Effect of cerebrolysin on neurodevelopmental outcome of high risk preterm infants: A randomized controlled trial

Abstract

BACKGROUND:

A significant proportion of preterm infants experience developmental delay despite receiving a post discharge early interventional care. Cerebrolysin is a peptide mixture which acts similar to endogenous neurotrophic factors through promoting neurogenesis and enhancing neuronal plasticity.

OBJECTIVE:

To compare the effect of Cerebrolysin plus routine intervention program versus routine intervention program alone on the outcome of preterm infants at high risk for neurodevelopmental delay.

METHODS:

In a randomized controlled trial, high-risk preterm infants < 32 weeks’ gestation who have abnormal neurological assessment at two months corrected post-natal age were randomized at 6 months corrected post natal age to receive either early intervention program or early intervention program plus Cerebrolysin injection of 0.1 mL/kg body weight every week for 3 months as an adjuvant therapy. The primary outcome was the rate of failure of the gross motor assessment at 12 months of corrected age and secondary outcomes included fine motor, language, and personal social development at 12 months corrected post-natal age as assessed by Denver Developmental Screening Test II.

RESULTS:

Cerebrolysin group had a significant lower number of infants diagnosed with failed gross motor development compared to infants in the routine intervention group [10 (33%) versus 21 (70%), p = 0.009]. Cerebrolysin group had a significant lower number of infants diagnosed with failed fine motor, language and personal social development compared to infants in the routine intervention group.

CONCLUSION:

Cerebrolysin, as an adjuvant therapy to routine early interventional care, may improve gross motor development of high-risk preterm infants at 12 months corrected post-natal age.

Keywords

Early intervention language development musculoskeletal development outcome assessment preterm infant

1 Introduction

Preterm, very low birth weight infants, are at increased risk for neurodevelopmental delay despite advances in the services provided by the neonatal intensive care teams [1]. Preterm infants are exposed to variable perinatal and neonatal risk factors which affect their neurodevelopmental outcome such as; intrauterine growth restriction, maternal chorioamnionitis, prolonged mechanical ventilation, neonatal sepsis, intraventricular hemorrhage, necrotizing enterocolitis, bronchopulmonary dysplasia, periventricular leukomalacia and retinopathy of prematurity [2 –4].

Various interventions such as prenatal magnesium sulfate, prenatal steroids, delayed umbilical cord clamping, use of non-invasive ventilation, post-natal caffeine therapy, proper early nutrition, use of mother’s own breast milk or donor milk for enteral feeding and post-natal Erythropoietin therapy were previously explored to improve the neurodevelopmental outcome of preterm infants [5 –9]. Despite the use of all the above mentioned protective strategies, a significant proportion of preterm infants still experience neurodevelopmental delay after being discharged from the neonatal intensive care unit (NICU) [10]. Brain of preterm infants is characterized by plasticity which gives the health caregivers an opportunity to extend their developmental care to the post-discharge period [11]. Previous researches have shown than the implementation of early interventional programs which focus on improving infant’s nutrition, motivating parental attachment, early detection and interaction with functional disabilities, and proper referral for specialized developmental program significantly improve the outcome of high-risk neonates [12, 13].

Cerebrolysin is a porcine brain-derived preparation of low-molecular-weight neuropeptides (10 kDa) and free amino acids which has a neuro-protective effect on cerebral neurons. Cerebrolysin has been previously used in adults with cerebral stroke and in children exposed to brain insults and was shown to be effective and well tolerated therapy in improving neurological outcomes of both age groups [14 –16].

We hypothesized that adding Cerebrolysin to the current early interventional strategies in the follow up care of high-risk preterm infants will improve their neurodevelopmental outcome. This study aims to comparing the effect of Cerebrolysin plus routine intervention program versus routine intervention program alone on the outcome of preterm infants at high-risk for neurodevelopmental delay at a corrected post-natal care of 12 months.

2 Methods

The study was conducted at the neonatal follow up clinic of Mansoura university children’s hospital, Mansoura, Egypt, between June 2016 and June 2019. The neonatal follow up clinic of Mansoura university children’s hospital is a developmental clinic supervised by pediatrician/neonatologist, neurologist/psychologist, physiotherapist, speech therapist, ophthalmologist, and dedicated specialized nurses trained for neurodevelopmental assessment and promotion. The study was approved by the local Medical Research Ethics Committee and written informed consent was obtained from a parent or guardian of each infant before randomization. This study was registered at www.clinicaltrials.gov (NCT03506841)

2.1 Study designs and participants

This was a prospective, non-blinded randomized controlled trial, comparing the effect of Cerebrolysin plus routine intervention program versus routine intervention program alone on the outcome of preterm infants at high-risk for neurodevelopmental delay.

