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 Table of Contents  
Year : 2020  |  Volume : 9  |  Issue : 2  |  Page : 111-120

Long- and short-term effects of propranolol hydrochloride treatment on very preterm newborns

1 Erciyes University Medical Faculty, Department of Pediatrics, Division of Neonatology Kayseri Training and Research Hospital, Kayseri, Turkey
2 Division of Neonatology, Kayseri Training and Research Hospital, Kayseri, Turkey

Date of Submission18-Mar-2019
Date of Decision01-Jan-2020
Date of Acceptance23-Jan-2020
Date of Web Publication21-Apr-2020

Correspondence Address:
Dr. Osman Bastug
Neonatalogy Unit, Kayseri Training and Research Hospital, Kayseri
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcn.JCN_28_19

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Background: While propranolol hydrochloride (PH) is being more widely used in adult patients, its administration in the neonatal period as well is progressively on the rise in our time. With the increasing use of PH in the neonatal age period, worries resulting from the potential adverse effects of the agent on vital organs, such as brain, in particular, have come to the fore. Such concerns increase even more when PH is used in treating preterm infants. Our study, aiming to clarify these increasing concerns, is the first clinical one of its kind in the literature, conducted on very preterm infants, the patient group most vulnerable to PH treatment. Aims: To investigate possible short- and long-term side effects of using PH during the neonatal period and to provide information to clinicians regarding such side effects. Study Design: Case–control study. Materials and Methods: This was a double-blind, randomized, and placebo-controlled trial. In the study, we included 36 very preterm infants subjected to PH treatment (0.5 mg/kg/6 h) initiated in the first postnatal month and lasting for approximately 1 month (PH group [PHG]) and 40 very preterm infants who received distilled water in place of PH (control group [CG]). The gestational age of all infants in the study was below 31+6 weeks, and their birth weight was under 1500 g. The patients' vital functions and physical development were monitored and recorded in patient follow-up forms. At approximately 1 year of age (CG: 9.73 ± 4.56 months and PHG: 10.8 ± 5.73 months), the Ankara Developmental Screening Inventory (ADSI) and the Denver Developmental Screening Test II (DDST-II) were used to assess the mental development of the children. Results: In the PHG patients, PH treatment was initiated at 27.0 ± 2.7 days of life and lasted for 26.5 ± 8.7 days. The newborns in the CG received distilled water for similar durations. A statistically significant difference in blood sugar levels was detected between CG (78.4 ± 12.5) and PHG (65.6 ± 7.5) (P = 0.006). However, no statistically significant difference was found between the two groups in terms of physical and mental development (ADSI and DDST-II) of the children at the end of the study (P > 0.05). Conclusions: When used on very preterm infants, PH may have some temporary effects on the patients' vital functions in the short term; however, no serious side effects were detected that may affect the physical and mental development in the long run.

Keywords: Long-term effects, propranolol hydrochloride, short-term effects, very preterm newborns

How to cite this article:
Korkmaz L, Ozdemir A, Korkut S, Bastug O. Long- and short-term effects of propranolol hydrochloride treatment on very preterm newborns. J Clin Neonatol 2020;9:111-20

How to cite this URL:
Korkmaz L, Ozdemir A, Korkut S, Bastug O. Long- and short-term effects of propranolol hydrochloride treatment on very preterm newborns. J Clin Neonatol [serial online] 2020 [cited 2021 Aug 1];9:111-20. Available from: https://www.jcnonweb.com/text.asp?2020/9/2/111/283029

  Introduction Top

Propranolol hydrochloride (PH) is a well-tolerated, nonselective (both β1 and β2), beta-adrenoreceptor blocker with increased use in the neonatal period.[1],[2] PH treatment is applied in a multitude of diseases in the neonatal period, primarily in chronic heart failure,[3] hypertrophic obstructive cardiomyopathy,[4] supraventricular tachycardia,[4] neonatal thyrotoxicosis,[5] management of hypercyanotic spells in tetralogy of Fallot,[6] and in the control of hypertension.[7]

