Impact of patent ductus arteriosus treatment on neonatal outcomes in preterm infants with or without perinatal acidosis: a nationwide cohort study

Abstract

Background

Perinatal acidosis is common in preterm infants and is associated with adverse short-term outcomes. However, its role in guiding the management of patent ductus arteriosus (PDA) remains unclear. This study aimed to evaluate the PDA treatment patterns and neonatal outcomes in preterm infants with and without perinatal acidosis.

Methods

We conducted a nationwide cohort study using the Korean Neonatal Network registry. Very low birth weight infants born before 30 weeks’ gestation between 2015 and 2021 were included. Perinatal acidosis was defined as a blood pH < 7.20 and a base deficit < 10 mEq/L within the first hour after birth. Multivariate logistic regression was used to evaluate the association between PDA treatment and neonatal outcomes stratified by acidosis status.

Results

Among 6,158 infants, 441 (7.2%) experienced perinatal acidosis. The incidence of PDA and its treatment rates did not significantly differ between infants with and without perinatal acidosis. After adjusting for confounders, PDA treatment was associated with a significantly reduced risk of mortality, and the composite outcome of bronchopulmonary dysplasia (BPD) or death before 36 weeks’ postmenstrual age, irrespective of acidosis status. However, PDA treatment increased the risk of BPD in both groups.

Conclusions

PDA treatment was associated with improved survival but increased BPD risk in preterm infants regardless of perinatal acid-base status. Perinatal acidosis should not be considered a contraindication to PDA treatment. These findings support individualized, physiology-guided PDA management in preterm infants.

Background

Impaired feto-maternal gas exchange during the perinatal period leads to progressive hypoxia and acidosis, depending on the extent and duration of this interruption [1, 2]. In particular, the transition to postnatal circulation is unfavorable for preterm infants with antenatal and intrapartum risk factors and immature organs, who may experience considerable acid‒base disturbances at birth [3]. Although perinatal acidosis in preterm infants lacks precise biochemical criteria [4], it plays a critical role in predicting mortality and morbidity in neonatal intensive care units (NICUs) [5, 6]. Specifically, perinatal acidosis is linked to adverse neonatal outcomes, including respiratory distress, intracranial hemorrhage, hypoxic–ischemic encephalopathy, necrotizing enterocolitis (NEC), and death [7–10].

Patent ductus arteriosus (PDA) is common in preterm infants and occurs in approximately 60–70% of infants born at < 30 weeks of gestation after the first 3 postnatal days [11]. PDA in preterm infants can have significant clinical consequences, such as excessive pulmonary blood flow and compromised systemic perfusion [12]. These conditions are associated with increased risks of mortality and morbidities, including bronchopulmonary dysplasia (BPD), NEC, intraventricular hemorrhage, and periventricular leukomalacia [13]. Pharmacological treatment with cyclooxygenase inhibitors has been widely used for PDA in preterm infants [14, 15]. However, meta-analyses of randomized controlled trials have not demonstrated improved neonatal outcomes with PDA treatment [16, 17]. In addition, there is significant variation in PDA management across NICUs that have recently considered closure of PDA [18, 19].

Given that preterm infants with perinatal acidosis have impaired organ function and are vulnerable to complications during episodes of hypoxia and/or hypoperfusion [20], it is inevitably burdensome to treat PDA in the early stages of life. This makes PDA challenging from the perspective of clinical management during the first few days of life in preterm infants with perinatal acidosis. To our knowledge, no large-scale studies have evaluated the associations between PDA treatment and neonatal outcomes in preterm infants with perinatal acidosis.

This study compares the treatment of PDA in preterm infants with and without perinatal acidosis using a large cohort from the Korean Neonatal Network (KNN). We also examined the associations between PDA treatment and neonatal outcomes in preterm infants with/without perinatal acidosis.

Methods

Study population and design

This was a cohort study using prospectively collected data for very low birth weight (VLBW) infants registered in the KNN registry who were born at 23⁺⁰–29⁺⁶ weeks gestational age (GA) between January 2015 and December 2021. The KNN is a national, multicenter, web-based registry for VLBW infants that prospectively collects demographic and clinical data from 70 participating NICUs using standardized operating procedures [21]. The KNN registry includes approximately 70% of all VLBW infants born in the Republic of Korea [21]. We excluded infants with significant congenital anomalies, missing blood gas data within the first hour of life, unknown PDA treatment policies, or prophylactic PDA treatment. Additionally, infants who died within 3 days after birth were excluded, as PDA treatment might not be adequately evaluated within 3 days of birth.

