfactant use
3.34
(0.89, 12.57)
0.074
2.04
(0.54, 7.64)
0.291
5 minute Apgar score group (ref. 7–10 group)
*
adjusted for GA
†
adjusted for GA, cesarean section, and 5 minute Apgar score group
30
uOR: unadjusted odds ratio, aOR; adjusted odds ratio, GA; gestational age, PIH; pregnancy–induced hypertension, SGA; small for gestational age, ACS; antenatal corticosteroid use
31
Figure Legends Figure 1 Study population identified with subsequent flowchart of the study. GA: gestational age at birth PDA: patent ductus arteriosus
32
S1875-9572(20)30056-5
DOI:
https://doi.org/10.1016/j.pedneo.2020.03.016
Reference:
PEDN 1029
To appear in:
Pediatrics & Neonatology
Received Date: 18 September 2019 Revised Date:
3 March 2020
Accepted Date: 31 March 2020
Please cite this article as: Lee JA, Sohn JA, Oh S, Choi BM, Perinatal Risk Factors of Symptomatic Preterm Patent Ductus Arteriosus and Secondary Ligation, Pediatrics and Neonatology, https:// doi.org/10.1016/j.pedneo.2020.03.016. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Copyright © 2020, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. All rights reserved.
PEDN-D-19-00105_After Eng edited_final
Perinatal Risk Factors of Symptomatic Preterm Patent Ductus Arteriosus and Secondary Ligation Jin A Lee1,2, MD, PhD, Jin A Sohn1,2 , MD, PhD, Sohee Oh3, PhD, Byung Min Choi4,5, MD, PhD 1
Department of Pediatrics, Seoul National University–Seoul Metropolitan Government
Boramae Medical Center, Seoul, Korea 2
Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
3
Department of Biostatistics, Seoul National University–Seoul Metropolitan Government
Boramae Medical Center, Seoul, Korea 4
Department of Pediatrics, Korea Ansan Hospital, Gyunggi-do, Korea
5
Department of Pediatrics, Korea University College of Medicine, Seoul, Korea
Running title: Perinatal Risk factor of preterm patent ductus arteriosus
Corresponding author Jin A Lee, M.D., Ph.D. Department of Pediatrics, Seoul National University–Seoul Metropolitan Government Boramae Medical Center, 20, Boramae-ro 5-gil, Dongjak-gu, Seoul 07061, South Korea Tel: +82-2-870-2364
Fax: +82-2-831-2826
E-mail: [email protected]
1
Perinatal Risk Factors of Symptomatic Preterm Patent Ductus Arteriosus and Secondary Ligation
Article category: Original article
Running title: Perinatal Risk factor of preterm patent ductus arteriosus
2
Abstract Background: There has been conflicting evidence for the association between antenatal factors and the development of symptomatic patent ductus arteriosus (PDA) or failure of pharmacologic treatment, especially for maternal pregnancy–induced hypertension (PIH) or chorioamnionitis. We assessed the perinatal risk factors of symptomatic PDA in preterm infants and those of secondary ligation in infants with pharmacologic treatment for symptomatic PDA using a national cohort. Methods: A total of 2,961 infants with 22–29 weeks of gestation with symptomatic PDA or no PDA were included from the Korean Neonatal Network database. To identify significant perinatal risk factors associated with symptomatic PDA or secondary ligation, all perinatal factors were included in the univariate and multivariate generalized estimating equation analysis and final model was selected using backward elimination method based on Quasilikelihood Information Criterion. Results: Lower gestational age (GA), female gender, maternal PIH and surfactant use were significant risk factors of symptomatic PDA. Antenatal corticosteroid use decreased the risk of symptomatic PDA. For secondary ligation, lower GA and cesarean section were significant risk factors. Adjusted odds ratio (aOR) of PIH as a risk factor of symptomatic PDA was 1.56 [95% confidence interval 1.17–2.08]. In the subgroup analysis according to the GA, lower GA, female gender, multiple pregnancy, maternal PIH and surfactant use increased the risk of symptomatic PDA, and histologic chorioamnionitis and antenatal corticosteroid use decreased the risk of symptomatic PDA only in GA 26–29 weeks group.
