The management of patent ductus arteriosus (PDA) in preterm neonates remains controversial. A retrospective review was conducted to determine the outcomes in preterm neonates with PDA. Data of neonates admitted to the Aga Khan University Hospital from January 2012 to December 2016 were retrieved from patient records. Of the 208 neonates included in the study, 143 (68.7%) received no treatment, while 65 (31.2%) underwent pharmacotherapy and/or surgical ligation for PDA closure. PDA closure was spontaneous in 109 (52.4%) neonates. The mean ±SD gestational age (GA) of neonates with spontaneous ductal closure was greater as compared to those who required some form of treatment [33±3.3 vs 29.7±3.1weeks, p=0.001]. Apnoea (OR:4.47; 95% CI:1.21-16.44), sepsis (OR:3.81; 95% CI:1.33-10.87), pulmonary haemorrhage (OR:4.88; 95% CI:1.24-19.19), and lower APGAR (OR:0.69; 95% CI:0.54-0.90) were associated with higher odds of mortality in our cohort. Our findings demonstrate that PDA resolves spontaneously in most preterm neonates and provide evidence that conservative treatment is not associated with mortality.
Keywords: Conservative treatment; ligation; mortality; patent ductus arteriosus; premature.
Patent ductus arteriosus (PDA) is one of the most common complications in preterm neonates.1 Without closure, the persistent left-to-right shunt can increase the risk of severe morbidities such as intraventricular haemorrhage (IVH), bronchopulmonary dysplasia (BPD), and necrotising enterocolitis (NEC) in these neonates.2 PDA can be treated by conservative management, pharmacotherapy (Ibuprofen, Indomethacin, and Acetaminophen), and surgical ligation. However, clinical practice remains inconsistent due to the uncertainty of the effectiveness and the complications caused by the current methods of PDA management.3
Studies have reported that most PDAs close spontaneously by the time the child is discharged from the hospital.4 Moreover, recent evidence suggests that conservative management of PDA does not increase morbidity or mortality and may be more beneficial than active treatment.5,6This is primarily due to several adverse effects associated with pharmacotherapy and ligation.7,8The traditional approach of early and aggressive treatment has shifted towards watchful waiting with close follow-ups in several high-income countries.5 However, scarce data about PDA management approaches and their outcomes from low- and middle-income countries prevent formulation of evidence-based protocols specific to low-resource settings. Therefore, we aimed to assess the short-term outcomes of interventional and non-interventional approaches to PDA management in preterm neonates (<37 weeks' gestation) and determine the predictors of mortality in this cohort.
Methods and Results
Data of all preterm neonates born from 24+0 to 36+6 weeks' gestation and admitted to the level 3 neonatal intensive care unit (NICU) of the Aga Khan University Hospital, Karachi from January 2012 to December 2016 were collected retrospectively. Data was retrieved from the online central laboratory system and patients' files. Outcomes included spontaneous ductal closure before discharge from hospital (average length of stay for preterm neonates is 15 days), frequency of NEC (modified Bell stage >II), IVH, BPD, retinopathy of prematurity (ROP), sepsis, pulmonary haemorrhage, and death before discharge. Neonates with severe congenital anomalies and heart defects requiring PGE1 infusion to keep the ductus patent were excluded from the study.
The initial diagnosis of PDA was based on clinical signs such as presence of a systolic murmur, wide pulse pressure, bounding peripheral pulses, tachycardia, hyperdynamic precordium, apnoea, and feeding difficulties as per the unit protocol. All patients with suspected PDA based on bed-side clinical findings subsequently underwent a routine confirmation by echocardiography. Although there is no universal definition of a haemodynamically significant PDA (HSPDA) in literature,9 for this study, we defined HSPDA as a defect >1.5mm, with a wide pulse pressure, grade II-III systolic murmur, and a left atrium to aortic root ratio (LA : Ao) of 1:4 or more.