Infants were divided into two groups according to blood gas values collected within the first hour of birth. The perinatal acidosis group included patients with a blood pH < 7.20 and base deficit < 10 mEq/L, which is consistent with the findings of previous studies of extremely preterm infants [22–24]. First-hour blood gas analysis is routinely performed for all VLBW infants irrespective of perinatal distress in the Korean NICU participating in the KNN. Blood gas values obtained within the first hour after birth were prioritized from neonatal arterial, venous, or capillary samples. If such samples were unavailable, umbilical arterial blood gas results collected immediately after delivery were entered, whereas umbilical venous samples or those with an unclear sampling site were not accepted.

We compared perinatal characteristics, PDA incidence, and PDA treatment between the perinatal acidosis and control groups. We also examined the associations between PDA treatment and neonatal outcomes in preterm infants with/without perinatal acidosis.

Data collection

The maternal data for this study included hypertension, diabetes, histological chorioamnionitis, and antenatal corticosteroid use. Neonatal data included GA, birth weight, sex, multiple gestation, delivery mode, Apgar scores at 1 and 5 min, and clinical risk index for babies (CRIB)–II score [25]. Clinical information included respiratory distress syndrome (RDS), PDA treatment, BPD, BPD or death before 36 weeks postmenstrual age (PMA), and NEC was collected.

Definitions

We applied the diagnostic and treatment guidelines for PDA in the Republic of Korea in accordance with previously published studies [26, 27]. The “no PDA group” included infants whose PDA had closed spontaneously or showed minimal ductal shunting before any signs and symptoms attributable to PDA appeared [26]. The “PDA group” included infants with echocardiographically confirmed PDA and was subdivided into a “PDA treatment” group and “PDA non-treatment” group. In clinical practice across Korean NICUs, the decision to initiate PDA treatment was based on echocardiographic confirmation of ductal patency and the presence of clinical symptoms suggesting hemodynamic significance. The presence of clinical symptoms attributable to PDA was defined when at least two of the following five criteria were met: (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 chest radiograph. Treatment decisions were made by the attending neonatologist at each center, based on a combination of echocardiographic findings and clinical criteria, in accordance with previous Korean studies [26, 27]. PDA treatment was defined as pharmacological and/or surgical ligation of the PDA during NICU hospitalization.

Maternal hypertension included preexisting and/or pregnancy-induced hypertension [28]. Antenatal steroid administration was defined as the successful completion of a dexamethasone or betamethasone regimen within 7 days before delivery [29]. RDS was defined as the presence of acute respiratory insufficiency (grunting, retraction, increased oxygen requirement, and tachypnea) with typical radiological findings after birth, requiring surfactant replacement therapy. BPD was diagnosed as oxygen dependence or respiratory support at 36 weeks’ PMA or NICU discharge, corresponding to moderate to severe BPD, using the severity-based definition of BPD in the National Institutes of Health consensus [30]. NEC was defined as stage 2 or higher NEC according to the modified Bell’s staging criteria [31].

Statistical analysis

Continuous variables are expressed as means ± standard deviations or as medians (interquartile ranges (IQR)). Categorical variables are expressed as numbers and proportions. Continuous variables were compared between groups using Student’s t test for normally distributed variables and the Mann–Whitney U test for non-normally distributed variables. Categorical variables were compared using Pearson’s chi-square test. Multivariate logistic regression analysis was performed to adjust for potential confounding variables, and adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were calculated. Birth weight was excluded in this statistical analysis due to its high correlation with GA. Statistical analyses were performed using SPSS software (version 27.0; IBM Corp., Armonk, NY, USA). Significance was set at p < 0.05.

Results

Patient population

Information on the study population is provided in Fig. 1. A total of 9,391 VLBW infants born before 30 weeks’ GA were registered with the KNN between January 2015 and December 2021. Among these infants, 266 with significant congenital anomalies, 2,488 with missing blood gas data within the first hour of life, 163 with unknown for PDA treatment policies, 133 who received prophylactic PDA treatment, and 183 who died within 3 days after birth were excluded.

