BACKGROUND

Patent ductus arteriosus (PDA) treatment is common among very low birth weight (VLBW) infants. Given limitations in evidence, controversy exists regarding treatment risks and benefits. In this study, we describe PDA treatment trends and variation in a large, US, multicenter VLBW infant cohort.

METHODS

Data were collected through Vermont Oxford Network on 291 292 VLBW infants born 2012–2019 at 806 US NICUs. PDA diagnosis and treatment rates, further categorized as pharmacologic, invasive, or combined, were determined. NICUs were classified as capable versus noncapable of invasive PDA treatment. Infant and hospital characteristics were examined by NICU type and treatment quartile. Geographic NICU distribution and treatment rates were described in 9 US census divisions.

RESULTS

Of all infants, 24.6% were diagnosed with and 20.5% were treated for PDA. Diagnosis and treatment rates decreased over the study period. Treatment was predominantly pharmacologic. Treatment rates varied widely among NICUs (0% to 67%) despite similar infant characteristics. The median treatment rate was higher at NICUs capable of pharmacologic and invasive treatment (20.3%, interquartile range 13.3–28.6) than at NICUs capable of only pharmacologic treatment (8.9%, interquartile range 2.9–14.8). Treatment rates were highest in the northeast and lowest in the west. Invasive treatment was more common in the west.

CONCLUSIONS

PDA diagnosis and treatment rates are trending downward. Wide variation exists in PDA treatment despite a largely uniform VLBW infant population. This variation correlates with differences in hospital treatment capabilities and geography. Further understanding of the effects of treatment disparity could aid in guiding clinical management.

What’s Known on This Subject:

Patent ductus arteriosus is common in very low birth weight infants and is associated with increased neonatal morbidity and mortality. Although several ductal closure methods are available, controversy exists regarding treatment indication and approach, given limited evidence and inherent risks.

What This Study Adds:

This study describes diagnosis and treatment trends of patent ductus arteriosus in very low birth weight infants, and associates wide treatment variability with NICU type, hospital capability, and US geography despite minimal differences in infant characteristics.

A patent ductus arteriosus (PDA) is common in preterm and very low birth weight (VLBW) infants and often persists beyond 1 week of life.1,2  Continued patency of the ductus may cause an extracardiac left-to-right shunt, affecting both cardiopulmonary circulation and end-organ perfusion. Serious comorbidities associated with PDA include necrotizing enterocolitis, intraventricular hemorrhage (IVH), pulmonary hemorrhage, respiratory distress syndrome (RDS), chronic lung disease (CLD), and neurodevelopmental impairment.26  These systemic sequelae contribute to the intensive care required for the VLBW population, and increase neonatal mortality.4,7,8 

Approaches to PDA treatment include pharmacologic (indomethacin, ibuprofen, and acetaminophen) and/or invasive (surgical ligation and transcatheter based–device closure) methods.7,9  Although treatment may mitigate the ductal shunt, the risks and benefits of intervention remain controversial.10  Data suggest increased neonatal morbidity and mortality associated with treatment adverse effects,2,10,11  with limited evidence of longer-term clinical benefit.7,12,13  Although there is no widespread consensus regarding VLBW PDA management,2,12,14  there is increasing interest in conservative approaches that allow for spontaneous PDA closure while limiting pharmacologic and invasive care to select patients.1519 

Given the prevalence of PDA in the VLBW population, the impact on neonatal care, and the controversy surrounding the therapeutic strategy, we sought to characterize national trends in PDA diagnosis and treatment, as well as variation in treatment methods. The primary aim was to identify the range of PDA treatment on the basis of hospital capability to offer invasive PDA therapies. The secondary aim was to describe patient and hospital characteristics associated with practice variation, and to examine regional patterns of treatment.

Data were collected through Vermont Oxford Network (VON). VON is a nonprofit, voluntary worldwide collaborative dedicated to improving the quality, safety, and value of care for newborns through a coordinated program of data-driven quality improvement, education, and research.20,21  Member hospitals report data on infants receiving care in NICUs using uniform definitions and systematic coding outlined in the VON Manual of Operations.22  Facility data and center capability are reported in the annual VON membership survey. The Institutional Review Board at the University of Vermont determined that use of the VON database for this analysis was not human subjects research.

VLBW infants were defined as 401- to 1500-g birth weight (BW) or 22 to 29 weeks’ gestational age (GA). VLBW infants born from January 1, 2012, through December 31, 2019, at 806 VON member hospitals in the United States were eligible for retrospective review. Further inclusion criteria required that they (1) were born at the reporting facility (inborn) or were admitted to the reporting facility within 3 days from birth and were never subsequently transferred, (2) survived delivery to NICU admission, and (3) were discharged from the hospital from the reporting hospital, died before discharge, or were still hospitalized on the first birthday. Infants with congenital heart disease diagnoses (per the VON congenital anomalies list)22  were excluded. Those with incomplete hospital or PDA treatment information were also excluded.

NICUs were classified on the basis of their PDA treatment capability as either NICUs with only pharmacologic treatment capability (NICU/P) (administration of ibuprofen, indomethacin, and/or acetaminophen) or NICUs with pharmacologic and invasive treatment capability (NICU/PI) (surgical ligation or catheter closure).

A PDA, per VON manual of operations,22  required evidence of a left-to-right or bidirectional ductal shunt on Doppler echo or a murmur (systolic or continuous) on physical examination. Additionally, at least 2 of the following were necessary: (1) hyperdynamic precordium, (2) bounding pulses, (3) wide pulse pressure, and (4) radiologic evidence of pulmonary vascular congestion and/or cardiomegaly. Details regarding echocardiographic findings, if any, or the specific criteria supporting the diagnosis were not collected.

Small for gestational age (SGA) was defined as BW in the <10th percentile for GA and sex, on the basis of the Fenton growth curves.23  Initial resuscitation collectively referred to any respiratory support, chest compressions, and/or epinephrine administration in the delivery room. Respiratory support was defined as use of any of the following after initial resuscitation: conventional mechanical ventilation, high-frequency oscillator ventilation, noninvasive positive pressure ventilation, continuous positive airway pressure (CPAP), or high-flow nasal cannula. RDS was defined as hypoxemia in room air and/or supplemental oxygen requirement, in addition to a chest radiograph consistent with RDS within the first 24 hours of life.22  CLD was defined as supplemental oxygen requirement at 36 weeks’ corrected GA or, if transferred in week 34 or 35, oxygen at discharge.