Management of PDA was classified into two categories: "no treatment" and "treatment". The no treatment approach aimed to stabilise the neonate through ventilation optimisation, fluid restriction, and loop diuretics. The treatment approach aimed to achieve ductal closure through pharmacotherapy and/or surgical ligation. The pharmacotherapy approach included administration of intravenous Indomethacin, oral Ibuprofen, or intravenous Acetaminophen. All neonates were initially managed according to the "no treatment" approach. Neonates who failed to improve and remained symptomatic (were ventilator-dependent, apnoeic, unable to tolerate reduced oxygen support, or had feeding intolerance) subsequently received pharmacologic management. Surgical ligation was considered for neonates who were unresponsive to pharmacologic therapy and deteriorated (exhibited pulmonary oedema, extubation failure, feeding difficulties, failure to thrive, aspirations, or needed persistent oxygen therapy). The decision to initiate pharmacologic or surgical management was subject to the clinical practices of the treating neonatologist and paediatric cardiologist.
Approximately, 620 preterm neonates are admitted to the Aga Khan University Hospital annually. As the prevalence of PDA in preterm neonates is 57.2%,10 and this study reviewed data over five years, the population size was taken as 1,770. Taking the frequency of spontaneous PDA closure by the seventh day of life as 78%,4 95% confidence level, and 6% precision, the sample size was estimated to be 167 neonates.
Data were analysed using SPSS v15.0 (IBM Corp., Armonk, NY, USA). Descriptive statistics were reported as mean±SD and median ± IQR for continuous variables and frequencies with percentages for categorical variables. Chi-square test of independence was performed to evaluate the association of morbidity with the treatment approach. Unpaired t-test was used to determine the association of gestational age (GA) with spontaneous closure of PDA. Multivariable logistic regression was carried out to identify the factors associated with mortality. Univariate analyses were first conducted to identify variables significant at p<0.2. Variables with p<0.10 were retained in the multivariable model. Model fitness was assessed via Hosmer-Lemeshow test. The results were reported as odds ratios and 95% CI.
This study was approved by the ethical review committee of the Aga Khan University (ERC:4971-Ped-ERC-17).
During the study period, 208 preterm neonates were diagnosed with PDA. The mean GA and birth weight of the cohort was 31.4±3.61 weeks and 1.59±0.67 kg, respectively. The median length of stay was 11( IQR 15.75) days. Neonatal characteristics are presented in Table-1.
The most observed clinical signs were murmur in 133 (63.9%) neonates and wide pulse pressure in 89 (42.8%), followed by bounding pulses in 25 (12%), tachycardia 24 (11.5%), apnoea in 23 (11.1%), feeding intolerance in 22 (10.6%), and hyperdynamic precordium in 20 (9.6%). Cardiomegaly on chest x-ray was seen in 8 (3.8%) neonates.
Echocardiographic data showed that 127 (61%) neonates had a defect larger than 1.5mm, 193 (92.8%) had a left-to-right shunt, 54 (26%) had left ventricular enlargement, and 73 (35.1%) had LA : Ao >1:4. According to the study criteria, only 17 (8.2%) neonates had an HSPDA.
A majority, i.e. 143 (68.7%) neonates received no treatment for PDA closure. This approach failed in 65 (31.2%) neonates who subsequently received pharmacologic treatment, which was successful in closing the PDA in 56 (26.9%) neonates. Ibuprofen was the most administered drug (n=47, 72.3%), followed by Acetaminophen in 11 (16.9%), and Indomethacin in 7 (10.8%). Nine (4.3%) neonates underwent surgical ligation which was performed at an average age of three weeks.
PDA spontaneously closed in 109 (52.4%) neonates by the time of discharge or death. The mean GA of neonates who underwent spontaneous closure was 33±3.3 weeks compared to 29.7 (±3.1) weeks in neonates without spontaneous closure (p<0.001).
The morbidities observed in the cohort included sepsis, IVH, ROP, NEC, BPD, and pulmonary haemorrhage. Sepsis was observed in 30 (21%) neonates in the no treatment group, compared to 23 (35.4%) in the treatment group (p=0.027). IVH was seen in 15 (10.5%) neonates who did not receive treatment and in 12 (24.6%) who did (p=0.008). BPD was diagnosed in four (2.8%) neonates who were not treated and in 8(12.3%) who were treated (p=0.010). None of the other morbidities were associated with the treatment approach.
