Reopening of the ductus arteriosus in preterm infants;Clinical aspects and subsequent consequences

Abstract

OBJECTIVE:

Patent ductus arteriosus is a common problem frequently encountered in preterm infants. We aimed to study the risk factors associated with reopening of patent ductus arteriosus and their short term outcomes in preterm infants.

METHODS:

A total of 162 preterm infants born between November 2013 and December 2015 with gestaional age less than 32 weeks and treated for hemodynamically significant patent ductus arteriosus are included in our study.

RESULTS:

113(69.8%) showed permanent closure and 49(30.2%) infants revealed symptoms of reopening after effective closure of patent ductus arteriosus. Low birth weight and small gestational age were more common in reopening group. Multivariete analysis showed that sepsis and multiple courses of drug treatment were independent factors affecting reopening of hemodynamically significant patent ductus arteriosus (OR: 3.01, 95% CI 1.48–6.13, p = 0.002) and (OR: 2.67, 95% CI 1.23–5.82, p = 0.013) respectively. Reopened group had a remarkable higher rate of developing necrotising nnterocolitis, bronchopulmonary dysplasia and retinopathy of prematurity than the closed group. (16.3% vs 4.4%, p = 0.01, 55.1% vs 28.3%, p = 0.001 and 55.1% vs 23.0%, p = 0.0001 respectively).

CONCLUSION:

Late neonatal sepsis and the need of multiple drug courses to close patent ductus arteriosus are risk factors affecting the reopening of patent ductus arteriosus in preterm infants.

Keywords

Patent ductus arteriosus preterm infants reopening risk factors short outcomes

1 Introduction

Patent ductus arteriosus is an important issue encountered in preterm neonates associated with high morbidity and affecting approximately half of infants born at less than 29 gestational weeks or weighing less than 1500 gram at birth [1, 2].

A hemodynamically significant Patent ductus arteriosus leads to cardiac failure that needs urgent medical approach [3]. The delay in initiation of medical or surgical treatment may decrease the chances of successfully closure [3, 4]. Indomethacin, ibuprofen and paracetamol have been used to treat hemodynamically significant patent ductus arteriosus in preterm infants over the last years. Ibuprofen seems to be the first drug of choice due to its higher safety and fewer gastrointestinal and renal side effects than indomethacin [5, 6]. Recent studies suggested that paracetamol had gained a significant role and becomes an alternative drug in the management of hemodynamically significant patent ductus arteriosus [7, 8].

Some premature infants showing successful clinical constriction of PDA after effective treatment develop ductus arteriosus reopening later in their follow up period [9 –11]. In the recent years, more attention has been paid to the importance of patent ductus arteriosus and its significance on the clinical course of pretem infants. As far as we know, few clinical studies investigated the risk factors affecting reopening of patent ductus arteriosus and its possible adverse effects on premature infants [9 –11]. The aim of our present study was to identify the risk factors associated with reopening of patent ductus arteriosus after persistent closure with ibuprofen or paracetamol treatment, and to estimate their short term outcomes on preterm infants.

2 Materials and methods

This study was carried out at the neonatal intensive care unit of the Zekai Tahir Burak Maternity Teaching Hospital between November 2013 and December 2015. Patients eligible for this study were infants born less than or equal to 32 gestaional weeks and treated for hemodynamically significant patent ductus arteriosus. Patients with major congenital malformations, chromosomal anomalies, perinatal asphyxia or congenital heart disease were excluded from this study. Patients with ASD, PFO and VSD are also excluded from our study.

2.1 Participant flow and follow-up

Gestational age was determined based on the last date of maternal menstruation, fetal ultrasonography findings or the New Ballard Scoring system [12].