The use of PH, apart from the disorders mentioned above, has recently become a prominent practice with increased use also in treating infantile hemangiomas (IHs)[1],[2],[8] and retinopathy of prematurity (ROP).[2],[9],[10] For all these reasons, the administration of PH in the neonatal period is increasing and gaining popularity every day; however, worries about its possible short- and long-term untoward side effects have become a current issue. When preterm infants are the subject, the hesitation to use PH is explainable.[2],[9],[11],[12]

As can be expected, the reason for the widespread hesitation regarding the use of PH is that the physical development of newborns has not been completed at birth yet and that PH may have a negative impact on organ development.[2],[9]

For all these reasons, the concerns resulting from the use of PH in the neonatal period are considerably important. There are few clinical studies in the literature on the reliability of PH use in the neonatal period, particularly in the long term.[9]

We performed our study on preterm infants, the patient group most vulnerable to PH, and evaluated the possible short- and long-term effects of the agent on physical and mental development. Thus, we aimed to share our experience and results regarding the possible side effects of PH and to contribute to the existing literature in this respect.

  Materials and Methods Top

Planning of the study, selection of the patients, and propranolol hydrochloride application

This study, planned as a sequel to the study[2] on a total of 171 very preterm newborns in the neonatal intensive care unit of Erciyes University Medical Faculty, was realized as randomized, double-blind, placebo-controlled in a single institution. Ninety-five newborns could not be taken to the current study due to various reasons, and the study was completed with 76 patients [Table 1], [Table 2], [Table 3], [Table 4] and [Figure 1], [Figure 2], [Figure 3].
Table 1: Somatic growth parameters and characteristics of patients

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Table 2: Vital functions of patients during propranolol hydrochloride treatment

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Table 3: Ankara Neurodevelopmental Screening Inventory results

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Table 4: Denver Neurodevelopmental Screening Test-II results

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Figure 1: Consolidated standards of reporting trials flow diagram, enrollment, randomization, and analysis of the 171 study very preterm infants

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Figure 2: Comparison of mean development values of cases in Ankara Developmental Screening Inventory four development areas

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Figure 3: Evaluation of normal, suspect, and abnormal cases in terms of Denver Developmental Screening Test-II parameters and comparisons according to the study groups

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The study sample consisted of 76 patients, 40 of whom received distilled water (control group [CG]), whereas the remaining 36 received PH (PH group [PHG]) [Table 1], [Table 2], [Table 3], [Table 4] and [Figure 1], [Figure 2], [Figure 3]. The preterm newborns included in the study were mostly those at risk of ROP and therefore were placed on prophylactic PH therapy (91.6%), whereas the remaining were those with cardiac problems for whom PH treatment was indicated. The PH treatment was initiated at 27.0 ± 2.7 days of life and its total duration was 26.5 ± 8.7 days [Table 1].

Preterm infants with gestational age (GA) below 31+6 weeks and gestational weight below 1500 g were enrolled in the study. Of the patients, 40 received distilled water only (CG) and 36 received PH (PHG). All patients in the PHG were administered PH for approximately 1 month (26.5 ± 8.7 days) initiated in the first postnatal month (27.0 ± 2.7 days). Since PH treatment of preterm infants with IH in the early period is controversial, such patients are not permitted to have PH in the early period. Consequently, there were not any newborns with IH among the patients included in our study. The newborns in the CG received distilled water for 30 days beginning in the 1st month after birth. The patients were followed first in the hospital and subsequently in the outpatient clinic. Care was taken to monitor the newborns in the hospital service in the period they were administered PH. In addition, the patients who were secure from the short-term side effects of PH were discharged after their parents were taught how to do the PH treatment of their babies, provided that their follow-ups would be done in the outpatient clinic.

The patients with sepsis, renal failure, bronchopulmonary dysplasia, apnea, central nervous system disorders, hypoglycemia, hypoxia, nutritional intolerance, and small for GA babies, those who require mechanical ventilation (before the administration of PH or placebo), and finally, the cases without parental consent were not included in the study.