3
Conclusion: Lower GA increased the risk of symptomatic PDA and secondary ligation. Maternal PIH and surfactant use increased the risk of symptomatic PDA; however, antenatal corticosteroid use decreased it. Close observation of the clinical symptoms of PDA is needed in preterm infants with maternal PIH.
Key Words: patent ductus arteriosus; premature infant; risk factor
4
1. INTRODUCTION
In preterm infants with gestational age (GA) < 30 weeks, about 60–70% of patients have persistently patent ductus arteriosus (PDA) after the first 3 postnatal days, which facilitates symptomatic PDA.1 Lower GA is the most potent risk factor of symptomatic PDA, and many perinatal variables such as respiratory distress syndrome (RDS) were also reported to be risk factors of symptomatic PDA and poor response to pharmacologic treatment; however, most studies were single–center study with a small number of participants and moderate to late preterm infants were also included.2–5 Hypertensive disorders of pregnancy (HDP) and chorioamnionitis (CA) are representative maternal diseases which can impact on neonatal outcomes in preterm infants. There are no reports on the association between maternal HDP and the development of symptomatic PDA and only a few reports on the association of the failure of the pharmacologic treatment about preterm PDA.6 For the association between clinical CA and preterm PDA, clinical CA was reported to decrease the risk of PDA.7 However, other meta-analyses8,9 showed conflicting evidence for CA on the development of PDA. For the association between histologic chorioamnionitis (HCA) and the response to PDA treatment, intrauterine inflammation was an independent risk factor of PDA after indomethacin therapy in extremely–low–birth– weight infants.10 However, another meta-analysis showed that CA did not increase the risk of surgical ligation.8 The aim of this study was to assess whether there are any significant perinatal risk factors of symptomatic PDA in preterm infants with a GA of 22–29 weeks using a nationwide large
5
cohort database. We also assessed whether the perinatal risk factors can affect the efficacy of the pharmacologic treatment of symptomatic PDA.
2. METHODS 2.1. Study design and data collection We identified a cohort of 3,865 preterm infants with GA 22–29 weeks born between 2013 and 2015 registered in the Korean Neonatal Network (KNN). Clinical data were prospectively recorded in the KNN database from 69 neonatal intensive care units (NICUs) as previously described11 and analyzed retrospectively for the purposes of this manuscript. We excluded 115 infants due to any major congenital anomaly, 71 infants of missing or mismatched information on the PDA treatment, 568 infants who received prophylactic or presymptomatic PDA treatment and 5 infants admitted for more than one year in the NICU. Additionally, 145 infants who died before 3 postnatal days were also excluded because confirmation of the presence of symptomatic PDA was impossible. A total of 2,961 infants were included in the final analysis (Figure 1). First, we compared the demographic and perinatal characteristics between symptomatic PDA and no PDA groups. We also assessed the independent perinatal risk factors of symptomatic PDA by multivaraite analysis. Second, we compared the demographic and perinatal characteristics according to the presence of secondary PDA ligation among preterm infants who received pharmacologic treatment due to symptomatic PDA to assess the failure of pharmacologic treatment for symptomatic PDA. Pharmacologic characteristics were also compared between secondary ligation and no secondary ligation groups. Finally we searched for perinatal risk factors of secondary ligation in preterm infants who received pharmacologic 6
treatment. Additionally, subgroup analysis was done dividing infants into two groups: GA 22–25 weeks and 26–29 weeks. The demographic and perinatal characteristics included GA, birthweight, gender, cesarean section (CS), multiple pregnancy, gestational diabetes mellitus, HCA, pregnancy–induced hypertension (PIH), small for gestational age (SGA), complete course of antenatal corticosteroid use (ACS), clinical risk index for babies (CRIB)–II score,12 Apgar score at 5 minutes, presence of delivery room resuscitation, surfactant use, early sepsis, inhaled nitric oxide use and hypotension within 7 days after birth, and pulmonary hemorrhage. The pharmacologic characteristics included the type and route of pharmacologic treatment and the first day of pharmacologic treatment.