PDA diagnosis and treatment rates were analyzed by year and averaged over the entire study period. In 2018, acetaminophen for PDA was added to the VON definition of pharmacologic PDA treatment, and surgical ligation was expanded to include thoracoscopic surgery and interventional catheterization. Median NICU treatment rates, with interquartile and full range, were determined by NICU treatment capability. Infant and hospital characteristics were described by using standard summary statistics and were categorized by NICU type and NICU treatment rate quartile. NICU types and PDA treatment rates were also reported by the US Census Bureau 9 geographic divisions (Supplemental Table 6).24  PDA treatment rates per geographic division were determined in total and by treatment method. Analyses were performed by using SAS 9.4 (SAS Institute, Inc, Cary, NC).

The study cohort consisted of 291 292 infants (Fig 1); 71% were admitted at NICU/PI facilities, of whom 23% received PDA treatment (18% pharmacologic, 2% invasive, and 3% combined). Among the 29% of the study cohort admitted to NICU/P facilities, 14% received PDA treatment, all pharmacologic.

FIGURE 1

US-born VLBW infants reported to VON, 2012–2019. Eligibility and inclusion criteria are as described in the Methods. NICUs are classified by PDA treatment capabilities.

FIGURE 1

US-born VLBW infants reported to VON, 2012–2019. Eligibility and inclusion criteria are as described in the Methods. NICUs are classified by PDA treatment capabilities.

Close modal

PDA diagnosis rates decreased from 28.4% in 2012 to 20.8% in 2019 (8-year average 24.6%). PDA treatment rates also decreased from 24.2% in 2012 to 18.6% in 2019 (8-year average 20.5%). The predominant treatment method was pharmacologic (Fig 2). Although there was a decrease in noninvasive and combined treatment from 2012 through 2017, those rates appeared to be relatively stable in the subsequent 2 years. Invasive treatment as a first therapy declined throughout the study period.

FIGURE 2

Annual study cohort PDA treatment rates, totaled and subdivided by modality, 2012–2019. Rates are the percentages of the total cohort. “Pharmacologic” includes treatment with ibuprofen, indomethacin, and/or, starting in 2018, acetaminophen. “Invasive” includes treatment with surgical ligation or, starting in 2018, catheter based–device closure. “Combined” includes both pharmacologic and invasive therapy.

FIGURE 2

Annual study cohort PDA treatment rates, totaled and subdivided by modality, 2012–2019. Rates are the percentages of the total cohort. “Pharmacologic” includes treatment with ibuprofen, indomethacin, and/or, starting in 2018, acetaminophen. “Invasive” includes treatment with surgical ligation or, starting in 2018, catheter based–device closure. “Combined” includes both pharmacologic and invasive therapy.

Close modal

Selected hospital characteristics associated with the NICU types are shown in Table 1. NICU/PIs had greater median capacity and more extensive subspecialty support. Surgery, both cardiac and noncardiac, as well as cardiac catheterization, were available at more NICU/PIs. Twenty-two percent of NICU/Ps had restrictions on ventilation requiring transfer to higher level of care. NICU/PIs were more likely to be at freestanding children’s hospitals and academic medical centers. Echocardiography was available at 97% of NICU/Ps and all NICU/PIs.

TABLE 1

Member Hospital Characteristics

NICU/P (n = 480)NICU/PI (n = 326)
Hospital data   
 NICU beds, median (IQR) 12 (7–20) 22 (12–40) 
 Obstetrics service, % 98.9 95.4 
 Neonatologists, median (IQR) 6 (3–10) 10 (6–15) 
 Pediatric surgeons, median (IQR) 0 (0–1) 4 (2–7) 
 Pediatric cardiology, % 78.4 97.3 
 Echocardiography, % 97.1 100.0 
 Freestanding children’s hospital, % 6.1 22.5 
 Academic medical center, % 29.7 64.5 
Respiratory support capability, %   
 CPAP 98.5 100.0 
 Conventional ventilation 98.3 100.0 
 High-frequency ventilation 76.1 97.8 
 Restrictions on ventilation 21.6 0.0 
Invasive capability, %   
 Surgery in house 23.1 78.8 
 Cardiac catheterization 1.6 43.8 
 Cardiac surgery requiring bypass 0.0 35.6 
NICU/P (n = 480)NICU/PI (n = 326)
Hospital data   
 NICU beds, median (IQR) 12 (7–20) 22 (12–40) 
 Obstetrics service, % 98.9 95.4 
 Neonatologists, median (IQR) 6 (3–10) 10 (6–15) 
 Pediatric surgeons, median (IQR) 0 (0–1) 4 (2–7) 
 Pediatric cardiology, % 78.4 97.3 
 Echocardiography, % 97.1 100.0 
 Freestanding children’s hospital, % 6.1 22.5 
 Academic medical center, % 29.7 64.5 
Respiratory support capability, %   
 CPAP 98.5 100.0 
 Conventional ventilation 98.3 100.0 
 High-frequency ventilation 76.1 97.8 
 Restrictions on ventilation 21.6 0.0 
Invasive capability, %   
 Surgery in house 23.1 78.8 
 Cardiac catheterization 1.6 43.8 
 Cardiac surgery requiring bypass 0.0 35.6 

Hospitals are separated by their NICU’s capability to provide invasive PDA treatment. All US hospitals who reported to VON 2012–2019 were included.

The median hospital PDA treatment rate among all US VON member NICUs was 13.3% (interquartile range [IQR] 6.7%–22.9%, range 0%–67%), depicted in Fig 3. The median hospital PDA treatment rate was higher at NICU/PIs (20.3%, IQR 13.3–28.6) compared with NICU/Ps (8.9%, IQR 2.9–14.8). There was wide treatment variation in both NICU/PIs (0%–67%) and NICU/Ps (0%–66.7%).