2.2 Participants

We recruited preterm infants with a gestational age < 32 weeks who were at increased risk for neurodevelopmental delay secondary to complicated course in the NICU and who were diagnosed with failed motor developmental assessment at 2 months corrected post-natal age. We excluded infants who has history of seizure activities, intraventricular hemorrhage (grade III –IV), congenital brain malformations, and chromosomal anomalies.

2.3 Intervention

Preterm infants who were diagnosed with failed motor developmental assessment at their initial, 2 months corrected post-natal age, visits were routinely included into an early interventional program in the neonatal follow up clinic of Mansoura university children’s hospital. Infants attended the clinic every two month until a corrected post-natal age of 6 months, every 3 months until a corrected post-natal age of 12 months unless otherwise stated by the health care team. Each visit is a one hour session with objectives of providing the targeted service to the infant and educating the parents on how to provide a continuous stimulation at home. The interventional program until 12 months corrected post-natal age include early nutrition enhancement to achieve a growth rate at the appropriate percentile for corrected post-natal age and physiotherapy sessions to improve developmental skills through postural support and movement facilitation techniques while the infant is in supine, prone, sidelying, supported sitting, and standing positions [13].

Infants were randomized based on intervention to either routine care group or Cerebrolysin plus routine care group. Infants in the routine care group received the above mentioned tool of the early interventional program by designated nurses and physiotherapist under the supervision of the attending neonatologist and neurologist. Infants in Cerebrolysin plus routine care group received, in addition to their routine early intervention program, a single weekly dose of intramuscular Cerebrolysin injection of 0.1 mL/kg body weight for 3 months (total of twelve injections) [15] starting from 6 months to 9 months corrected post-natal age.

2.4 Outcomes

The primary outcome was the rate of failure of the gross motor assessment at 12 months of corrected post-natal age. Secondary outcomes included fine motor-adaptive, language, and personal-social developmental skills at 12 months corrected post-natal age as well as gross motor, fine motor-adaptive, language, and personal-social developmental skills at 9 months of corrected post-natal ages. Cerebrolysin related side effects such as irritability, diarrhea, vomiting, injection site reaction and seizure not otherwise explained by other causes than Cerebrolysin toxicity as well as a decision to discontinue Cerebrolysin for related side effects were compared. Cerebrolysin therapy was discontinued if infant developed a single episode of new seizure activity or two episodes of other reported side effects.

Infants’ motor developmental skills at 2 months, baseline neurodevelopmental skills prior to randomization at corrected postnatal age of 6 month, neurodevelopmental achievement at corrected postnatal age of 9 months, and neurodevelopmental achievement at corrected postnatal age of 12 months were all assessed using the Denver Developmental Screening Test II (DDST-II) [17]. The Denver Developmental Screening Test II evaluate four developmental domains including: gross motor, language, fine motor-adaptive and personal-social skills against the age of the infant. During scoring, developmental items that intersects or is just adjacent to the infant’s age line were scored while items that can be passed by report of assessor were scored as pass. Items were scored as pass, fail, no opportunity, or refused based on infant’s response to the assessor. Infant developmental skills were reported as advanced if the infant passes items on which the age line falls below the 25th percentile; normal if the infant passes, fails, or refuses item on which the age line falls between the 25th and 75th percentile; caution if the infant fails or refuses item on which the age line falls between the 75th and 90th percentile; or delayed if the infant fails or refuses item on which the age line falls above the 90th percentile. The overall developmental assessment of the infant in each of the assessed domains was reported as failed if there were more than or equal to two reported delays, questionable if there was one reported delay and/or more than or equal to two reported cautions, and normal if there were no delays and a maximum of one caution.

Denver Developmental Screening Test II assessment was performed by a single trained assessor for all infants included in the study, who was blinded to the group of intervention. The intra-observer reproducibility was evaluated by repeated measurements of Denver Developmental Screening Test II by the same assessor with 1 hour in between measurements. Ten preterm infants, age and sex cross-matched with the studied group, were randomly selected for this purpose. Provider of early interventional program in the follow up clinic were also blinded to the group allocation of the included infants. Infants who did not show up in their appointed visits were contacted by phone to arrange a replacement visit within 7 days.

2.5 Sample size

Our neonatal follow up clinic data (non-published) showed that the implementation of early interventional program decreased the proportion of preterm infants initially diagnosed with motor developmental delay from 100% down to 73% at 12 months corrected postnatal age. Previous study has shown that administration of Cerebrolysin therapy for a duration of three months to infants initially diagnosed with neonatal asphyxia/Perinatal brain insult decreased the proportion of those diagnosed with communication and symbolic behavior concerns from 71.6% to 28.3% [15]. We calculated a total enrollment of 60 infants to detect a further reduction in the proportion of high-risk preterm infants with motor developmental delay from 73% to 28% at 12 months corrected post-natal age after a similar duration of Cerebrolysin therapy, with 80% power and 5% significance.