Fig. 1.

Flow diagram of the study population. PDA, patent ductus arteriosus

A total of 6,158 VLBW infants were included in the analysis. The mean GA was 27⁺² ± 1⁺⁵ weeks, and the mean birth weight was 989 ± 261 g. Of these 6,158 infants, 441 (7.2%) were assigned to the perinatal acidosis group and 5,717 (92.8%) to the control group.

Comparison of baseline characteristics between the perinatal acidosis and control groups

Baseline characteristics were compared between the perinatal acidosis and control groups (Table 1). Mothers of infants with perinatal acidosis had a lower rate of antenatal steroid use and fewer multiple gestations than those in the control group. Compared with the control group, infants with perinatal acidosis were born at a lower mean GA and had lower birth weights, lower 1- and 5-min Apgar scores, and higher rates of RDS. The median CRIB-II score was significantly greater in the perinatal acidosis group than in the control group (17.9 ± 7.1 vs. 10.6 ± 4.1, p < 0.001), indicating greater illness severity among infants with perinatal acidosis. After adjustments for potential confounders were made, the incidence rate of PDA was not significantly different between the groups (aOR, 1.164; 95% CI 0.941–1.439, p = 0.162).

Table 1.

Comparison of baseline characteristics between the perinatal acidosis and control groups

	Control group N = 5,717	Perinatal acidosis group N = 441		p value	Adjusted OR* (95% CI)	Adjusted p value*
Maternal hypertension (%)	996 (17.4)	89 (20.2)	0.143
Maternal diabetes (%)	639 (11.2)	53 (12.0)	0.590
Histologic chorioamnionitis (%)	2,175 (38.0)	169 (38.3)	0.404
Antenatal corticosteroids (%)	2,845 (49.8)	120 (27.2)	< 0.001
Cesarean section (%)	4,480 (78.4)	336 (76.2)	0.287
Gestational age (weeks+days)	27+2 ± 1+5	26+4 ± 2+0	< 0.001
Birth weight (g)	998 ± 259	887 ± 267	< 0.001
Male (%)	2,974 (52.0)	249 (56.5)	0.072
Multiple gestation (%)	1,978 (34.6)	94 (21.3)	< 0.001
1-min Apgar score	4.5 ± 1.9	2.8 ± 1.8	< 0.001
5-min Apgar score	6.8 ± 1.7	5.0 ± 2.2	< 0.001
CRIB-II score	17.9 ± 7.1	10.6 ± 4.1	< 0.001
RDS (%)	5,260 (92.0)	433 (98.2)	< 0.001
PDA (%)	2,939 (51.4)	272 (61.7)	< 0.001		1.164 (0.941–1.439)	0.162

Values are presented as means ± standard deviations, or numbers (%)

^*ORs and p values were calculated using logistic regression analysis adjusted for gestational age, antenatal steroids, multiple gestation, and RDS

OR Odds ratio, CI Confidence interval, CRIB-II Clinical risk index for babies, RDS Respiratory distress syndrome, PDA Patent ductus arteriosus

Comparison of PDA treatment between the perinatal acidosis and control groups

Data on PDA treatment in the perinatal acidosis and control groups are presented in Table 2. After adjusting for potential confounders, the rate of PDA treatment did not differ significantly between the groups (aOR, 1.056; 95% CI 0.862–1.293, p = 0.599). Similarly, no significant differences were observed in the rates of pharmacological treatment for PDA between the groups (aOR, 0.960; 95% CI 0.784–1.176, p = 0.696). No significant difference in surgical ligation of the PDA was noted between the groups (aOR, 1.028; 95% CI 0.783–1.349, p = 0.841). The median postnatal age at first pharmacological treatment for PDA and surgical ligation of the PDA were not significantly different between the groups.

Table 2.