2.2. Definitions The “no PDA group” was defined as the group of patients with a spontaneously closed PDA or without any significant left–to–right shunt through PDA by echocardiography and without any symptoms and treatment attributable to PDA during hospitalization.13 Symptomatic PDA was defined as the presence of more than 2 out of 5 following symptoms caused by PDA with a confirmation of a large left–to–right ductal flow by echocardiography: 1) a systolic or continuous murmur; 2) a bounding pulse or hyperactive precordial pulsation; 3) hypotension; 4) respiratory difficulty; and 5) pulmonary edema or cardiomegaly (cardiothoracic ratio > 60%) on a chest radiograph.14 Actually, KNN classified the cohort population according to the therapeutic strategies for PDA as follows; group 1, no PDA as described above; group 2, prophylactic treatment when PDA treatment was done without any clinical symptoms or 7
diagnostic abnormalities in the echocardiography or any increased brain natriuretic peptide; group 3, pre-symptomatic treatment, in which PDA was confirmed by echocardiography, and PDA treatment was done without any clinical symptoms due to PDA; group 4, symptomatic treatment as PDA treatment was done because there were clinical symptoms due to PDA; and group 5, conservative treatment applying only conservative and supportive treatment without any pharmacologic or surgical intervention for PDA although there were clinical symptoms due to PDA. We defined the symptomatic PDA group as both symptomatic treatment group and conservative treatment group. Secondary ligation was defined as a patient receiving PDA ligation after the pharmacological treatment failed to close the PDA. Primary ligation was defined as a receiving PDA ligation without any pharmacological treatment for preterm PDA. PIH was defined as any maternal diagnosis of gestational hypertension, eclampsia or preeclampsia. HCA was defined as a documented case of CA shown by a placental biopsy.15 In Korea, almost all of the hospitals with NICUs routinely perform placental biopsies in the case of preterm deliveries. In our cohort, 83% of the study population received histologic confirmation of HCA. SGA was defined as a Z-score of less than the 10th percentile based on the KNN cohort. Delivery room resuscitation was defined when cardiac compression was done or medication was administered in the delivery room. Surfactant use was defined as any surfactant use for prophylactic or rescue treatment of RDS. Early sepsis was defined as a positive blood culture less than 7 days from birth with antibiotics use for more than 5 days. Hypotension was defined as hypotension requiring any inotropic or hydrocortisone use within 7 days after birth. Postnatal day of the first day of treatment for preterm PDA was defined as the difference 8
between the date of the first day of treatment and the date of birth. In this study, 0 day means less than 24 hours from birth.
2.3. Statistical analysis All the continuous variables are expressed as median and interquartile range (IQR), and the categorical variables are expressed as numbers and proportions. For the univariate analysis comparing the factors between symptomatic PDA and no PDA groups or between the secondary ligation and no secondary ligation groups, a generalized estimating equation (GEE)16 was done to consider correlation between twins from the same mother. To identify the risk factors of symptomatic PDA or secondary ligation, we performed the univariable and multivariable GEEs with adjustment for only GA. After that, all antenatal risk factors were included in the multivariable GEE. The final model was selected using backward elimination based on Quasi-likelihood Information Criterion (QIC) to avoid the multicollinearity problem.17 For the chosen model, predictability was evaluated with the area under the receiver operating characteristic curve (AUC), and goodness of fit was assessed using the Hosmer–Lemeshow test.18 The same methods were repeated in the subgroup analysis according to the GA group. The statistical analysis was done with R version 3.5.3. (http://www.r-project.org). P values less than 0.05 were considered statistically significant.