FIGURE 3

NICU PDA treatment rates represented by box (median, IQR) and whisker (range) plots: rates at all VON member NICUs and per NICU type separated by PDA treatment capability. Total treatment variation range for all was 0% to 67%.

FIGURE 3

NICU PDA treatment rates represented by box (median, IQR) and whisker (range) plots: rates at all VON member NICUs and per NICU type separated by PDA treatment capability. Total treatment variation range for all was 0% to 67%.

Close modal

VLBW infant characteristics examined by NICU type are shown in Table 2. Infants at NICU/PIs had a lower median GA and BW compared with those at NICU/Ps. Initial resuscitation was more common in NICU/PIs, as was more extensive respiratory support, inhaled nitric oxide use, and surfactant administration. NICU/PI infants also had higher rates of RDS and CLD.

TABLE 2

Cohort Infant Characteristics by NICU Type

VLBW Infants at NICU/P (n = 85 695)VLBW Infants at NICU/PI (n = 205 967)
Demographic data   
 BW, g, median (IQR) 1180 (920–1370) 1090 (810–1323) 
 GA, wk, median (IQR) 29 (27–31) 28 (26–30) 
 Male sex, % 49.0 50.4 
Maternal race, %   
 White non-Hispanic 44.8 43.2 
 Black non-Hispanic 31.7 29.7 
 Asian American non-Hispanic 4.5 5.1 
 Hispanic 16.4 19.2 
 Other non-Hispanic 1.9 2.0 
Birth data   
 Cesarean delivery, % 74.2 73.5 
 Antenatal steroids, % 84.7 85.5 
 SGA, % 19.0 18.1 
 Any initial resuscitation, % 89.1 92.2 
 1-min Apgar score, median (IQR) 6 (4–8) 5 (3–7) 
 5-min Apgar score, median (IQR) 8 (7–9) 8 (6–9) 
Respiratory data, %   
 Any respiratory support 89.9 93.2 
 Inhaled nitric oxide 2.7 5.7 
 Surfactant 53.7 60.8 
 RDS 70.4 72.3 
 Oxygen at wk 36a 22.5 30.7 
VLBW Infants at NICU/P (n = 85 695)VLBW Infants at NICU/PI (n = 205 967)
Demographic data   
 BW, g, median (IQR) 1180 (920–1370) 1090 (810–1323) 
 GA, wk, median (IQR) 29 (27–31) 28 (26–30) 
 Male sex, % 49.0 50.4 
Maternal race, %   
 White non-Hispanic 44.8 43.2 
 Black non-Hispanic 31.7 29.7 
 Asian American non-Hispanic 4.5 5.1 
 Hispanic 16.4 19.2 
 Other non-Hispanic 1.9 2.0 
Birth data   
 Cesarean delivery, % 74.2 73.5 
 Antenatal steroids, % 84.7 85.5 
 SGA, % 19.0 18.1 
 Any initial resuscitation, % 89.1 92.2 
 1-min Apgar score, median (IQR) 6 (4–8) 5 (3–7) 
 5-min Apgar score, median (IQR) 8 (7–9) 8 (6–9) 
Respiratory data, %   
 Any respiratory support 89.9 93.2 
 Inhaled nitric oxide 2.7 5.7 
 Surfactant 53.7 60.8 
 RDS 70.4 72.3 
 Oxygen at wk 36a 22.5 30.7 

All eligible US VLBW infants reported to VON 2012–2019 admitted to NICUs with and without invasive PDA treatment capability.

a

Subject to incomplete reporting (NICU/P: n = 61 815 and NICU/PI: n = 159 394).

Characteristics of all VLBW infants treated for PDA are shown in Table 3. Regardless of center capability, infants receiving only pharmacologic treatment had a higher median BW and GA compared with those receiving invasive treatment or combined therapies. Characteristics of infants treated pharmacologically at NICUs with and without invasive treatment capability were similar. More SGA infants underwent invasive PDA treatment exclusively. Infants who received combined treatment more frequently received surfactant and were more often diagnosed with RDS compared with other treated infants.

TABLE 3

Treated Infant Characteristics by NICU Type

Treated VLBW Infants at NICU/PTreated VLBW Infants at NICU/PI
n = 11 861Pharmacologic (n = 37 900)Invasive (n = 3690)Combined (n = 6202)
Demographic data     
 BW, g, median (IQR) 850 (690–1040) 820 (665–1005) 720 (605–890) 725 (620–860) 
 GA, wk, median (IQR) 26 (25–28) 26 (24–27) 25 (24–26) 25 (24–26) 
 Male sex, % 49.2 51.5 52.7 50.1 
Maternal race, %     
 White non-Hispanic 44.9 43.7 37.9 40.7 
 Black non-Hispanic 32.2 31.0 27.6 30.1 
 Asian American non-Hispanic 4.1 4.4 5.4 5.3 
 Hispanic 16.4 18.4 26.3 21.2 
 Other non-Hispanic 1.6 1.7 2.1 1.7 
Birth data     
 Cesarean delivery, % 73.1 72.2 71.3 69.3 
 Antenatal steroids, % 84.5 84.8 83.6 84.8 
 SGA, % 10.2 11.5 14.5 8.9 
 Any initial resuscitation, % 98.3 98.9 99.0 99.5 
 1-min Apgar score, median (IQR) 5 (3–7) 4 (2–6) 4 (2–6) 4 (2–6) 
 5-min Apgar score, median (IQR) 7 (6–8) 7 (6–8) 7 (5–8) 7 (5–8) 
Respiratory data, %     
 Any respiratory support 99.4 99.7 99.9 100.0 
 Inhaled nitric oxide 6.0 9.1 15.4 15.0 
 Surfactant 88.0 89.2 91.0 94.9 
 RDS 93.0 90.8 92.9 95.3 
 Oxygen at wk 36a 50.1 52.2 75.2 79.0 
Treated VLBW Infants at NICU/PTreated VLBW Infants at NICU/PI
n = 11 861Pharmacologic (n = 37 900)Invasive (n = 3690)Combined (n = 6202)
Demographic data     
 BW, g, median (IQR) 850 (690–1040) 820 (665–1005) 720 (605–890) 725 (620–860) 
 GA, wk, median (IQR) 26 (25–28) 26 (24–27) 25 (24–26) 25 (24–26) 
 Male sex, % 49.2 51.5 52.7 50.1 
Maternal race, %     
 White non-Hispanic 44.9 43.7 37.9 40.7 
 Black non-Hispanic 32.2 31.0 27.6 30.1 
 Asian American non-Hispanic 4.1 4.4 5.4 5.3 
 Hispanic 16.4 18.4 26.3 21.2 
 Other non-Hispanic 1.6 1.7 2.1 1.7 
Birth data     
 Cesarean delivery, % 73.1 72.2 71.3 69.3 
 Antenatal steroids, % 84.5 84.8 83.6 84.8 
 SGA, % 10.2 11.5 14.5 8.9 
 Any initial resuscitation, % 98.3 98.9 99.0 99.5 
 1-min Apgar score, median (IQR) 5 (3–7) 4 (2–6) 4 (2–6) 4 (2–6) 
 5-min Apgar score, median (IQR) 7 (6–8) 7 (6–8) 7 (5–8) 7 (5–8) 
Respiratory data, %     
 Any respiratory support 99.4 99.7 99.9 100.0 
 Inhaled nitric oxide 6.0 9.1 15.4 15.0 
 Surfactant 88.0 89.2 91.0 94.9 
 RDS 93.0 90.8 92.9 95.3 
 Oxygen at wk 36a 50.1 52.2 75.2 79.0 