The diagnosis of hemodynamically significant patent ductus arteriosus was defined in infants showing the cutoffs for diagnosing of hemodynamically significant patent ductus arteriosus reported by Jain et al. [1]. Preterm infants with ≤32 weeks of gestational age who had clinical signs and symptoms of hsPDA like; tachypnea, apnea, increased need for oxygen, difficulty with feeding, murmur, cyanosis and symptoms of congestive heart failure were soon evaluated by echocardiography. The diagnosis of hsPDA was made by echocardiographic findings in terms of ductal diameter >1.5 mm and any of the following: Atrial: aortic root ratio >1.5 mm, peak velocity in the diastole of the left pulmonary artery and the evaluation of end-diastolic retrograde flow in the descending aorta and poor cardiac function including, persistent tachycardia (heart rate >160 beats/min), bounding pulse, hyperactive precordium, pulse pressure >25 mmHg, hepatomegaly, pulmonary hemorrhage, increasing respiratory support, the need of oxygen supplementation or in pressure support and evidence of cardiomegaly or pulmonary congestion on chest x-ray [1, 4].

Patients who had hemodynamically significant patent ductus arteriosus were treated with either oral ibuprofen (Dolven, Zentiva, Istanbul, Turkey) (initial dose of 10 mg/kg, followed by 5 mg/kg at 24 and 48 h) or intravenous paracetamol (Parol, Atabay, Istanbul, Turkey) (15 mg/kg 4 times aday for 5 days). Once hsPDA was diagnosed, oral ibuprofen was first administered to all infants. Infants who had feeding intolerance or those with contraindications of ibuprofen therapy (Suspected or proven sepsis, active bleeding, thrombocytopenia ≤50000/mm³, coagulation disorders, necrotising enterocolitis, renal failure, daily urine output ≤0.6 ml/kg/hour, serum creatinine >1.6 mg/dl) were administered intravenous paracetamol. Patients were re-evaluated by echocardiography 24 hours after stopping medical treatment. An additional course was given to infants whose patent ductus arteriosus was not closed. A final echocardiography was performed for all patients. Infants who had complete closure or residual luminal flow without signs of hemodynamically significant patent ductus arteriosus were included in our study. During follow-up period, if patient showed clinical symptoms of patent ductus arteriosus again, a control echocardiography was performed. If the results (ductal diameter >1.5 mm) of echocardiography showed hemodynamically significant patent ductus arteriosus the patient was classified into the reopened group Patients who responded to treatment and then were never symptomatic particularly presence of a murmur were classified as control group.

In our retrospective study, we evaluated the hospital records of the eligible infants. Prenatal, natal and postnatal medical history of infants, demographic, clinical and radiological data, complete blood conunt and arterial blood gas findings were recorded.

Clinical, biochemical and radiographical parameters used in our multivariate analysis were obtained on the actual day of PDA reopening in the study group and on the second postnatal week in the control group and we compared the differences in the clinical aspects between the two groups.

Bronchopulmonary dysplasia was defined as chest radiographic evidence of lung disease and persistent oxygen requirement at 36 weeks postmenstrual age [13].

Necrotising enterocolitis was diagnosed in terms of clinical signs and abdominal radiographs and categorized according to the criteria originally proposed by Bell et al. subsequently modifiedby Walsh and Kliegman [14]. Retinopathy of prematurity was defined according to the international classifications as grades 3 or greater [15]. Intraventricular hemorrhage was classified according to Papile and Bursten who categorize grades III and IV as severe [16]. Positive blood culture for bacterial growth was considered as the gold standard for diagnosis of proven sepsis.

2.2 Statistical analysis

Statistical analysis was performed using SPSS17.0 version (Statistical Package for Social Sciences, SPSS Inc, Chi-106 cago, IL). Continuous variables were expressed as mean±SD for normally distributed variables and as median [min-max)] for variables that were not normally distributed. Categorical data were presented as number and/or percentage. Chi square for categorical variables and independent samples t test (for parametric continous variables) or Mann–Whitney U test (for non- parametric continous variables) was used for univariete analysis. Variables with a p value <0.20 were taken into multivariate regression analysis. Then, binary logistical regression analysis using the stepwise method (backward selection) was performed to identify independent predictors that were associated with reopening of PDA. The evaluation of the model adjustment/adequacy was acquired by the method of Hosmer and Lemeshow test [17]. The results of the regression analysis are presented with odds ratios (ORs) and their 95% confidence intervals (CIs). Statistical significance was set at p < 0.05.

This study was approved by the Medical Ethics Committee of Zekai Tahir Burak Hospital.