2.4. Statement of Ethics The KNN registry was approved by the institutional review board (IRB) at each participating 9
hospital, and informed consent to collect and use the clinical data and outcome of very–low– birth–weight infants was obtained from the parents at enrollment by the NICUs participating in the KNN. This study was exempted for IRB approval from the IRB of Seoul National University Boramae Hospital (IRB exemption number 07–2017–11).
3. RESULTS A total of 2,961 infants were included with 1,451 infants (49.0%) of symptomatic PDA. Among the infants with symptomatic PDA, 1,063 infants (73.3%) received pharmacological treatment for symptomatic PDA, and 333 (31.3%) received secondary ligation among the infants who received pharmacological treatment (Figure 1).
3.1. Perinatal risk factors of symptomatic PDA In the univariate analysis, infants with symptomatic PDA were younger and lighter at birth. More infants were female and had a lower 5 minute Apgar score in the symptomatic PDA group. There were fewer infants who received a complete course of ACS and the CRIB score was higher in the symptomatic PDA group. More infants received surfactant treatment in the symptomatic PDA group (Table 1). Multivariable analysis adjusting for only GA revealed that lower GA, female gender, CS, PIH, and surfactant use were significant risk factors of symptomatic PDA. A complete course of ACS and HCA lowered it. For the best model, GA, gender, CS, multiple pregnancy, PIH, HCA, complete course of ACS, and surfactant use were chosen [AUC = 0.696, 95% 10
confidence interval (CI) 0.675–0.717, Hosemer–Lemeshow test P–value 0.077]. In the multivariate analysis adjusting for those variables, lower GA, female gender, PIH, and surfactant use were significant risk factors of symptomatic PDA and a complete course of ACS decreased it (Table 2).
3.2. Perinatal risk factors of secondary PDA ligation In the univariate analysis, infants with secondary PDA ligation were younger and lighter at birth. The 5 minute Apgar score was lower, and CRIB score was higher in secondary ligation group (Table 3). In pharamcologic characteristics, there were no significant differences in the type of medication and the time to the first pharmacologic treatment between secondary ligation and no secondary ligation groups (Supplement 1). The median postnatal days of secondary ligation were 16 days from birth (IQR 9–25 days from birth). More infants received pharmacologic treatment by intravenous route in the secondary ligation group (P = 0.013). According to the multivariate analysis adjusted for GA only, lower GA and CS increased the risk of secondary ligation. For the best model, the GA, CS, and 5 minute Apgar score were chosen (AUC = 0.664, 95% CI 0.624–0.704, Hosemer–Lemeshow test P–value 0.258). In the multivariate analysis adjusting for those variables, only lower GA and CS increased the risk of secondary ligation (Table 4).
3.3. Subgroup analysis according to the GA (GA 22–25 weeks versus 26–29 weeks)
11
In infants with a GA of 22–25 weeks, there were no significant risk factors of symptomatic PDA after the multivariate analysis adjusting for GA, gender, CS, multiple pregnancy, PIH, HCA, complete course of ACS use, and surfactant use. Multivariate analysis in infants with a GA of 26–29 weeks showed that a lower GA at birth, female gender, multiple pregnancy, PIH, and surfactant use increased the risk of symptomatic PDA; however, HCA and a complete course of ACS use decreased it [AUC = 0.663, 95% CI 0.637–0.689, Hosemer– Lemeshow test P–value 0.118, Supplement 2]. For secondary ligation, in infants with a GA of 22–25 weeks, there were no significant risk factors after the multivariate analysis adjusting for the GA, CS, and 5 minute Apgar score. In infants with a GA of 26–29 weeks, only a lower GA at birth increased the risk of secondary ligation after the multivariate analysis [AUC = 0.614, 95% CI 0.568–0.659, Hosemer– Lemeshow test P–value 0.485, Supplement 3].