In all, 25 (12%) neonates from this cohort died. Neonates with a lower APGAR score at 1 minute (OR: 0.69; 95%CI: 0.54-0.90), apnoea (OR: 4.47; 95%CI: 1.21-16.44), sepsis (OR: 3.81; 95%CI: 1.33-10.87), and pulmonary haemorrhage (OR: 4.88; 95% CI: 1.24, 19.19) had higher odds of mortality (Table-2).
PDA closed spontaneously in over half of the cohort before discharge. Gestational age was significantly associated with spontaneous closure. Although all neonates were initially managed with the no-treatment approach, approximately one-third of the cohort eventually received some form of treatment for ductal closure. A statistically significant difference in neonatal morbidities (sepsis, IVH, and BPD) was observed between the treatment and no-treatment groups. Mortality was not associated with the treatment approach. Our findings corroborate recent studies that favour conservative management for PDA and have shown a lack of association of treatment approach with mortality. Prospective studies are recommended with evidence-based local unit PDA management guidelines to evaluate various modalities of treatment and outcomes.
Acknowledgement: We acknowledge Almas Aamir for assisting in data collection, Arjumand Rizvi for assisting in data analysis, and Vinod Kumar and Ali Shabbir for reviewing the manuscript.
Disclaimer: This manuscript has not been presented or published elsewhere, nor is it under consideration for publication elsewhere.
Conflict of Interest: There are no financial, personal, or professional interests that could be construed to have influenced the work.
Funding Disclosure: This study was not funded.
1. Abu-Shaweesh JM, Almidani E. PDA: Does it matter? Int J Paediatr Adolesc Med. 2020; 7:11-4.
2. Dani C, Pratesi S. Patent ductus arteriosus and oxidative stress in preterm infants: a narrative review. Transl Paediatr. 2020; 9:835-9.
3. Lokku A, Mirea L, Lee SK, Shah PS. Trends and Outcomes of Patent Ductus Arteriosus Treatment in Very Preterm Infants in Canada. Am J Perinatol. 2017; 34:441-50.
4. de Klerk JCA, Engbers AGJ, van Beek F, Flint RB , Reiss IKM, Völler S, et al. Spontaneous Closure of the Ductus Arteriosus in Preterm Infants: A Systematic Review.Front Paediatr. 2020; 8:541.
5. Sehgal A, McNamara PJ. International perspective on management of a patent ductus arteriosus: Lessons learned. Semin Foetal Neonatal Med. 2018; 23:278-84.
6. Clyman RI, Liebowitz M, Kaempf J, Erdeve O, Bulbul A, Håkansson S, et al. PDA-TOLERATE trial: an exploratory randomized controlled trial of treatment of moderate-to-large patent ductus arteriosus at oneweek of age. J Paediatr. 2019; 205:41-8.
7. Mitra S, Florez ID, Tamayo ME, Mbuagbaw L, Vanniyasingam T, Veroniki AA, et al. Association of placebo, indomethacin, ibuprofen, and acetaminophen with closure of haemodynamically significant patent ductus arteriosus in preterm infants: a systematic review and meta-analysis. JAMA. 2018; 319:1221-38.
8. Reese J, Scott TA, Patrick SW. Changing patterns of patent ductus arteriosus surgical ligation in the United States. Semin Perinatol. 2018; 42:253‐61.
9. Shepherd JL, Noori S. What is a hemodynamically significant PDA in preterm infants? Congen Heart Dis. 2019; 14:21-6.
10. Soliman RM, Mostafa FA, Abdelmassih A, Sultan E, Mosallam D. Patent ductus arteriosus in preterm infants; experience of a tertiary referral neonatal intensive care unit: prevalence, complications, and management. Egypt Paediatr Assoc Gazet. 2020; 68:1-9.