Only infants treated for PDA included and separated by NICU capability for invasive treatment and treatment method as reported to VON 2012–2019.

a

Subject to incomplete reporting (NICU/P: n = 9531; NICU/PI: pharmacologic: n = 31 434, invasive: n = 3440; and combined: n = 5916)

Infant and hospital characteristics sorted by NICU PDA treatment rate quartile are shown in Tables 4 and 5. There was remarkably little variation in BW, GA, maternal race, birth data, or respiratory support parameters across the range of NICUs, regardless of the reported frequency of PDA treatment. Analysis of hospital characteristics reveals a progressively increasing treatment rate in larger NICUs with greater physical and subspecialty resources.

TABLE 4

Treated Infant Characteristics by NICU Treatment Rate Quartiles

First Treatment Quartile (Treatment Rate: 0%–6.2% [n = 202])Second Treatment Quartile (Treatment Rate: 6.2%–13.5% [n = 201])Third Treatment Quartile (Treatment Rate: 13.5%–22.6% [n = 201])Fourth Treatment Quartile (Treatment Rate: 22.6%–67% [n = 202])
No. infants per quartile, n 850 6945 16 568 35 414 
Demographic data     
 BW, g, median (IQR) 830 (670–1050) 790 (660–980) 790 (650–980) 820 (660–1000) 
 GA, wk, median (IQR) 26 (25–28) 26 (24–27) 26 (24–27) 26 (24–27) 
 Male sex, % 50.9 50.9 50.9 51.0 
Maternal race, %     
 White non-Hispanic 40.3 42.3 41.7 44.3 
 Black non-Hispanic 30.7 30.3 30.1 31.4 
 Asian American non-Hispanic 5.3 5.4 5.0 4.0 
 Hispanic 21.3 18.8 20.2 18.1 
 Other non-Hispanic 2.0 2.3 1.8 1.5 
Birth data     
 Cesarean delivery, % 74.7 71.6 72.7 71.7 
 Antenatal steroids, % 84.8 85.0 84.8 84.6 
 SGA, % 10.0 9.7 11.0 11.6 
 Any initial resuscitation, % 98.0 98.6 98.9 98.9 
 1-min Apgar score, median (IQR) 4 (2–7) 4 (2–6) 4 (2–6) 4 (2–6) 
 5-min Apgar score, median (IQR) 7 (6–8) 7 (6–8) 7 (6–8) 7 (6–8) 
Respiratory data, %     
 Any respiratory support 98.9 99.5 99.8 99.7 
 Inhaled nitric oxide 6.9 8.2 9.9 9.6 
 Surfactant 88.4 90.0 90.4 89.2 
 RDS 93.1 94.2 93.6 90.5 
 Oxygen at wk 36a 55.1 58.8 60.7 54.2 
First Treatment Quartile (Treatment Rate: 0%–6.2% [n = 202])Second Treatment Quartile (Treatment Rate: 6.2%–13.5% [n = 201])Third Treatment Quartile (Treatment Rate: 13.5%–22.6% [n = 201])Fourth Treatment Quartile (Treatment Rate: 22.6%–67% [n = 202])
No. infants per quartile, n 850 6945 16 568 35 414 
Demographic data     
 BW, g, median (IQR) 830 (670–1050) 790 (660–980) 790 (650–980) 820 (660–1000) 
 GA, wk, median (IQR) 26 (25–28) 26 (24–27) 26 (24–27) 26 (24–27) 
 Male sex, % 50.9 50.9 50.9 51.0 
Maternal race, %     
 White non-Hispanic 40.3 42.3 41.7 44.3 
 Black non-Hispanic 30.7 30.3 30.1 31.4 
 Asian American non-Hispanic 5.3 5.4 5.0 4.0 
 Hispanic 21.3 18.8 20.2 18.1 
 Other non-Hispanic 2.0 2.3 1.8 1.5 
Birth data     
 Cesarean delivery, % 74.7 71.6 72.7 71.7 
 Antenatal steroids, % 84.8 85.0 84.8 84.6 
 SGA, % 10.0 9.7 11.0 11.6 
 Any initial resuscitation, % 98.0 98.6 98.9 98.9 
 1-min Apgar score, median (IQR) 4 (2–7) 4 (2–6) 4 (2–6) 4 (2–6) 
 5-min Apgar score, median (IQR) 7 (6–8) 7 (6–8) 7 (6–8) 7 (6–8) 
Respiratory data, %     
 Any respiratory support 98.9 99.5 99.8 99.7 
 Inhaled nitric oxide 6.9 8.2 9.9 9.6 
 Surfactant 88.4 90.0 90.4 89.2 
 RDS 93.1 94.2 93.6 90.5 
 Oxygen at wk 36a 55.1 58.8 60.7 54.2 

Quartiles by NICU PDA treatment rate reported to VON 2012–2019. All VLBW infants treated for PDA were included.

a

Subject to incomplete reporting (first quartile: n = 732; second quartile: n = 5886; third quartile: n = 14 319; and fourth quartile: n = 29 483).