4. DISCUSSION In our study, many perinatal factors were associated with the development of symptomatic PDA; however, only lower GA and CS were significant risk factors for the failure of the pharmacologic treatment of preterm PDA. We suggest that lower GA, female gender, maternal PIH, and surfactant use are significant risk factors of symptomatic PDA, and ACS use is protective against the development of symptomatic PDA. HCA decreased the risk of symptomatic PDA only in GA 26–29 weeks group. In the multivariate analysis, we included GA as a continous variable (groups) because there was no significant difference when we divided GA variable into two or three groups. 12
Furthermore, according to the QIC criterion, the model with GA as a continous variable was better than that with GA groups. We performed subgroup analysis according to the GA to compensate for the non-linear effect of GA. There have been many reports on the risk factors of preterm PDA with a small study population2–5 and lower GA and birthweight were the most powerful risk factors of symptomatic PDA. A recent large observational study suggested that maternal antepartum hemorrhage, RDS, birthweight, female gender, GA and 5 minute Apgar score were significant risk factors of preterm PDA.4 For risk factors of pharmacologic response, lower GA, ACS, respiratory distress, and race were independent risk factors for persistent PDA after indomethacin treatment.2 Although many large cohort studies have suggested the adverse effect of male gender on the mortality and major neonatal outcomes in preterm infants,19,20 female gender was a significant risk factor of symptomatic PDA in our study and in another report.4 However, in other studies,21, 22 sex was not a significant risk factor of preterm PDA. Pourarian S et al23 showed that male gender might affect the refractory drug response to preterm PDA. Further studies are needed to ascertain the effect of gender difference on preterm symptomatic PDA and pharmacologic response to PDA treatment. RDS and mechanical ventilation are known to be potent risk factors of PDA requiring treatment.22,24 Surfactant use in infants with RDS can decrease the pulmonary resistance rapidly, which can increase the left–to–right shunting through preterm PDA and the clinical symptoms due to PDA. Actually, KNN did not collect the initial respiratory status including ventilator care within the first several days; thus we could not judge the effect of mechanical
13
ventilation or initial respiratory status on symptomatic PDA and pharmacologic response to PDA treatment. There have been many studies showing that ACS use reduced the symptomatic preterm PDA.25–27 In the lamb model, glucocorticoid treatment decreased the incidence of PDA in premature infants by affecting the interaction of prostaglandin E2 with the ductal tissue.28 ACS also reduces RDS, which is a potent risk factor of preterm PDA. There are reports that preeclampsia is a risk factor of major morbidities associated with preterm birth including bronchopulmonary dysplasia (BPD),29,30 necrotizing enterocolitis (NEC),31,32 and retinopathy of prematurity33; however, there are no reports about the association between PIH or preeclampsia and preterm symptomatic PDA. Actually, PIH and preeclampsia do not coincide exactly, and only PIH, not SGA, was a statistically significant risk factor of symptomatic PDA in our study. Studies about the association between preeclampsia/eclampsia and