Because of the absence of other PH preparations in Turkey, 40 mg dideral tablets (Sanofi-Aventis) were used in the therapy. Dideral tablets were dissolved in 20 mL distilled water. Since the stabilization duration of PH in distilled water is not known, the amount of the oral solution remaining after each administration was not used again, and the solutions were freshly prepared on each occasion. The solutions were administered orally or with an orogastric tube 30 min before feeding at times different from those of other treatments. It had been demonstrated in previous studies that the PH dose of 0.5 mg/kg/6 h (which we used in our research) is enough to ensure an ideal drug blood level in the neonatal period.[4]

PH administration was started in low doses which were increased in stages until it reached the therapeutic dose in 3 days. On the 1st day, PH was administered at a dose of 0.2 mg/kg/6 h and was increased to 0.5 mg/kg/6 h on the 3rd day. The discontinuation of the medicine was achieved gradually in 1 week by tapering the dose.

The follow-up of vital functions and somatic development

The patients' postnatal somatic development values (length, weight, and head circumference) thought to reflect the long-term effects of PH treatment were recorded at birth and at approximately 1 year of age (corrected age) [Table 1]. The patients' somatic development values (the values obtained during the study) were recorded in the same period as those of the mental development tests [Table 1].

Vital functions thought to reflect the short-term effects of PH treatment (apnea, blood glucose, blood pressure, heart rate, and respiratory rate) were monitored only during the PH administration and were recorded in the study cards. The vital functions in question were monitored closely, particularly in the 1-h period following PH administration. The vital function values obtained during the first 3-h period after PH administration were taken into consideration and recorded in patient follow-up cards to be used in the study [Table 2].

Each patient's blood pressure was measured at least 4 times a day and between the 3rd and 4th h after each PH administration. The systolic and diastolic blood pressure values were recorded on a daily basis in the study cards. Heart rate and respiratory rate were measured 12 times a day, but only those values obtained between the 3rd and 4th h after PH administration were recorded and taken into consideration in the study.

Bradycardia was defined as the cardiac rate falling below 100/min, apnea as the cessation of respiration longer than 20 s in addition to accompanying bradycardia and saturation below 88%, and hypotension as the mean arterial blood pressure <10th percentile for gestation/birth weight and postnatal age.[13] Detection of bradycardia, apnea, and hypotension twice at different times and detection of persistent bradycardia, apnea, and hypotension once in any case in our study were reasons for exclusion.

In our study, hypoglycemia was considered when blood glucose level decreased below 40 mg/dL.[14] Blood sugar was measured 2–4 times a day by means of peripheral capillary method in each newborn. The cases in which hypoglycemia was detected were monitored more closely; sporadic hypoglycemia was not a reason for exclusion from the study.

At the outset of the study, the time at which the patients started to be fed and the time of their transition to being fully fed were also included among our study parameters. However, we had to remove these parameters from the study owing to discrepancies in monitoring these patients (outpatients, in particular).

Assessment of the patients' mental development

The Ankara Developmental Screening Inventory (ADSI) and the Denver Developmental Screening Test-II (DDST-II), again thought to reflect the long-term effects of PH treatment, were administered at the corrected ages shown in [Table 1]. The mental developmental values obtained were recorded in the study cards [Table 3], [Table 4] and [Figure 2], [Figure 3].

The tests were administered by two psychologists, experts in their field, who were blind to the patients' PH treatment. They were the people specially trained for these tests and were employed in Kayseri Training and Research Hospital to conduct these tests only.

One of the mental development tests was ADSI, which is in frequent use in Turkey. In this test, four parameters were assessed as follows: Communication Cognitive Area (CCA, 65 items), Fine Motor Area (FMA, 26 items), Gross Motor Area (GMA, 24 items), and Social Skills-Self Care Area (SS-SCA, 38 items). The value corresponding to each parameter was recorded in the test form as the time (month) appropriate for this. The inventory consists of 153 items which are answered by the mothers, and responses are given as “yes,” “no,” or “don't know.” The total score of the test reflects the newborn's general developmental level. Those with an average of two standard deviations below the norm are evaluated as developmentally retarded [Table 3].[15]

The other development test used in our study was DDST-II, which is the first developmental test standardized for Turkish children after being adapted to the Turkish population in 1982. The DDST-II is a simple method of evaluating the development of infants and preschool children. The DDST-II has particular importance in following the development of infants and for early identification of developmental deviations, thereby permitting earlier commencement of rehabilitation. DDST-II assesses the child's development in four general areas: Personal Social Area (PSA, 21 items), Language Area (LA, 42 items), Fine Motor Adaptive Area (FMAA, 33 items), and Gross Motor Abilities (GMA, 37 items). According to the scores obtained with this scale, the patients were categorized as normal, suspect, and abnormal.[16]

In this test, while failure–retardation (FR) defines the patients who fail to go beyond the question corresponding to 25%–75% of the area of the item questioned in the patient's age line, Caution© defines the patients who fail to go beyond the question corresponding to 75%–90% of the item questioned in the patient's age line.