TABLE 5

Hospital Characteristics by NICU Treatment Rate Quartiles

First Treatment Quartile (Treatment Rate: 0%–6.2%[n = 202])Second Treatment Quartile (Treatment Rate: 6.2%–13.5% [n = 201])Third Treatment Quartile (Treatment Rate: 13.5%–22.6% [n = 201])Fourth Treatment Quartile (Treatment Rate: 22.6%–67% [n = 202])
No. infants per quartile, n 850 6945 16 568 35 414 
Hospital data     
 NICU beds, median (IQR) 12 (8–18) 20 (12–29) 27 (20–44) 32 (20–50) 
 Obstetrics service, % 98.5 97.0 98.5 92.6 
 Neonatologists, median (IQR) 6 (3–10) 7 (4–12) 8 (5–14) 8 (4–14) 
 Pediatric surgeons, median (IQR) 0 (0–0) 0 (0–3) 3 (0–6) 3 (2–6) 
 Pediatric cardiology, % 75.1 85.4 95.5 97.0 
 Freestanding children’s hospital, % 1.0 4.7 9.7 16.8 
 Academic medical center, % 8.5 29.4 40.4 55.7 
Respiratory support capability, %     
 CPAP 97.0 99.5 99.5 100.0 
 Conventional ventilation 96.5 99.5 99.5 100.0 
 High-frequency ventilation 48.0 92.0 97.5 99.5 
 Restrictions on ventilation 39.1 5.5 2.5 2.0 
Invasive capability, %     
 Surgery in house 10.1 32.2 58.3 76.1 
 Cardiac catheterization 2.0 9.5 25.4 35.1 
 Cardiac surgery requiring bypass 1.5 6.5 18.9 30.7 
First Treatment Quartile (Treatment Rate: 0%–6.2%[n = 202])Second Treatment Quartile (Treatment Rate: 6.2%–13.5% [n = 201])Third Treatment Quartile (Treatment Rate: 13.5%–22.6% [n = 201])Fourth Treatment Quartile (Treatment Rate: 22.6%–67% [n = 202])
No. infants per quartile, n 850 6945 16 568 35 414 
Hospital data     
 NICU beds, median (IQR) 12 (8–18) 20 (12–29) 27 (20–44) 32 (20–50) 
 Obstetrics service, % 98.5 97.0 98.5 92.6 
 Neonatologists, median (IQR) 6 (3–10) 7 (4–12) 8 (5–14) 8 (4–14) 
 Pediatric surgeons, median (IQR) 0 (0–0) 0 (0–3) 3 (0–6) 3 (2–6) 
 Pediatric cardiology, % 75.1 85.4 95.5 97.0 
 Freestanding children’s hospital, % 1.0 4.7 9.7 16.8 
 Academic medical center, % 8.5 29.4 40.4 55.7 
Respiratory support capability, %     
 CPAP 97.0 99.5 99.5 100.0 
 Conventional ventilation 96.5 99.5 99.5 100.0 
 High-frequency ventilation 48.0 92.0 97.5 99.5 
 Restrictions on ventilation 39.1 5.5 2.5 2.0 
Invasive capability, %     
 Surgery in house 10.1 32.2 58.3 76.1 
 Cardiac catheterization 2.0 9.5 25.4 35.1 
 Cardiac surgery requiring bypass 1.5 6.5 18.9 30.7 

Quartiles by NICU PDA treatment rate reported to VON 2012–2019. All US member hospitals were included.

The geographic distribution of NICU types by US census division is demonstrated in Fig 4 A and B. Most regions had similar proportions of NICUs with and without invasive PDA treatment capability except East South Central, where NICU/Ps were almost twice as common. PDA treatment rates varied notably by geographic division (Fig 5). New England had the highest overall treatment rate, with 27.4% of eligible VLBW infants, followed by East South Central (26.3%), and West North Central (25.5%). Treatment rates were lowest in the Mountain (17.6%), Pacific (17.5%), and middle Atlantic divisions (17.3%). Pharmacologic treatment was more commonly used in eastern and midwestern regions (25.0% in New England, 24.2% in East South Central, and 21.0% in West North Central). The rate of primary invasive treatment was highest in western and southwestern regions (2.3% in West South Central and 2.0% in both Pacific and Mountain). Combined treatment rates ranged between 1.7% and 3.1% across the country without a distinct regional pattern.

FIGURE 4

Geographic VON member NICU distribution per US Census division, 2012–2019. A, Geographic distribution of VON member NICU/Ps (n = 480) as percentage of total VON member PICU/Ps. B, Geographic distribution of VON member NICU/PIs (n = 326) as percentage of total VON member PICU/PIs.

FIGURE 4

Geographic VON member NICU distribution per US Census division, 2012–2019. A, Geographic distribution of VON member NICU/Ps (n = 480) as percentage of total VON member PICU/Ps. B, Geographic distribution of VON member NICU/PIs (n = 326) as percentage of total VON member PICU/PIs.

Close modal
FIGURE 5

PDA treatment rates, 2012–2019. Total treatment rates (%) are bolded per division. Treatment rates are depicted within geographic census division by method: pharmacologic (solid), invasive (dots), and combined (dashes). Census divisions are color coded to match Fig 4.

FIGURE 5

PDA treatment rates, 2012–2019. Total treatment rates (%) are bolded per division. Treatment rates are depicted within geographic census division by method: pharmacologic (solid), invasive (dots), and combined (dashes). Census divisions are color coded to match Fig 4.