preterm symptomatic PDA are needed. There are conflicting reports on the association between HCA and symptomatic PDA8,9 or the treatment failure of the pharmacologic treatment.10 In our study, HCA was a protective factor for the development of symptomatic PDA in GA 26–29 weeks group, and there was no association with the performance of secondary ligation. In fact, HCA has been known to be associated with reduced RDS,34,35 which is known to be a significant risk factor of preterm PDA,24 so this can be one of the reasons why HCA is a protective factor for symptomatic PDA in our study. In our study, only lower GA and CS were significant risk factors of a pharmacologic response. Although there were no reports on the association between CS and the 14
pharmacologic response to PDA treatment, both CS and the prophylactic use of antibiotics in preparation of the CS can affect the gut microbiome of infants, which can be a risk factor of NEC.36,37 We did not include NEC in the risk factor analysis because we could not know the order of events between NEC and symptomatic PDA or secondary ligation. Furthermore, reduced intrapartum exposure to mechanical forces and stress hormones during CS can skip the important physiologic stimuli provided by vaginal delivery.37 The strength of our study is its population–based cohort study design with a large patient number, which represents about 80% of very–low–birth–weight infants delivered in about 80% of all the NICUs in South Korea. Moreover, the KNN database offers data on symptomatic PDA defined according to a previously published article14 and a more detailed treatment policy (prophylactic, pre-symptomatic, symptomatic, and conservative treatment),13 which is different from other nationwide cohorts. Second, we could collect information on HCA from KNN using the known histopathologic definition.15 We also defined SGA using the Z-score based on our own study population. The clear definition of such important antenatal risk factors can make our study results more accurate. Our study has some limitations. First, our study could not show the detailed information of echocardiography from KNN cohort. Second, although data about PDA group by therapeutic strategies for PDA in KNN were collected according to the previously defined criteria, the possibility of misclassification due to the differences in the treatment strategies and the timing of echocardiographic follow–up in each hospital cannot be totally excluded. Third, although the missing value for PIH was 0 and we were able to get the placental biopsy results from 83% of the study population, a reporting bias may still exist. Fourth, we were only able to collect the information about PIH, but not about preelampsia/eclampsia or the degree/ 15
severity of preeclampsia. Fifth, we did not assess the association between such perinatal factors, symptomatic PDA, and long–term outcomes such as BPD or pulmonary hypertension. Sixth, we could not get more information including the duration of ductal opening, the date of ductal closure and reopening, and the number of courses/dosage of pharmacologic treatment. Further studies are needed focusing on the association between perinatal factors and the duration of ductal patency. Seventh, we tried to make an efficient model to predict symptomatic PDA or secondary ligation in our cohort; however, because the highest AUC value did not exceed 80, we did not suggest any model using our cohort. In our study using a nationwide population based cohort, lower GA, female gender, maternal PIH, and surfactant use were significant risk factors of symptomatic PDA. In contrast, ACS use decreased it. HCA decreased the risk of symptomatic PDA in more mature preterm infants. Only lower GA and CS increased the risk of secondary ligation. Close follow–up with clinical assessment of PDA symptoms should be done in preterm infants with maternal PIH.