Our psychologists who applied the tests assumed the patient normal when the child did not fail in any item of the test without being classified as FR or when they received C only in one item. The patients who received FR only in one item of the test or those who received C in two or more items without FR were assessed as a suspect. Those who received FR in two or more items were considered to be abnormal, regardless of whether they had received C or not. The number of patients classified as normal, suspect, and abnormal in the DDST-II was recorded in their respective developmental areas, and statistical analyses were made between the groups (CG and PHG) in terms of the number of patients [Table 4].

Exclusion criteria

The newborns without any reliable retrospective data obtainable from patient records or from computer systems and those without parental consent were excluded from the study. The patients with all or any of the complications such as bradycardia, apnea, and hypotension during PH treatment and those whose PH treatment has been interrupted for at least 24 h for some reason were excluded from the study.

Statistical analysis

The data were analyzed using the SPSS 16.0 (SPSS Inc., Chicago, IL, USA) statistical package program. Distribution of the data was controlled through the Shapiro–Wilk normality test. Between the groups, normally distributed variables were compared using the independent sample t-test; variables without normal distribution were compared using the Mann–Whitney U-test. The Chi-square test was applied to analyze rational data. P < 0.05 was accepted as statistically significant.

  Results Top

The values illustrating the physical development of the patients in the study and their demographic parameters and vital functions are presented in [Table 1] and [Table 2]. The sex distribution of the infants in CG was equal, whereas the number of male patients was greater in the PHG [Table 1]. There was no statistically significant difference between the groups regarding the following parameters: patients' GA at birth and corrected age after PH therapy and weight, height, and head circumference at birth [P > 0.05, [Table 1].

The vital functions of the patients in the PHG were watched closely in the period of PH treatment. Apnea occurred in 12 patients in both the groups (30.0% in the CG and 33.3% in the PHG). There was no statistically significant difference between the groups in terms of cardiac rate, respiratory rate, systolic blood pressure, and diastolic blood pressure [P > 0.05, [Table 2]. The statistically significant difference between their blood sugar levels was conspicuous [P < 0.05, [Table 2]. The prominent feature of these findings was that the values representing the respiratory rate, heart rate, systolic blood pressure, and diastolic blood pressure were low. However, no value of these parameters in both the groups fell to levels low enough to endanger the patients' lives [Table 2].

The low blood glucose levels in PHG patients did not persist in pathological values. The absence of hypoglycemia in the history of the patients included in the study and the exclusion of the unstable patients from the study prevented us from experiencing problems during the study. The feeding of the patients detected to be hypoglycemic in the PHG was arranged according to the time of PH administration. Following this practice, it was observed that hypoglycemia in these patients was not persistent. As a result, in our study, there was no patient on PH treatment excluded from the study owing to hypoglycemia perse.

In some studies on PH treatment, it has been reported that hypotension occurs within 48 h after PH administration. In some publications, it has been mentioned that PH treatment should be started in low doses and that otherwise hypotension and bradycardia occur more frequently.[11]

