PDA’s prevalence is inversely proportional to the gestational age with the prevalence of 20% at 32 weeks gestational age and exceeding 90% at 26 weeks gestational age. Prematurity not only increases the likelihood of PDA but also decreases the likelihood of its closure [16].
Management of PDA range from a less aggressive approach of modest fluid restriction and “watchful waiting,” to pharmacologic and/or surgical intervention. Pharmacotherapy includes the cyclo oxygenase inhibitors; indomethacin or ibuprofen, these agents have side effects including renal failure, brain white matter injury, spontaneous intestinal perforation, necrotizing enterocolitis, and increased bleeding tendency secondary to reduced platelet function, all in the face of treatment failure rates as high as 40% in very premature infants [17].
Clinical trials did not provide clear evidence to support the practice of closing PDA to improve short-term and long-term outcomes of premature infants. Trials conducted to introduce pharmacological treatment of PDA demonstrated the efficacy of these medications in closing PDA, but did not impact major outcomes such as mortality, CLD, NEC, and neurodevelopmental outcome [1].
In spite of the findings that acetaminophen showed promising results in closing PDA, there have been concerns about its effect on brain development and function. Without long-term outcome studies, the use of acetaminophen is still investigational [18].
Similarly, surgical ligation has not been shown to improve mortality and the incidences of certain morbidities associated with the procedure including vocal cord paralysis, thoracotomy, chylothorax, pneumothorax, scoliosis, retinopathy of prematurity (ROP), and most importantly increased incidences of cognitive delay and neurosensory/neurodevelopmental impairment are not uncommon. These findings caused reluctance to expose premature infants to the possible risks associated with surgical ligation whereas the benefit of PDA closure is still considered theoretical. For these reasons, a recent clinical report from the American Academy of Pediatrics attested that early and routine PDA treatment does not improve long-term outcome and that the value of selective treatment remains uncertain [1].
Hemodynamically significant PDA (hsPDA) is observed in more than 30% of premature infants with gestational age of 32 weeks [5]. Early identification of preterm infants who will subsequently fail to achieve ductal closure allows early initiation of intervention and reduces treatment failure. The diagnosis of hemodynamically significant ductal patency requires echocardiographic assessment. However, the definition of hemodynamically significant patent ductus arteriosus remains controversial [19].
Sehgal and Meneham [14] considered PDA as hemodynamically significant according to the following echocardiographic criteria: PDA diameter> 3 mm, LA:Ao > 1.5, LVO:SVC ≥ 4, PDA:LPA ≥ 1, EDLPAv > 30 cm/s, PDA Vmax < 1.5 m/s .
Yoo et al. [20] defined hsPDA if PDA had a transductal diameter ≥ 1.4 mm/kg with significant left to right shunt confirmed by echocardiography. Presence of clinical symptoms due to hsPDA was defined as at least one of the three following clinical symptoms: oliguria ≤ 1 mL/kg/h in the preceding 8 h before ibuprofen treatment, hypotension caused by PDA requiring inotropics more than 10 μg/kg/min or respiratory difficulty requiring invasive mechanical ventilation.
Schwarz et al. [21] defined hsPDA if there was a left-to-right shunt through PDA confirmed by echocardiography and at least 3 of the following 6 criteria were met: LA/Ao-ratio > 1.5, PDA diameter ≥ 1.5 mm/kg bodyweight, need of respiratory support (mechanical Ventilation or continuous positive airway pressure with supplemental oxygen), reverse, or zero end diastolic flow in ACA (= RI_ACA ≥ 1), LVPEP/LVET < 0.32.
The complications of hsPDA transcend heart failure to involving several organs leading to need for respiratory support, need for supplemental oxygen, prolonged mechanical ventilation, bronchopulmonary dysplasia, pulmonary hemorrhage, intraventricular hemorrhage, abnormal cerebral perfusion, necrotizing enterocolitis, and increased mortality [22].
Although none of the studies could prove a cause-and-effect relationship between PDA and these morbidities, it is biologically plausible that a significant shunt across PDA causes fluctuation in cerebral blood flow contributing to the pathogenesis of IVH, persistently increased volume in pulmonary vascular bed leading to CLD, and steal from splanchnic circulation producing NEC [11].
One hundred fifty-two preterm babies ≤ 34 weeks gestation admitted to NICU over 6 months period were included in the present study, 87 babies (57.2%) had PDA, 33 (37.9%) of them had hemodynamically significant PDA, while 54 (62.1%) babies had hemodynamically non-significant PDA and 65 babies (42.8%) did not have PDA.
Our results came in concordance with Danfang et al. [23] who studied 105 neonates ≤ 34 weeks gestational age and found 34 (43.5%) having hsPDA, 44 (56.5%) having non-hsPDA and 27 (25.7%) having no PDA.
Khositseth et al. [24] reported that prevalence of hsPDA among his preterm population babies was 29.3%, non-hsPDA was 20.7%, and 50% did not have PDA.