Close modal

Studies performed over the last 25 years have shown several trends in the diagnosis and management of PDAs in VLBW infants.7,2528  First, the proportion of VLBW infants diagnosed with PDA has been decreasing, with rates typically approaching or exceeding 50% of all such infants in earlier studies, declining to <40% in more recent reviews. Second, the percentage of VLBW infants treated for PDA has also been steadily decreasing, from ∼40% to ∼20% over the same interval, in most studies. Third, there has been consistently wide variation in reported practice among NICUs, with a range of 0% to 100% in treatment rates.

In our investigation, which overlaps the more recent of these reports, we confirm these trends by using a larger national database. A diagnosis of PDA averaged 24.6% in our population from 2012 to 2019, decreasing from 28.4% to 20.8% over the 8 years of this review. Historically, the diagnosis of a PDA could be made either clinically or by echocardiograph, and this latitude remains true in our study. However, we suspect that the decreasing frequency of PDA diagnosis, despite no change in the VON definition, may reflect the elective use of more rigorous diagnostic criteria in recent years, excluding trivial ductal shunts and increasingly requiring echocardiographic features of hemodynamic effects. There may also be a trend away from surveillance echocardiographic evaluation in VLBW infants, with diagnostic imaging primarily pursued in the setting of clinical instability.

The overall treatment rate of 20.5% that we observed is similar to 21.7% reported in California in 201427  and 18% in a national survey in 2015.29  The decline in treatment roughly parallels the pattern seen in PDA diagnosis, decreasing from 24.2% in 2012% to 18.6% in 2019. It is possible that several of the studies cited above that have raised questions about potential adverse effects of treatment have resulted in this more judicious use of intervention for VLBW infants. This simultaneous decrease in diagnosis and treatment rates are probably interrelated and reflective of a more restrained global approach to PDA management.

Combined pharmacologic and invasive treatment, as well as primary invasive therapy, represent a small percentage of treated infants and, like pharmacologic therapy alone, became less frequent over the study period. The advent of catheter closure methods in the last few years of the study period did not make an obvious difference in treatment frequency or choice, but it remains to be seen if these technical advances will have any effect on clinical behavior.

One of the most persistent and striking findings of ours and other studies is the extreme variability among NICUs in their decision to treat PDA. This phenomenon has been generally regarded as a manifestation of uncertainty as to the benefit and risks of treatment, and the consequent lack of consensus on treatment indications.

In the current study, we examined treatment patterns stratified by NICU type, specifically the capability of the center to provide invasive PDA therapy. More than 70% of our cohort were treated at facilities capable of all therapeutic options, and infants in those NICUs were more likely to be treated for a PDA. Not surprisingly, these NICU/PI were larger and more likely to be associated with academic centers or children’s hospitals; they also cared for somewhat smaller, younger, and sicker infants. Invasive therapy for PDA represented only a small percentage of treated infants and did not explain the substantial difference in treatment rates between NICU/PIs and NICU/Ps.

When assessing infant characteristics, the degree of prematurity and markers of pulmonary morbidity appeared to be surrogates for the medical complexity associated with the decision to treat for PDA. Infants who were more premature, those receiving initial resuscitation and continued respiratory support, and those diagnosed with RDS and CLD were more likely to receive PDA treatment, particularly invasive or combined treatment. Reese at al also recognized this association of lower BW and pulmonary morbidity among other neonatal morbidities as markers for medical complexity and increased rates of invasive PDA treatment (ie, surgical ligation).30 

However, the treatment variation we observed appeared not to be explained by differences in infant characteristics alone. In fact, when stratified by NICU PDA treatment rate quartile, we found, virtually, no difference in the reported infant profiles between NICUs that treated between 0% and 6.2% of infants and those that treated 22.6% to 67%. The treatment quartile analysis did reveal a strong association between increasing NICU size and resources and the likelihood of PDA treatment.

Geographic differences in PDA treatment of VLBW infants on a US national level have been described for only surgical ligation.30  Similar observations of regional treatment variation independent of infant characteristics have been described in Canada and Europe.26,31  We found that although western states used invasive measures more frequently, overall treatment rates were higher in eastern regions. In the absence of evidence-based guidelines, these regional differences may simply represent differences in local expert opinion or training culture.

The VON data set provides little insight regarding causality and longer-term outcomes. Of note, however, the reporting of oxygen requirement at 36 weeks’ GA, which is a marker of CLD, varied minimally across NICU treatment rate quartiles, suggesting that aggressive PDA treatment had little effect on this single outcome variable. It has previously been described, though, that NICUs with a moderate approach, compared with both low and high PDA treatment rates, have had more favorable outcomes with respect to mortality or severe neurologic injury.28 

Although controversy remains regarding the ideal approach to VLBW PDA management, 2 predominate clinical trends have emerged: (1) conservative treatment to avoid adverse effects in the absence of proven outcome benefits,2,12,32,33  and (2) a more aggressive approach to minimize neonatal morbidity, and potentially mortality, by decreasing the ductal shunt.3,34,35  In both strategies, surgical ligation is considered second line after conservative or pharmacologic treatment failure because of additional serious side effects that include vocal cord paralysis, hemorrhage, infection, shock, and death.30  To better unify management strategies, and in the absence of evidence-based guidelines, an expert panel recently proposed a tiered PDA treatment algorithm, incorporating the individual risk factor constellations of GA, need for IVH prophylaxis, echocardiographic PDA characteristics, patient symptoms and comorbidities, chronological age, and previous treatment attempts.16  Ongoing trials continue to investigate the role of expectative management in PDA treatment (NCT02884219) and aim to develop prediction models for targeted treatment of high-risk infants, who might benefit the most from PDA closure (NCT03782610).18,36,37 

Study limitations include the absence of data on timing of PDA treatment, as well as the sequence of methods used. The VON database provides limited clinical data of infants receiving treatment and no information on either the hemodynamic significance of the PDA shunt or on the intention for treatment (versus nontreatment). As reported in other studies, a proportion of the pharmacologically treated infants included in this study undoubtedly received indomethacin prophylactically and, therefore, primarily for IVH prevention and not PDA treatment, although early administration could have affected the likelihood of a subsequent PDA.7  Both ibuprofen and acetaminophen, in contrast, were administered specifically for PDA treatment. In addition, we cannot comment on which PDA diagnostic criteria were met and have no insight as to the hemodynamic severity of the ductus in treated or untreated infants. VON databases are also subject to incomplete reporting and do not include all US NICUs. However, considering the number of infants and NICUs included, and the geographic uniformity of NICU distribution with and without invasive PDA treatment capability reporting to VON, this database is likely to be a fair approximation of the behavior of our national neonatal health care system.