In our study also, low blood pressure values were observed, though sporadic and few in number. For this reason, we also started PH therapy in small doses but increased them subsequently and thus observed that the number of sporadic hypotension and bradycardia in our patients diminished. We did not find any difference between CG and PHG in terms of cardiac functions (systolic blood pressure, diastolic blood pressure, and heart rate) and respiratory functions (apnea and respiratory rate) [Table 2]. However, four patients in total were excluded from the study owing to hypotension in the PHG. Increased need for ventilation and sepsis were detected in these four patients. The number of newborns excluded from the study due to the possible side effects of PH (such as apnea, patent ductus arteriosus [PDA], hypotension, hypoglycemia, and increased need for ventilation) was 10 (PHG: 6 and CG: 4). In fact, the number of patients excluded from the study in the period when the newborns were on PH (postnatal day: 27.0 ± 2.7) [Table 1] was much higher than this (approximately 35 patients). The number of newborns who had to be excluded from the study for reasons unrelated to the undesirable side effects of PH was 25 in total (6 patients upon the request of their parents, 13 patients for medication administration errors, and 6 patients for other medical treatments). The clinical follow-ups of these patients within the scope of our study were discontinued.

For reasons of untoward side effects of PH, ten newborns had to be excluded from the study: six patients in the PHG (two patients owing to PDA, hypotension, and apnea and four patients owing to hypotension, increased need for ventilation, hypoglycemia, and sepsis) and four patients in the CG (one patient owing to sepsis, necrotizing enterocolitis, and apnea; one patient owing to increased need for ventilation, one patient owing to PDA and hypotension; and one patient owing to hypoglycemia). One of the four patients in the PHG who were detected to have increased need for ventilation, hypotension, and sepsis died. No vital problem was found in nine of the ten patients excluded from the study owing to untoward side effects of PH.

PH induces apoptosis in capillary endothelial cells, and a massive and abrupt breakdown of cells is a known cause of hyperkalemia. For this reason, hyperkalemia associated with IH therapy occurs frequently.[12] Since we had not included patients with IH in our study, we encounter neither hyperkalemia (in particular) nor other electrolyte impairments in our PHG patients.

We investigated the main subject of our study, the effects of PH on subsequent mental functions, with ADSI and DDST-II. In ADSI tests, we did not find any statistically significant difference in CCA, FMA, GMA, SS-SCA between the study groups (P > 0.05) [Table 3]. We did not find any statistically significant difference in PSA, FMAA, LA, and GMA between the study groups in the DDST-II as well (P > 0.05) [Table 3], [Table 4] and [Figure 1], [Figure 2].

  Discussion Top

In our time, the wide use of PH has brought about an increasing discussion on the reliability of the agent.[2],[9],[17] The short-term effects of PH on newborns (such as bradycardia, hypotension, bronchospasm, apnea, hypoglycemia, hypothermia, and hyperkalemia) have been researched in a large number of studies.[10],[11],[12] However, there exist no studies in the literature on potential long-term side effects of PH (such as communication skills, cognitive skills, fine motor skills, gross motor skills, social skills, personal-social skills, and language skills).

When using PH in the neonatal period, clinicians are more concerned about its possible long-term side effects on vital organs (such as the brain, in particular) rather than its short-term adverse effects. We performed our study on preterm infants, the most vulnerable patient group to PH treatment, and aimed to find an answer to the question of what the long-term somatic and cognitive effects of PH use in the neonatal period are; a question to which the answer has yet not been researched completely.

We did not observe any statistically significant difference between CG and PHG in any of the parameters in the ADSI and DDST-II. In addition, we did not detect any statistically significant difference between the two groups in the somatic and mental development of the children at the follow-up visits [Table 1], [Table 3], and 4]. At the end of the study, a statistically significant difference between PHG and CG was found only in blood glucose levels [Table 2].

Accordingly, our study has corroborated the idea that caution should be exercised in the early period in monitoring the blood glucose of preterm infants on PH and that the use of PH is reliable in terms of the consequences it may produce in the long run.

It has been demonstrated in animal studies (oxygen-induced retinopathy) that PH reduces only the level of vascular endothelial growth factor (VEGF) produced excessively in hypoxic tissues, but it does not affect the normal concentrations of VEGF in normoxic tissues.[2],[9] This difference in the effect of the agent has been ascribed to VEGF regulation being different in hypoxic and normoxic tissues.