Comparison of PDA treatment between the perinatal acidosis and control groups

		Control group N = 5,717		Perinatal acidosis group N = 441		p value		Adjusted OR* (95% CI)		Adjusted p value*
PDA treatment (%)		2,485 (43.5)		222 (50.3)		0.005		1.056 (0.862–1.293)		0.599
Pharmacological treatment for PDA (%)		2,255 (39.4)		190 (43.1)		0.132		0.960 (0.784–1.176)		0.696
Surgical ligation of the PDA (%)		751 (13.1)		76 (17.2)		0.015		1.028 (0.783–1.349)		0.841
Age at the start of pharmacological treatment for PDA, median (IQR)		4 (2–9)		5 (2–11)		0.168
Age at the start of surgical ligation of the PDA, median (IQR)		18 (12–28)		18 (11–33)		0.821

Values are presented as means ± standard deviations or numbers (%)

^*The ORs and p values were calculated using logistic regression analysis adjusted for gestational age, antenatal steroids, multiple gestation, and RDS

OR Odds ratio, CI Confidence interval, PDA Patent ductus arteriosus, IQR Interquartile range, RDS Respiratory distress syndrome

Association of PDA treatment with neonatal outcomes in infants with perinatal acidosis

In the perinatal acidosis group, 272 (61.7%) infants were diagnosed with PDA. Among them, 222 (81.6%) received PDA treatment, and 50 (18.4%) did not receive treatment.

Compared with the non-treatment group, the PDA treatment group had significantly lower mortality (12.6% vs. 34.0%, p < 0.001), and BPD or death before 36 weeks’ PMA (20.7% vs. 36.0%, p = 0.027) but a higher incidence of BPD (61.2% vs. 38.7%, p = 0.019) (Table 3). After adjustment for GA, sex, antenatal steroids, multiple gestations, and RDS, PDA treatment was independently associated with a lower risk of death (aOR 0.190; 95% CI 0.081–0.447, p < 0.001), and BPD or death before 36 weeks’ PMA (aOR 0.435; 95% CI 0.211–0.897, p = 0.024), but the odds of BPD (aOR 3.140; 95% CI 1.590–6.202, p = 0.001) increased significantly in infants who received PDA treatment.

Table 3.

Association of PDA treatment with neonatal outcomes among infants with perinatal acidosis

	PDA non-treatment N = 50	PDA treatment N = 222	p value	Adjusted OR* (95% CI)	Adjusted p value*
BPD (%)	12 (38.7)	115 (61.2)	0.019	3.140 (1.590–6.202)	0.001
BPD or death at 36 weeks’ PMA (%)	18 (36.0)	46 (20.7)	0.027	0.435 (0.211–0.897)	0.024
Death before 36 weeks’ PMA (%)	17 (34.0)	28 (12.6)	< 0.001	0.190 (0.081–0.447)	< 0.001
NEC (≥ stage II) (%)	2 (6.5)	26 (13.8)	0.254	1.410 (0.535–3.715)	0.487

^*ORs and p values were calculated using logistic regression analysis adjusted for gestational age, sex, antenatal steroids, multiple gestation, and RDS

PDA Patent ductus arteriosus, OR Odds ratio, CI Confidence interval, BPD Bronchopulmonary dysplasia, PMA Postmenstrual age, NEC Necrotizing enterocolitis, NICU Neonatal intensive care unit, RDS Respiratory distress syndrome

Association of PDA treatment with neonatal outcomes in infants without perinatal acidosis

In the control group, 2,939 (51.4%) infants were diagnosed with PDA. Among them, 2,485 (84.5%) received PDA treatment, and 454 (15.4%) did not.

Compared with the non-treatment group, the PDA treatment group had significantly lower mortality (9.8% vs. 23.3%, p < 0.001), NEC (10.4% vs. 15.2%, p = 0.003), and BPD or death before 36 weeks’ PMA (14.5% vs. 28.2%, p < 0.001) but a higher incidence of BPD (48.1% vs. 40.1%, p = 0.002) (Table 4). After adjustment for GA, sex, antenatal steroids, multiple gestations, and RDS, PDA treatment was independently associated with a lower risk of death (aOR 0.425; 95% CI 0.323–0.559, p < 0.001), and BPD or death before 36 weeks’ PMA (aOR 0.489; 95% CI 0.383–0.623, p < 0.001), but the odds of BPD (aOR 1.590; 95% CI 1.289–1.963, p < 0.001) increased significantly in infants who received PDA treatment.

Table 4.