3 Results

A total of 162 patients 113 (69.8%) controls and 49 (30.2%) patients with reopening were included in the study. Demographic features of control and reopening group is depicted in Table 1. Median (min-max) gestational weeks of the patients with reopening were significantly lower than controls (27.0 (24.0–31.0) vs 28.0 (23.0–33.0), p = 0.024). Sepsis and acidosis were more common in patients with reopening than controls (57.1% vs 29.2%, p = 0.001 and 38.8% vs 21.2%, p = 0.002, respectively). There was no other significant difference between the two groups in terms of gender, birth weight, respiratory distress syndrome drug of medication (either ibuprofen or paracetamol), daily volume of fluid intake, thrombocytopenia and anemia.

Table 1
Demographic features of the patients

Closed group (n = 113) Reopening group (n = 49) P-value

Gestational weeks (median, min-max) 28.0 (23.0–33.0) 27.0 (24.0–31,0) 0.024

Gender 0.26

Male (n = 85; 52,5%) 49.6% 59.2%

Female (n = 77;47,5%) 50.4% 40.8%

Birth weight (gm) 1010.81±32 929.59±200 0.055

RDS (n = 14; 87%) 87.6% 85.7% 0.741

First treatment

Ibuprofen (n = 114; 70,4%) 73.5% 75.5% 0.784

Paracetamol (n = 42; 25,9%) 26.5% 24.5%

Result of first treatment

Closed (n = 96; 59,3%) 69.0% 36.7% 0.0001

Patent (n = 66; 40,7%) 31.0% 63.3%

Age at first drug treatment (day) 3.66±2.16 3.61±1.56 0.881

Number of drug treatment courses (median, min-max) 1.0 (1.0–2.0) 1.0 (1.0–2.0) 0.004

Daily fluid intake (ml) (median, min-max) 160.0(120.0–180.0) 160.0(140.0–175.0) 0.539

Thrombocytopenia (n = 29; 17,9%) 16.8 20.4 0.584

Anemia (n = 86; 53,1%) 52.1 55.1 0.735

Sepsis (n = 61; 37,7%) 29.2 57.1 0.001

Acidosis (n = 43; 26,5%) 21.2 38.8 0.02

	Closed group (n = 113)	Reopening group (n = 49)	P-value
Gestational weeks (median, min-max)	28.0 (23.0–33.0)	27.0 (24.0–31,0)	0.024
Gender			0.26
Male (n = 85; 52,5%)	49.6%	59.2%
Female (n = 77;47,5%)	50.4%	40.8%
Birth weight (gm)	1010.81±32	929.59±200	0.055
RDS (n = 14; 87%)	87.6%	85.7%	0.741
First treatment
Ibuprofen (n = 114; 70,4%)	73.5%	75.5%	0.784
Paracetamol (n = 42; 25,9%)	26.5%	24.5%
Result of first treatment
Closed (n = 96; 59,3%)	69.0%	36.7%	0.0001
Patent (n = 66; 40,7%)	31.0%	63.3%
Age at first drug treatment (day)	3.66±2.16	3.61±1.56	0.881
Number of drug treatment courses (median, min-max)	1.0 (1.0–2.0)	1.0 (1.0–2.0)	0.004
Daily fluid intake (ml) (median, min-max)	160.0(120.0–180.0)	160.0(140.0–175.0)	0.539
Thrombocytopenia (n = 29; 17,9%)	16.8	20.4	0.584
Anemia (n = 86; 53,1%)	52.1	55.1	0.735
Sepsis (n = 61; 37,7%)	29.2	57.1	0.001
Acidosis (n = 43; 26,5%)	21.2	38.8	0.02

RDS: Respiratory distress syndrome.

In patients with reopening, reopening date was 17.183 ± 7.172 postnatal day. Three (6.1%) patients in reopening group underwent ductal ligation as a final treatment of hemodynamically significant patent ductus arteriosus. Table 2 shows short term outcomes of patients. Retinopathy of prematurity, bronchopulmonary dysplasia and necrotising enterocolitis were more common in reopening group than controls (55.1% vs 23.0%, p = 0.0001; 55.1% vs 28.3%, p = 0.001 and 16.3% vs 4.4%, p = 0.01, respectively). Necrotising enterocolitis occurred after the reopening of PDA in the study group. Mortality rate was 27.7% in reopening group and 20.4% in control group (p = 0.313).