In the limited number of studies on newborns who have received PH therapy, it has been reported that no impairment occurred in their growth and development, corroborating the experimental animal studies. However, these studies were not intended to address primarily the short- and long-term effects of PH treatment on newborns. The information presented in these studies regarding the effects of PH use on newborns has been generally introduced as additional data of the conclusions drawn from the research, and the short- and long-term effects of PH have not been evaluated at all.[10],[11],[12],[18]

We have chosen the possible short- and long-term side effects of PH as the main subject of our study, which we performed on the most susceptible patient group – preterm newborns. In our study, no significant difference was found in head circumference, weight, and height of the patients in the two groups both at birth and afterward [Table 1]. In addition, detection of no significant difference, as determined by the DDST-II and ADSI, in terms of possible future side effects of PH treatment on preterm infants was consistent with the findings from previous experimental and clinical studies mentioned-above.[9],[18]

In contrast to the limited number of studies which have reported that PH use in newborn cases does not have harmful effects, it has been demonstrated in some experimental studies that subcutaneous PH in high doses (20 mg/kg/day) impairs neuronal response and that intracerebral administration of PH causes amnesia. However, the PH doses used in those experimental studies were 10–20 times higher than those used in our study (known as therapeutic doses).[4],[17],[19] Therefore, the greater effects of PH observed in the studies in question can be attributed to the high dose of PH administered.

It has been reported that the use of PH does not affect somatic development even in infants of very low weight. However, in these studies, the somatic development of the infants has been monitored during the period of PH therapy only, and the long-term effects of the agent have not been considered.[18] Yet, the conclusion obtained from these studies is consistent with the finding from our study that PH does not, in the long run, affect the somatic development (length, weight, and head circumference) [Table 1].

The PH dosage used in our study was the optimal recommended one, and the patients included in the study were stable in terms of vital functions. We believe that such a practice is an important factor which helped us reach the conclusion that PH use in neonatal period is reliable in the long term, regarding both somatic and cognitive development.

The half-time of PH in adults is seen to be shorter than its half-time in newborns, and this is attributable to the relative immaturity of the newborn liver. In preterm cases, the organs involved in pharmacokinetic processes of PH are immature. Consequently, the PH dose to be used has been discussed in the literature. In our study, the dosage we used was the one recommended in previous reports as necessary to achieve an effective blood level of PH, i.e., 0.5 mg/kg/6 h.[4]

In some studies, hypoglycemia has been reported to possibly affect the patients' long-term mental functions. In parallel with this, prolonged hypoglycemia is thought to be the mechanism underlying the long-term neurologic outcomes caused by beta-blocker use.[20],[21] Hypoglycemia associated with propranolol may not be dose-dependent. While the mechanism by which hypoglycemia develops in some children taking propranolol is not completely understood, normal glucose homeostasis is thought to be impaired through the inhibition of β-adrenergic-mediated glycogenolysis, glucogenesis (through the blockage of glycogen phosphorylase in the liver), and lipolysis. Children and infants (especially those under 3 months of age) seem to be at higher risk for this adverse effect because their glucose utilization rates are higher in the fasting state (as much as 3-fold higher in infants), attributed partly to their greater brain mass relative to their body weight. In addition, glycogen stores are lower in infants and children compared with adults, leading to reduced fasting ability.[22]

Some studies report that occult hypoglycemia occurs even without symptoms.[11] Hypoglycemia tends to occur within the first 2–3 h after PH administration. Feeding within the first 2–3 h following PH treatment prevents hypoglycemia.[11] In our study, we began feeding within the first 30 min after PH administration. Consequently, while the blood sugar levels in the PHG were found to be lower compared to the CG [Table 2], hypoglycemia in clinically significant levels was not detected in PHG patients.

The feeding of the patients detected to be hypoglycemic in our study was arranged according to the time they took PH, and hypoglycemia did not persist. Therefore, no patient in the PHG was excluded from the study only because of hypoglycemia which, in turn, showed us that hypoglycemia in PH users was a controllable side effect unworthy of worry. On the other hand, further hypoglycemic episodes were prevented by monitoring closely the blood glucose levels in the PHG patients which may explain why no statistically significant difference was found between the two groups in the ADSI and DDST-II, reflecting the long-term mental effects of PH.