Association between PDA treatment and neonatal outcomes among infants without perinatal acidosis

	PDA non-treatment N = 454	PDA treatment N = 2485	p value	Adjusted OR* (95% CI)	Adjusted p value*
BPD (%)	182 (40.1)	1195 (48.1)	0.002	1.590 (1.289–1.963)	< 0.001
BPD or death at 36 weeks’ PMA (%)	128 (28.2)	361 (14.5)	< 0.001	0.489 (0.383–0.623)	< 0.001
Death before 36 weeks’ PMA (%)	106 (23.3)	244 (9.8)	< 0.001	0.425 (0.323–0.559)	< 0.001
NEC (≥ stage II) (%)	69 (15.2)	259 (10.4)	0.003	0.765 (0.569–1.028)	0.076

^*ORs and p values were calculated using logistic regression analysis adjusted for gestational age, sex, antenatal steroids, multiple gestation, and RDS

PDA Patent ductus arteriosus, OR Odds ratio, CI Confidence interval, BPD Bronchopulmonary dysplasia, PMA Postmenstrual age, NEC Necrotizing enterocolitis, NICU Neonatal intensive care unit, RDS Respiratory distress syndrome

Discussion

In this nationwide, population-based cohort study of infants born before 30 weeks’ gestation, we found that the incidence of PDA and the rate of its treatment did not significantly differ between infants with and without perinatal acidosis. Furthermore, no significant differences were found in the rates of pharmacological or surgical PDA treatment after adjusting for confounding factors. PDA treatment was associated with a significantly reduced risk of mortality, and the composite outcome of BPD or death before 36 weeks’ PMA, irrespective of acidosis status. However, PDA treatment was also associated with an increased risk of BPD in both groups.

Compared with those in the control group, the infants in the perinatal acidosis group were more premature, had lower birth weights and Apgar scores, and were more likely to develop RDS. In addition, antenatal steroid administration was less common among mothers of infants in the perinatal acidosis group, likely reflecting the emergent nature of deliveries in this population. These findings are consistent with previous studies showing that infants with perinatal acidosis have lower GA, birth weight, and Apgar scores, reduced exposure to antenatal steroids, and a higher incidence of RDS [8, 32]. These factors suggest that perinatal acidosis serves as a marker of both acute intrapartum compromise and overall perinatal instability, which can influence both postnatal adaptation and clinical decisions such as PDA management.

A left-to-right ductal shunt of the PDA causes pulmonary hyperperfusion and systemic hypoperfusion and thus can have adverse effects on preterm infants [11]. Risk factors, such as lower GA and RDS, are well-established predictors of PDA [27]. More mature preterm infants are likely to experience spontaneous ductal closure and fewer hemodynamic effects from PDA [33]. In this study, despite a higher prevalence of such risk factors in the perinatal acidosis group, the incidence of PDA and its treatment were not significantly different between the two groups; this may reflect the multifactorial nature of PDA pathophysiology, where perinatal acidosis itself may not be a sufficient or independent determinant of ductal patency.

Our study demonstrated that PDA treatment was associated with a significant reduction in mortality in both the perinatal acidosis and control groups. These findings support previous reports suggesting that PDA closure can alleviate systemic hypoperfusion, reduce the risk of pulmonary hemorrhage, and ultimately improve survival [19, 34]. The therapeutic benefit is likely mediated by improved hemodynamic stability resulting from a reduction in diastolic runoff and enhancement of organ perfusion, particularly in preterm infants with limited cardiovascular reserve. However, meta-analyses of randomized controlled trials have not shown an improvement in mortality with PDA treatment [16, 17]. This discrepancy can be attributed to heterogeneity in study populations, variations in the timing of intervention, and differing clinical criteria for initiating PDA treatment.

Despite reduced mortality, PDA treatment was associated with an increased risk of BPD in both groups. This finding is consistent with previous studies and likely reflects both underlying disease severity and treatment-related factors, including prolonged mechanical ventilation and oxygen exposure [12, 13]. Hemodynamically significant PDA can lead to pulmonary hyperperfusion, increased lung water content, and impaired gas exchange, all of which can predispose preterm infants to ventilator dependence and subsequent development of BPD. In addition, the increased BPD risk may reflect survivor bias, whereby treated infants who survive longer are more likely to develop BPD.