Conflicts of Interest Statement All authors have no conflicts of interest to disclose
Acknowledgements This research was supported by a fund (2016–ER6307–00#) by Research of Korea Centers for Disease Control and Prevention.
16
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21
Table 1 Demographic, antenatal, and perinatal characteristics of the study population according to the presence of symptomatic patent ductus arteriosus. Symptomatic PDA
P–value
Yes
No
(N = 1,451, 49.0%)
(N = 1,510, 51.0%)
GA at birth (weeks)
26.6 [25.3, 28.1]
28.3 [26.7, 29.1]
<0.001
Birth weight (g)
900 [720, 1,090]
1,090 [880, 1,270]
<0.001
Male gender
712 (49.1%)
825 (54.6%)
0.002
Cesarean section
1,046 (72.1%)
1,068 (70.7%)
0.432
Multiple pregnancy
507 (34.9%)
472 (31.3%)
0.126
Gestational diabetes mellitus
87 (6.0%)
107 (7.1%)
0.076
Histologic chorioamnionitis
509 (42.5%)
555 (44.0%)
0.654
PIH
174 (12.0%)
157 (10.4%)
0.155
SGA
163 (11.2%)
167 (11.1%)
0.999
Complete course of ACS
613 (42.2%)
749 (49.6%)
<0.001
Delivery room resuscitation
97 (6.9%)
80 (5.6%)
0.115
5 minute Apgar score
<0.001
22
0–3
135 (9.4%)
93 (6.2%)
4–6
570 (39.6%)
489 (32.5%)
7–10
735 (51.0%)
923 (61.3%)
CRIB-II score
11 [9, 14]
9 [7, 11]
<0.001
Surfactant use
1,431 (98.6%)
1,421 (94.1%)
<0.001
Early sepsis (<7 postnatal days)
100 (6.9%)
78 (5.2%)
0.119
iNO use < 7 postnatal days
76 (5.2%)
30 (2.0%)
<0.001
Hypotension(< 7 postnatal days)
610 (42.0%)
322 (21.3%)
<0.001
GA; gestational age, PIH; pregnancy–induced hypertension, SGA; small for gestational age, ACS; antenatal corticosteroid use, CRIB; clinical risk index for babies, iNO; inhaled nitric oxide
23
Table 2 Perinatal risk factors of symptomatic patent ductus arteriosus by univariate and multivariate analyses. Symptomatic PDA Univariate analysis
Multivariate analysis 1*
Multivariate analysis 2†
uOR
95% CI
P–value
aOR
95% CI
P–value
aOR
95% CI
P–value
GA at birth (per week)
0.70
(0.67, 0.74)
<0.001
0.70
(0.67, 0.74)
<0.001
0.69
(0.65, 0.73)
<0.001
Male gender
0.80
(0.69, 0.92)
0.002
0.78
(0.67, 0.91)
0.001
0.77
(0.65, 0.91)
0.002
Ceserean section
1.07
(0.91, 1.26)
0.432
1.27
(1.07, 1.51)
0.006
1.17
(0.97, 1.42)
0.107
Multiple pregnancy
1.14
(0.96, 1.36)
0.126
1.13
(0.95, 1.36)
0.174
1.23
(0.99, 1.51)
0.052
Gestational diabetes mellitus
0.76
(0.56, 1.03)
0.076
0.99
(0.72, 1.35)
0.940
PIH
1.18
(0.94, 1.49)
0.155
1.59
(1.24, 2.04)
<0.001
1.56
(1.17, 2.08)
0.002
24
Histologic chorioamnionitis
0.96
(0.82, 1.14)
0.654
0.76
(0.63, 0.90)
0.002
SGA
1.00
(0.80, 1.26)
0.999
1.04
(0.81, 1.33)
0.754
Delivery room resuscitation
1.27
(0.94, 1.71)
0.115
0.92
(0.66, 1.27)
0.598
Complete course of ACS
0.76
(0.65, 0.88)
<0.001
0.79
(0.68, 0.93)
0.004
0–3 group
1.82
(1.37, 2.40)
<0.001
0.99
(0.72, 1.35)
0.951
4–6 group
1.43
(1.22, 1.67)
<0.001
1.09
(0.92, 1.29)
0.315
Surfactant use
4.51
(2.78, 7.34)
<0.001
2.85
(1.73, 4.71)
<0.001
0.83
(0.69, 1.00)
0.053
0.82
(0.69, 0.98)
0.030
2.62
(1.54, 4.46)
<0.001
5 minute Apgar score group (ref. 7–10 group)
*
adjusted for GA
25
†