Low blood pressure and low cardiac rate occur more frequently in the early hours after PH administration.[18] Especially in unstable newborns, when PH is administered, the risk of bradycardia and hypotension may increase as a result of the decreased response to catecholamines. Such problems have also been observed in healthy newborns, but they may be clinically relevant in unstable preterm newborns. As a result of the premature nature of myocardium, preterm infants' cardiac output largely depends on the heart rate, and the capability of cardiac output to rise with the increase in stroke volume is limited.[9],[23],[24]

With this very important myocardial feature of newborns, it may be thought that PH use can potentially increase mortality, especially in preterm infants. As mentioned earlier, our study groups consisted of preterm infants with stable vital signs, thus decreasing the incidence of adverse cardiac effects of PH. Moreover, the inclusion of preterm infants in the study and the maturation of vascular beta-receptors in these patients occurring later than other receptors do can be thought to reduce the undesirable cardiac side effects in newborns on PH treatment.[25]

It is important that our study is the first in the literature to address the short- and long-term effects of PH treatment in preterm neonates. We concluded that blood sugar regulation and normal cardiac/respiratory functions are crucial in newborns planned for PH treatment in order to prevent the potential side effects of PH. However, one conclusion from our study is that, as was reported also in other studies, the vital functions of the patients on PH therapy should be monitored closely at least until more extensive studies and meta-analysis are published. In addition, we have concluded that in the long run, there is no significant difference between the mental development of preterm infants subjected to PH therapy and of their counterparts who did not receive the treatment.


We were able to enroll only 76 patients in our study. The enlargement of the study groups may provide more reliable data on the subject. In addition, if developmental tests can be administered at subsequently corrected ages, more concrete data can be obtained about the mental development of preterm neonates who had undergone PH treatment.

  Conclusions Top

In our study conducted on preterm newborns, the patient group most susceptible to PH therapy, we have concluded that, as was reported in earlier studies, monitoring closely the vital functions of the patients during PH therapy should be a logical practice. Another conclusion that can be drawn from our study is that, albeit with some reservations, PH therapy has no significant side effects on the long-term mental development of preterm neonates (particularly in the DDST-II-PSA and DDST-II-LA).

These conclusions might, despite some reservations, alleviate the concerns about the long-term adverse effects of PH therapy on preterm neonates, corroborating the idea that it is reliable in the long run.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

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Korkmaz L, Bastug O, Ozdemir A, Korkut S, Karaca C, Akin MA, et al. The efficacy of propranolol in retinopathy of prematurity and its correlation with the platelet mass index. Curr Eye Res 2016;3:1-10.  Back to cited text no. 2
Bruns LA, Canter CE. Should beta-blockers be used for the treatment of pediatric patients with chronic heart failure? Paediatr Drugs 2002;4:771-8.  Back to cited text no. 3
Filippi L, Cavallaro G, Fiorini P, Malvagia S, Della Bona ML, Giocaliere E, et al. Propranolol concentrations after oral administration in term and preterm neonates. J Matern Fetal Neonatal Med 2013;26:833-40.  Back to cited text no. 4
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Filippi L, Cavallaro G, Bagnoli P, Dal Monte M, Fiorini P, Donzelli G, et al. Oral propranolol for retinopathy of prematurity: Risks, safety concerns, and perspectives. J Pediatr 2013;163:1570-7.e6.  Back to cited text no. 9
Sanghvi KP, Kabra NS, Padhi P, Singh U, Dash SK, Avasthi BS. Prophylactic propranolol for prevention of ROP and visual outcome at 1year (PreROP trial). Arch Dis Child Fetal Neonatal Ed 2017;102:F389-94.  Back to cited text no. 10
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Pavlakovic H, Kietz S, Lauerer P, Zutt M, Lakomek M. Hyperkalemia complicating propranolol treatment of an infantile hemangioma. Pediatrics 2010;126:e1589-93.  Back to cited text no. 12
Nuntnarumit P, Yang W, Bada-Ellzey HS. Blood pressure measurements in the newborn. Clin Perinatol 1999;26:981-96, x.  Back to cited text no. 13
Farrag HM, Cowett RM. Hypoglycemia in the newborn. In: Lifshitz F, editors. Pediatric Endocrinology. 5th ed. New York: Informa Healthcare; 2007. p. 329-58.  Back to cited text no. 14
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  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2], [Table 3], [Table 4]


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