Table 2

Consequences of patent ductus arteriosus

	Closed group (n = 113)	Reopening group (n = 49)	P-value
Hospitalization (day)	58.98±28.52	69.42±41.49	0.091
Neonatal mortality (hospitalization duration) (n = 36;22,2%)	20.4%	27.7%	0.313
Weight at discharge (g)	2139±510	2088±450	0.621
ROP (n = 53; 32,7%)	23.0%	55.1%	0.0001
BPD (n = 59; 36,4%)	28.3%	55.1%	0.001
IVH (n = 135; 83,3%)	85.8%	77.6%	0.193
NEC (n = 13; 8,%)	4.4%	16.3%	0.01
Need of Surgical Ligation	(n = 3; 0.05%)	(n = 0; 0%)

ROP: retinopathy of prematurity, BPD: bronchopulmonary dysplasia, IVH: intraventricular hemorrhage, NEC: necrotizing enterocolitis.

Multivariete analysis showed number of treatment courses (OR: 2.67, 95% CI 1.23–5.82, p = 0.013) and presence of sepsis (OR: 3.014, 95% CI 1.48–6.13, p = 0.002) as independent factors affecting reopening (Table 3).

Table 3

Multivariate analysis of factors affecting reopening

	Adjusted odds ratio	95% Confidence interval		P- value
		Lower	Upper
Number of treatment courses	2.67	1.23	5.82	0.013
Presence of late onset sepsis	3.01	1.48	6.13	0.002

4 Discussion

In our present study, we reported reopening in 30.2% of cases. Weiss et al. [10] and Uchiyama et al. [11] reported reopening in 23% and 26% respectiveley. This difference in rates might be due to some factors underlying reopening of patent ductus arteriosus. Prematurity, low birth weight, residual luminal flow after indomethacin treatment and extra volume of fluid adminstered daily before patent ductus arteriosus treatment were factors significantly affecting reopening in Weiss’s study [10], whereas, presence of residual luminal flow after indomethacin treatment was the major factor underlying reopening in Uchiyama’s study [11]. In consistent with the previous studies [18, 19], residual luminal flow after ibuprofen or paracetamol medications was found in 60% of our patients before showing reopening of their patent ductus arteriosus and only in 15% of control group. Another study on patent ductus arteriosus reopening deduced that 75% of infants with residual luminal flow after medical treatment developed hemodynamically significant patent ductus arteriosus later in their clinical course [20]. We also found that infants who did not respond to the first course of ibuprofen or paracetamol treatment and need multiple courses of medications were more prone to reopening than those who showed permanent closure after the first course of medication. multivariate logistic regression analysis revealed that multiple medication courses needed for patent ductus arteriosus constriction were considered to be independent risk factors for reopening of patent ductus arteriosus (adjusted odds ratio 2.67:95% confidence interval 1.23–5.82; p = 0.013). These findings are in consistent with Keller’s who found that additional indomethacin treatment was unlikely to produce permanent ductus closure in preterm infants born before 28 weeks’ gestaional age [21].

Previous clinical studies on preterm infants had investigated the role of indomethacin on patent ductus arteriosus reopening [10 , 20]. To the best of our knowledge, there was no any published study that examined the role of ibuprofen or paracetamol on patent ductus arteriosus reopening and this will be the first study in the literature that analysed the risk factors and the short term outcomes of patent ductus arteriosus reopening after using ibuprofen and paracetamol for patent ductus arteriosus closure. Yucel et al. [7] reported successful closure of hemodynamically significant patent ductus arteriosus in all patients treated with paracetamol and there was no reopening in any case. In the same feild, Yurttutan et al. [8] reported reopening in one patient and permanent closure in 5 patients. Erdeve et al. reported a higher reopening rate in infants who received oral ibuprofen than those with intravenous ibuprofen [6]. In our present study, multivariate logistic regression analysis revealed there was no statistical difference between patients treated with ibuprofen or paracetamol.