However, our study also showed that PDA treatment was associated with a significantly lower rate of the composite outcome of BPD or death before 36 weeks’ PMA. This composite outcome accounts for competing risks between early mortality and long-term respiratory morbidity. The reduction in this composite outcome suggests that PDA treatment may contribute to both improved survival and potentially BPD in a subset of preterm infants.

Despite initial concerns that perinatal acidosis might predispose infants to greater treatment-related complications, we found no significant increase in NEC or mortality attributable to PDA treatment. These findings suggest that PDA treatment is not only safe but may confer greater relative benefit in infants with perinatal acidosis, whose compromised systemic perfusion places them at heightened risk of end-organ dysfunction. Rather than using perinatal acidosis as a reason to delay or avoid treatment, clinicians should consider individualized, physiology-based approaches that incorporate echocardiographic evidence of hemodynamic significance, perfusion indices, and clinical signs of compromised systemic blood flow.

The strengths of this study include the use of a large, nationwide, prospectively collected cohort and the application of consistent biochemical criteria for defining perinatal acidosis. However, several limitations must be acknowledged. First, we did not collect detailed echocardiographic.

parameters such as ductal diameter, left atrium-to-aortic root ratio, or flow patterns. Therefore, we could not stratify PDA by its hemodynamic significance, which would have facilitated the identification of the target population for treatment. Prospective studies incorporating these parameters would enable more precise stratification of treatment benefit. Second, we analyzed only the short-term effects of PDA management during the neonatal period. Long-term neurodevelopmental and pulmonary outcomes were not evaluated because these data were not collected in the KNN registry. This limitation restricts our ability to fully assess the long-term risks and benefits of PDA treatment. Future studies incorporating standardized neurodevelopmental follow-up and long-term pulmonary assessment are essential to determine the broader impact of PDA treatment strategies in this vulnerable population. Third, center-level practice variability could not be controlled, because the registry anonymized institutional data; this may have influenced treatment thresholds.

Despite these limitations, this is the most extensive study to date examining the association between PDA treatment and neonatal outcomes stratified by perinatal acid–base status in preterm infants. These findings provide valuable insight into risk stratification and therapeutic decision-making in this vulnerable population.

Conclusions

In this nationwide cohort of preterm infants born before 30 weeks’ gestation, perinatal acidosis was not associated with significant differences in the incidence or treatment of PDA. PDA treatment was independently associated with reduced mortality and a lower risk of the composite outcome of BPD or death at 36 weeks’ PMA, regardless of perinatal acid‒base status. Although the risk of BPD increased among treated infants, no excess NEC or other significant complications were observed. These findings suggest that perinatal acidosis should not be considered a contraindication to PDA treatment and may help identify infants who benefit most from early intervention.

Abbreviations

NICU

Neonatal intensive care unit

NEC

Necrotizing enterocolitis

PDA

Patent ductus arteriosus

BPD

Bronchopulmonary dysplasia

KNN

Korean neonatal network

VLBW

Very low birth weight

GA

Gestational age

RDS

Respiratory distress syndrome

ROP

Retinopathy of prematurity

aOR

Adjusted odds ratio

CI

Confidence interval

IQR

Interquartile range

Authors’ contributions

E.K.C. and H.R.K. designed the study, conducted data analysis, drafted and revised the initial manuscript, and approved the final version. S.H.S. and H.K. conducted data analysis and critically reviewed the manuscript. S.Y.H. critically reviewed the statistical plan, carried out statistical analysis, and critically reviewed the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Funding

This study was supported by Korea University Guro Hospital (designated as a “Korea Research-Driven Hospital”), by a Research Programme of the National Institute of Health (Grant No. 2022-ER0603-02), and by grants from Korea University Medicine (Grant Nos. K2225701 and K2507501). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Declarations

Ethical approval and consent to participate

The KNN registry was approved by the Institutional Review Board of CHA Bundang Medical Center, CHA University (Institutional Review Board No. CHAMC 2013-08-082) and the KNN (2022-029). All methods were performed in accordance with the ethical standards of our institutional research committee and the 1964 Helsinki Declaration and its subsequent amendments. Informed consent was obtained from the parents of each infant before participation in the KNN registry.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.