On the other hand, El-Saiedi et al. [25] found that prevalence of hemodynamically significant PDA among her study population was 52% which was higher than in our study (37.9%). This may be explained by that the gestational age of included preterms was 32 weeks versus 34 weeks in the current study.
When we compared demographic data of PDA vs non-PDA group and hsPDA vs non-hsPDA we did not find any significant difference between the two groups, apart from APH which was higher among mothers of PDA group and PIH which was higher among hsPDA group (P = 0.002,0.039 respectively).
Okur et al. [26] studied a total of 119 patients with gestational age ≤ 32 weeks and birth weight ≤ 1500 gms, his results contrasted with ours regarding birth weight which was lower in hsPDA but agreed with our results concerning length of NICU stay which did not differ significantly between the two groups.
In the current study, PDA group depicted poor Apgar scores (less than 5 at 1 min) when compared to non-PDA group (P = 0.047). Okur et al [26] and Lee et al [27] reported similar results.
The number of babies who needed CPAP or were mechanically ventilated and duration of mechanical ventilation were significantly higher in hsPDA when compared to non-hsPDA group (P = 0.007, 0.003, 0.001, respectively). This came in agreement with Okur et al [26] who found that the duration of mechanical ventilation was longer in the hsPDA group when compared to non-hsPDA group.
Our study revealed more babies suffered metabolic acidosis and had high lactate level in PDA and hsPDA groups (P = 0.001, < 0.001, respectively). This came in contrast with El-Saiedi et al. [25] study which did not find difference in serum lactate level between hsPDA and non-hsPDA.
According to the present study, hemodynamic parameters: tachycardia, hypotension, wide pulse pressure measured on day 3 of life, were found significantly higher in the PDA and hsPDA group vs non-PDA and non-hsPDA (P = 0.009, 0.005, 0.001, 0.038, 0.001, 0.001), respectively; these results coincided with those of Seghal and Menahem [14] who found that diastolic and mean blood pressure in his studied population were significantly lower whereas pulse pressure was significantly higher in hsPDA when compared to non-hsPDA and no PDA group (P = 0.005). On the other hand, Benitz et al. [8] did not find any difference in the heart rate between hsPDA and non-HSPDA.
Lee JA et al. [27] stated that the core issue in management of PDA is to select patients who will benefit from the pharmacological and surgical ligation using epidemiological, clinical, and echocardiographic data, to avoid the unnecessary adverse consequences of such modalities. Controversy still remains regarding the benefit of treating PDA in preterm infants and studies are providing contradictory results.
Sehgal and Menahem [14] recommended that in practice PDA size on echocardiogram, chronic lung disease, and prolonged ventilation should be taken into consideration regarding the management of PDA.
In the current study, 29 preterm infants had hemodynamically significant PDA and received first course of paracetamol 15 mg/kg/6 h for 3 days. Of them, 20 (68.9%) cases closed, 9 babies failed closure and received 2nd course paracetamol. Four of them (13.7%) closed, 5 babies (50%) failed closure after 2nd course paracetamol and were assigned for device closure by catheterization or surgical ligation.
Our treatment strategy coincided with Pharandi et al [19]. Twenty babies whose gestational age ≥ 25 weeks suffering from PDA were included in his study; 10 babies (50%) closed after first course paracetamol; 10 babies failed closure and received second course paracetamol; of them, 4 closed and 6 failed closure after second course [28].
On the other hand, Bagheri et al. [29] treated 67 babies whose gestational age < 37 weeks with paracetamol for duct closure; 82% of his studied population closed after first course. Second course was given to those who failed closure; of them, 50% closed. We attributed difference between our results and this is regarding PDA closure rate after 1st course paracetamol to the higher gestational age of his studied population which was < 37 weeks gestation vs ≤ 34weeks of our population. Accordingly, some of his babies would have undergone spontaneous closure regardless of paracetamol administration [28].
Regarding comorbidities and complications reported in the current study, sepsis and pulmonary hemorrhage were significantly associated with PDA when compared to non-PDA group (P = 0.009, 0.016, 0.07), respectively. Pulmonary hemorrhage was significantly associated with HS PDA when compared to non-hsPDA (P = 0.031). This data came in agreement with Okur et al. [26] who reported no difference in early neonatal sepsis, IVH, BPD between hsPDA and non-hsPDA groups.
However, Lee et al. [27] found more infants suffering from early sepsis in the PDA group when compared with the non-PDA group. Visconti et al. [30] concluded that late sepsis was significantly coexisting with hsPDA. In his study, four infants had re-opening of ductus arteriosus and three other infants developed PDA in the course of late sepsis attacks which may be explained by the effects of cytokines released during sepsis.
We found that more babies died in PDA group when compared to non-PDA group and more babies suffering from hsPDA died compared to non-hsPDA; however, we do not attribute this to PDA nor can we prove a cause effect relationship.
This data comes in agreement with the studies of Okur et al. and Visconti et al. [26, 30] which revealed that hsPDA patients have higher mortality rate compared with non-hsPDA patient. On the other hand, Okur et al. [26] reported no significant difference between hsPDA group and non-hsPDA groups regarding mortality.