adjusted for GA, male gender, cesarean section, multiple pregnancy, PIH, histologic chorioamnionitis, complete course of ACS use, and
surfactant use uOR: unadjusted odds ratio, aOR; adjusted odds ratio, GA; gestational age, PIH; pregnancy–induced hypertension, SGA; small for gestational age, ACS; antenatal corticosteroid use
26
Table 3 Demographic, antenatal, and perinatal characteristics of the preterm infants who received pharmacologic treatment for symptomatic patent ductus arteriosus according to the presence of secondary ligation. Secondary ligation
P–value
Yes
No
(N = 333, 31.3%)
(N = 730, 68.7%)
GA at birth (weeks)
26.1 [25, 27.4]
27.3 [26.0, 28.6]
<0.001
Birth weight (g)
840 [710, 1,000]
980 [810, 1,163]
<0.001
Male gender
151 (45.3%)
362 (49.6%)
0.254
Cesarean section
247 (74.2%)
520 (71.2%)
0.395
Multiple pregnancy
105 (31.5%)
254 (34.8%)
0.367
Gestational diabetes mellitus
16 (4.8%)
50 (6.8%)
0.271
Histologic chorioamnionitis
116 (45.3%)
251 (41.8%)
0.403
PIH
36 (10.8%)
93 (12.7%)
0.354
SGA
32 (9.6%)
73 (10.0%)
0.844
Complete course of ACS
142 (42.6%)
287 (39.3%)
0.389
Delivery room resuscitation
22 (6.9%)
39 (5.6%)
0.466
27
5 minute Apgar score
0.002
0–3
40 (12.1%)
46 (6.4%)
4–6
142 (42.9%)
281 (38.9%)
7–10
149 (45.0%)
149 (45.0%)
CRIB-II score
12 [10, 14]
10 [8, 12]
<0.001
Surfactant use
331 (99.4%)
714 (97.8%)
0.074
Early sepsis<7 postnatal days
28 (8.4%)
40 (5.5%)
0.087
iNO use < 7 postnatal days
11 (3.3%)
18 (2.5%)
0.405
Hypotension(< 7 postnatal days)
181 (54.4%)
235 (32.2%)
<0.001
Pulmonary hemorrhage
46 (13.8%)
70 (9.6%)
0.028
GA; gestational age, PIH; pregnancy–induced hypertension, SGA; small for gestational age, ACS; antenatal corticosteroid use, CRIB; clinical risk index for babies, iNO; inhaled nitric oxide
28
Table 4 Perinatal risk factors of secondary ligation in infants who received pharmacologic treatment for symptomatic patent ductus arteriosus by univariate and multivariate analyses. Secondary ligation Univariate analysis
Multivariate analysis 1*
Multivariate analysis 2†
uOR
95% CI
P–value
aOR
95% CI
P–value
aOR
95% CI
P–value
GA at birth (per week)
0.74
(0.68, 0.80)
<0.001
0.74
(0.68, 0.80)
<0.001
0.73
(0.67, 0.80)
<0.001
Male gender
0.86
(0.66, 1.12)
0.254
0.82
(0.63, 1.07)
0.151
Ceserean section
1.14
(0.85, 1.52)
0.395
1.42
(1.04, 1.93)
0.026
1.40
(1.03, 1.91)
0.033
Multiple pregnancy
0.87
(0.65, 1.17)
0.367
0.93
(0.68, 1.26)
0.631
Gestational diabetes mellitus
0.71
(0.39, 1.30)
0.271
0.89
(0.49, 1.64)
0.713
PIH
0.82
(0.54, 1.24)
0.354
1.15
(0.75, 1.76)
0.512
29
Histologic chorioamnionitis
1.14
(0.84, 1.54)
0.403
0.89
(0.64, 1.23)
0.470
SGA
0.96
(0.62, 1.48)
0.844
1.02
(0.64, 1.62)
0.942
Delivery room resuscitation
1.23
(0.71, 2.12)
0.466
0.95
(0.52, 1.73)
0.861
Complete course of ACS
1.13
(0.86, 1.48)
0.389
1.15
(0.87, 1.53)
0.334
0–3 group
2.26
(1.41, 3.61)
0.001
1.51
(0.91, 2.51)
0.110
1.51
(0.91, 2.53)
0.114
4–6 group
1.35
(1.02, 1.78)
0.037
1.11
(0.83, 1.49)
0.485
1.12
(0.84, 1.50)
0.450
Surfactant use
3.34
(0.89, 12.57)
0.074
2.04
(0.54, 7.64)
0.291
5 minute Apgar score group (ref. 7–10 group)
*
adjusted for GA
†
adjusted for GA, cesarean section, and 5 minute Apgar score group
30
uOR: unadjusted odds ratio, aOR; adjusted odds ratio, GA; gestational age, PIH; pregnancy–induced hypertension, SGA; small for gestational age, ACS; antenatal corticosteroid use
31
Figure Legends Figure 1 Study population identified with subsequent flowchart of the study. GA: gestational age at birth PDA: patent ductus arteriosus
32