In this study, we used a large US VLBW NICU database to demonstrate decreasing trends in diagnosis and treatment rates for PDA and to highlight wide variation in medical decision-making regarding PDA treatment. This treatment variation did not appear to be explained by differences in infant characteristics but was strongly associated with NICU size and capability. Geographic location was also found to influence both the frequency of and method used for PDA treatment. Considering the continued uncertainty regarding treatment recommendations, further investigation should include more formal and uniform criteria for diagnosis of a PDA and assessment of hemodynamic effects and incorporate randomization schemes to sort out measurable treatment benefits or associated morbidity.

We thank our colleagues who submit data to VON on behalf of the infants and their families. A list of hospitals contributing data to this study is supplied in Supplemental Table 7.

Dr Runte conceptualized and designed the study, organized data collection, drafted the initial manuscript, and reviewed and revised the final manuscript; Drs Flyer and Yeager conceptualized and designed the study, drafted the initial manuscript, and reviewed and revised the final manuscript; Dr Edwards conceptualized and designed the study, designed the data collection instruments, conducted analyses, and reviewed and revised the final manuscript; Dr Soll conceptualized and designed the study and reviewed and revised the final manuscript; Dr Horbar conceptualized and designed the study, designed the data collection instruments, and reviewed and revised the final manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

FUNDING: No external funding.