Patent ductus arteriosus closure is inversely correlated to the gestational age and birth weight. Any delay in initiation of medical or surgical treatment may decrease the chances of successfully closure [4, 18]. In our study, the median (min-max) gestational age of reopening group were significantly lower than controls (27.0 (24.0–31.0) vs 28.0 (23.0–33.0), p = 0.024). Birth weight were lower in reopening group than in controls (929.59±200.23 vs 1010.81±326.03, p = 0.055). In accordance with the former studies [4, 18]. We concluded that, low birth weight and small gestational age were significantly correlated to reopening of patent ductus arteriosus.

Recent clinical studies showed that neonatal sepsis was one of the most predictive factor affecting reopening of patent ductus arteriosus [22, 23]. There are many possibilities that might explain the relationship between sepsis and hemodynamically significant patent ductus arteriosus. Sepsis is frequently accompanied by hypotension, altered vascular tone and inflammation induced vasoactive cytokines. These factors lead to the relaxation of smooth muscles of the ductus and influences the permanent closure of patent ductus arteriosus in preterm infants [22, 23]. We found that sepsis was more common in patients with reopening than controls (57,1% vs 29.2%, p = 0.001), and it was the most common factor affecting reopening in our study group. The multivariate logistic regression analysis revealed neonatal sepsis was one of the independent risk factors for reopening of patent ductus arteriosus (adjusted odds ratio 3.014:95% confidence interval 1.480–6.139; p = 0.002). Multiple investigators reported the significant relationship between sepsis and patent ductus arteriosus reopening. Stoll et al. [24] reported a particular association between early neonatal sepsis and hemodynamically significant patent ductus arteriosus. The same author [25] reported again in a second study a remarkable relation between late-onset neonatal sepsis and reopening of patent ductus arteriosus. Gonzalez et al. [26] found that sepsis increased the risk for late reopening of the ductus in very low birth weight infants.

Several clinical studies reported a considerable association between hemodynamically significant patent ductus arteriosus and neonatal short term outcomes [10 , 27–29]. We found that bronchopulmonary dysplasia was more common in our reopening group than controls (55.1% vs 28.3%, p = 0.001). These findings are in consistent with the previous studies [10, 11] who reported higher rates of bronchopulmonary dysplasia in premature infants with PDA. We also deduced that retinopathy of prematurity, and necrotizing enterocolitis were more common in our reopening group than in controls (55.1% vs 23.0%, p = 0.0001; and 16.3% vs 4.4%, p = 0.01, respectively). Intraventricular hemorrhage was more common in control group than in reopening (85.8% vs 77.6% p = 0.193). Uchiyama et al. [11] reported that Intraventricular hemorrhage and retinopathy of prematurity did not differ significantly between reopening and control groups. Yang et al. [18] reported that there were no meaningfull differences in major morbidities such as retinopathy of prematurity, necrotizing enterocolitis, bronchopulmonary dysplasia and retinopathy of prematurity after early adminstration of indomethacin for patent ductus arteriosus constriction. The differences in these findings might be related not only to hemodynamically significant patent ductus arteriosus but also to multiple factors that adversely influence pretem infants morbidities [18 –30].

As far as we know, this was the first study in the literature that investigated both the risk factors and the subsequent out comes of hemodynamically significant patent ductus arteriosus reopening in premature infants. Nevertheless, the number of our hemodynamically significant patent ductus arteriosus cases were more much that those of the previous studies on the same feild, and our study was among the few studies that researched the relationship between residual luminal flow and reopening of hemodynamically significant patent ductus arteriosus. These facts strengthen our study and make it more valuable.

Early screening and treatment for hemodynamically significant patent ductus arteriosus are effective preventive strategies in preterm infants to cope with undesirable medical issues and outcomes. The investigation of these long term outcomes will be important directions and guides for future researches.

4.1 Limitations of the study

Data of our retrospective study depended upon data collected from hospital records. We could not identify patients who had their PDA re-open but remain asymptomatic because these patients were not rescanned as they did not any suggestive symptoms.

5 Conclusion

Reopening of PDA in preterm infants is influenced by the presence of late neonatal sepsis and increased directly in those who need multiple courses of drug treatment. Reopened group had a higher rate of developing NEC, BPD and ROP than closed group. Early approch to hsPDA and assesment of risk factors may play an important role in preventing subsequent consequences in preterm infants.

Funding sources

None.

Conflict of interest

Authors have no conflicts of interest to disclose.

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