BW

birth weight

CLD

chronic lung disease

CPAP

continuous positive airway pressure

GA

gestational age

IQR

interquartile range

IVH

intraventricular hemorrhage

NICU/P

NICU with only pharmacologic treatment capability

NICU/PI

NICU with pharmacologic and invasive treatment capability

PDA

patent ductus arteriosus

RDS

respiratory distress syndrome

SGA

small for gestational age

VLBW

very low birth weight

VON

Vermont Oxford Network

1
Koch
J
,
Hensley
G
,
Roy
L
,
Brown
S
,
Ramaciotti
C
,
Rosenfeld
CR
.
Prevalence of spontaneous closure of the ductus arteriosus in neonates at a birth weight of 1000 grams or less
.
Pediatrics
.
2006
;
117
(
4
):
1113
1121
2
Benitz
WE
;
Committee on Fetus and Newborn, American Academy of Pediatrics
.
Patent ductus arteriosus in preterm infants
.
Pediatrics
.
2016
;
137
(
1
):
e20153730
3
Clyman
RI
.
Patent ductus arteriosus, its treatments, and the risks of pulmonary morbidity
.
Semin Perinatol
.
2018
;
42
(
4
):
235
242
4
Hamrick
SE
,
Hansmann
G
.
Patent ductus arteriosus of the preterm infant
.
Pediatrics
.
2010
;
125
(
5
):
1020
1030
5
Janz-Robinson
EM
,
Badawi
N
,
Walker
K
,
Bajuk
B
,
Abdel-Latif
ME
;
Neonatal Intensive Care Units Network
.
Neurodevelopmental outcomes of premature infants treated for patent ductus arteriosus: a population-based cohort study
.
J Pediatr
.
2015
;
167
(
5
):
1025
32.e3
6
Dollberg
S
,
Lusky
A
,
Reichman
B
.
Patent ductus arteriosus, indomethacin and necrotizing enterocolitis in very low birth weight infants: a population-based study
.
J Pediatr Gastroenterol Nutr
.
2005
;
40
(
2
):
184
188
7
Laughon
M
,
Bose
C
,
Clark
R
.
Treatment strategies to prevent or close a patent ductus arteriosus in preterm infants and outcomes
.
J Perinatol
.
2007
;
27
(
3
):
164
170
8
Noori
S
,
McCoy
M
,
Friedlich
P
, et al
.
Failure of ductus arteriosus closure is associated with increased mortality in preterm infants
.
Pediatrics
.
2009
;
123
(
1
).
9
Heuchan
AM
,
Clyman
RI
.
Managing the patent ductus arteriosus: current treatment options
.
Arch Dis Child Fetal Neonatal Ed
.
2014
;
99
(
5
):
F431
F436
10
Chorne
N
,
Leonard
C
,
Piecuch
R
,
Clyman
RI
.
Patent ductus arteriosus and its treatment as risk factors for neonatal and neurodevelopmental morbidity
.
Pediatrics
.
2007
;
119
(
6
):
1165
1174
11
Mirea
L
,
Sankaran
K
,
Seshia
M
, et al;
Canadian Neonatal Network
.
Treatment of patent ductus arteriosus and neonatal mortality/morbidities: adjustment for treatment selection bias
.
J Pediatr
.
2012
;
161
(
4
):
689
94.e1
12
Sankar
MN
,
Bhombal
S
,
Benitz
WE
.
PDA: to treat or not to treat
.
Congenit Heart Dis
.
2019
;
14
(
1
):
46
51
13
Bose
CL
,
Laughon
MM
.
Patent ductus arteriosus: lack of evidence for common treatments
.
Arch Dis Child Fetal Neonatal Ed
.
2007
;
92
(
6
):
F498
F502
14
Mohamed
MA
,
El-Dib
M
,
Alqahtani
S
,
Alyami
K
,
Ibrahim
AN
,
Aly
H
.
Patent ductus arteriosus in premature infants: to treat or not to treat?
J Perinatol
.
2017
;
37
(
6
):
652
657
15
Weber
SC
,
Weiss
K
,
Bührer
C
,
Hansmann
G
,
Koehne
P
,
Sallmon
H
.
Natural history of patent ductus arteriosus in very low birth weight infants after discharge
.
J Pediatr
.
2015
;
167
(
5
):
1149
1151
16
Hamrick
SEG
,
Sallmon
H
,
Rose
AT
, et al
.
Patent ductus arteriosus of the preterm infant
.
Pediatrics
.
2020
;
146
(
5
):
e20201209
17
Kaempf
JW
,
Wu
YX
,
Kaempf
AJ
,
Kaempf
AM
,
Wang
L
,
Grunkemeier
G
.
What happens when the patent ductus arteriosus is treated less aggressively in very low birth weight infants?
J Perinatol
.
2012
;
32
(
5
):
344
348
18
Hundscheid
T
,
Onland
W
,
van Overmeire
B
, et al
.
Early treatment versus expectative management of patent ductus arteriosus in preterm infants: a multicentre, randomised, non-inferiority trial in Europe (BeNeDuctus trial)
.
BMC Pediatr
.
2018
;
18
(
1
):
262
19
Semberova
J
,
Sirc
J
,
Miletin
J
, et al
.
Spontaneous closure of patent ductus arteriosus in infants ≤1500 g
.
Pediatrics
.
2017
;
140
(
2
):
e20164258
20
Horbar
JD
,
Soll
RF
,
Edwards
WH
.
The Vermont Oxford Network: a community of practice
.
Clin Perinatol
.
2010
;
37
(
1
):
29
47
21
Edwards
EM
,
Ehret
DEY
,
Soll
RF
,
Horbar
JD
.
Vermont Oxford Network: a worldwide learning community
.
Transl Pediatr
.
2019
;
8
(
3
):
182
192
22
Vermont Oxford Network
.
2020 Manual of Operations: Part 2, Data Definitions & Infant Data Forms, Release 240
.
Burlington, VT
:
Vermont Oxford Network
;
2019
23
Fenton
TR
,
Kim
JH
.
A systematic review and meta-analysis to revise the Fenton growth chart for preterm infants
.
BMC Pediatr
.
2013
;
13
:
59
24
National Center for Health Statistics (US)
.
Figure, U.S. Census Bureau: four geographic regions and nine divisions of the United States
.
Health, United States, 2019. Available at: https://www2.census.gov/geo/pdfs/maps-data/maps/reference/us_regdiv.pdf. Accessed December 28, 2020
25
Bixler
GM
,
Powers
GC
,
Clark
RH
,
Walker
MW
,
Tolia
VN
.
Changes in the diagnosis and management of patent ductus arteriosus from 2006 to 2015 in United States neonatal intensive care units
.
J Pediatr
.
2017
;
189
:
105
112
26
Edstedt Bonamy
AK
,
Gudmundsdottir
A
,
Maier
RF
, et al;
collaborators from the EPICE Research Group
.
Patent ductus arteriosus treatment in very preterm infants: a European population-based cohort study (EPICE) on variation and outcomes
.
Neonatology
.
2017
;
111
(
4
):
367
375
27
Ngo
S
,
Profit
J
,
Gould
JB
,
Lee
HC
.
Trends in patent ductus arteriosus diagnosis and management for very low birth weight infants
.
Pediatrics
.
2017
;
139
(
4
):
e20162390
28
Isayama
T
,
Kusuda
S
,
Reichman
B
, et al;
International Network for Evaluating Outcomes of Neonates (iNeo) Investigators
.
Neonatal intensive care unit-level patent ductus arteriosus treatment rates and outcomes in infants born extremely preterm
.
J Pediatr
.
2020
;
220
:
34
39.e5
29
Lee
HC
,
Durand
DJ
,
Danielsen
B
,
Dueñas
GV
,
Powers
RJ
.
Hospital variation in medical and surgical treatment of patent ductus arteriosus
.
Am J Perinatol
.
2015
;
32
(
4
):
379
386
30
Reese
J
,
Scott
TA
,
Patrick
SW
.
Changing patterns of patent ductus arteriosus surgical ligation in the United States
.
Semin Perinatol
.
2018
;
42
(
4
):
253
261
31
Lokku
A
,
Mirea
L
,
Lee
SK
,
Shah
PS
;
Canadian Neonatal Network
.
Trends and outcomes of patent ductus arteriosus treatment in very preterm infants in Canada
.
Am J Perinatol
.
2017
;
34
(
5
):
441
450
32
Chock
VY
,
Goel
VV
,
Palma
JP
, et al
.
Changing management of the patent ductus arteriosus: effect on neonatal outcomes and resource utilization
.
Am J Perinatol
.
2017
;
34
(
10
):
990
995
33
Chock
VY
,
Punn
R
,
Oza
A
, et al
.
Predictors of bronchopulmonary dysplasia or death in premature infants with a patent ductus arteriosus
.
Pediatr Res
.
2014
;
75
(
4
):
570
575
34
Clyman
RI
,
Liebowitz
M
,
Kaempf
J
, et al;
PDA-TOLERATE (PDA: TO LEave it alone or Respond And Treat Early) Trial Investigators
.
PDA-TOLERATE Trial: an exploratory randomized controlled trial of treatment of moderate-to-large patent ductus arteriosus at 1 week of age
.
J Pediatr
.
2019
;
205
:
41
48.e6
35
Clyman
RI
,
Hills
NK
,
Liebowitz
M
,
Johng
S
.
Relationship between duration of infant exposure to a moderate-to-large patent ductus arteriosus shunt and the risk of developing bronchopulmonary dysplasia or death before 36 weeks
.
Am J Perinatol
.
2019
;
37
(
2
):
216
223
36
Slaughter
JL
,
Cua
CL
,
Notestine
JL
, et al
.
Early prediction of spontaneous patent ductus arteriosus (PDA) closure and PDA-associated outcomes: a prospective cohort investigation
.
BMC Pediatr
.
2019
;
19
(
1
):
333
37
El-Khuffash
A
,
Bussmann
N
,
Breatnach
CR
, et al
.
A pilot randomized controlled trial of early targeted patent ductus arteriosus treatment using a risk based severity score (the PDA RCT)
.
J Pediatr
.
2021
;
229
:
127
133

Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: Drs Horbar and Soll are employees of Vermont Oxford Network. Dr Edwards receives salary support from Vermont Oxford Network; and Drs Runte, Flyer, and Yeager have indicated they have no financial relationships relevant to this article to disclose.