2.6 Randomization

Infants were assigned randomly to treatment groups using internet based random table technique with a block size of six. Cards in sequentially numbered, opaque, sealed envelopes kept in the follow up clinic away from investigators. A designated pharmacist who was not involved in the study was responsible for the randomization of selected infants and the preparation of Cerebrolysin.

2.7 Statistical analysis

Statistical analysis was performed using SPSS statistical software (version 21; IBM Corporation, Armonk, NY, USA). Student-t test was used to compare continuous parametric variables; Mann–Whitney U test was used for continuous non-parametric variables; Chi-square test or Fisher exact test were used for categorical variables when appropriate. Kolmogrov Smirnov test was done to examine the distribution of data. A p-value of < 0.05 is considered to be statistically significant. Data are expressed as mean±standard deviation, median (inter-quartile range), or number (percentage) unless otherwise stated. Statistical analysis was done on an intention to treat base. Reproducibility of the diaphragmatic measurements was assessed by intra-observer correlation coefficient

3 Results

During the study period, 84 eligible preterm (<32 weeks) infants were discharged with abnormal motor assessment as failed at 2 months corrected post-natal age of whom 6 infants were excluded before enrolment because of seizure and 18 infants were not enrolled due to parental refusal. A total of 60 infants were assigned randomly to treatment groups, 30 in the Cerebrolysin group and 30 in the routine interventional care group (Fig. 1). Baseline characteristics were broadly similar between the two groups (Table 1). Cerebrolysin course was administered as planned for all 30 infants assigned into the Cerebrolysin group without missed doses and all infants completed the follow up schedules until the endpoint of the study. Measurements of Denver Developmental Screening Test II were highly reproducible with a high degree of agreement between different developmental domains assessed by intra-observer correlation coefficient. The intra-observer correlation coefficient values were above 0.8 and p values were < 0.01 for all measured developmental domains.

Fig. 1

Diagram showing the flow of participants through stages of the trial.

Table 1

Base line characteristics of the studied groups

Characteristics	Cerebrolysin plus routine intervention group	Routine intervention group	p value
	(n = 30)	(n = 30)
Gestational age (weeks) (mean±SD)	28.1±0.93	28.2±1.2	0.71
Birth weight (grams) (mean±SD)	1265±305	1210±318	0.49
Male sex	15 (50%)	14 (47%)	0.98
Maternal age (years) (mean±SD)	24.9±4.71	24.4±4.65	0.67
Maternal gravidity [median (Q1-Q3)]	2 (1–4)	2 (1–5)	0.65
Maternal education
Postgraduate	1 (3%)	0 (0%)	0.9
College/University	24 (80%)	26 (87%)	0.73
Primary or Secondary school	5 (17%)	4 (13%)	0.9
Pregnancy related complications
•Premature rupture	4 (13%)	9 (30%)	0.21
of membranes
•Diabetes	3 (10%)	1 (3%)	0.62
•Preeclampsia	6 (20%)	5 (17%)	0.98
•Chorioamnionitis	4 (13%)	0 (0%)	0.12
•Severe anemia	2 (7%)	0 (0%)	0.49
•Ante partum hemorrhage	2 (7%)	4 (13%)	0.67
Apgar score
•1 minute [median (Q1-Q3)]	5 (3 –6)	4 (4 –6)	0.62
•5 minutes [median (Q1-Q3)]	8 (6 –9)	8 (7 –8)	0.86
Mode of Delivery
•Vaginal delivery	8 (27%)	7 (23%)	0.98
•Cesarean Section	22 (73%)	23 (77%)
Small for gestational age	6 (20%)	5 (17%)	0.98
Antenatal steroid therapy	20 (67%)	18 (60%)	0.79
Surfactant therapy	14 (47%)	15 (50%)	0.98
Duration of mechanical ventilation	18 (4–40)	21 (5–43)	0.21
(Days) [median (Q1-Q3)]
Duration of oxygen therapy (Days)	20 (7–45)	22 (2–42)	0.69
Feeding
•Breast milk	2 (7%)	0 (0%)	0.60
•Formula milk	15 (50%)	18 (60%)
•Mixed breast and formula milk	13 (43%)	12 (40%)
Neonatal sepsis
•Early onset	9 (30%)	8 (27%)	0.98
•Late onset	11 (37%)	13 (43%)	0.79
Bronchopulmonary dysplasia	4 (13%)	5 (17%)	0.98
Hemodynamic significant PDA
•Medically treated	4 (13%)	3 (10%)	0.98
•Surgically treated	1 (3%)	0 (0%)
Necrotizing enterocolitis	2 (7%)	3 (10%	0.98
Periventricular leukomalacia	11 (37%)	12 (40%)	0.98
Duration of NICU stay (Days)	30 (7–60)	30 (7–63)	0.87

Q1-Q3 = Quartile 1-Quartile Q3 PDA = Patent Dactus Arteriosus.

3.1 Effect of early interventional program on developmental characteristics at 6 months corrected postnatal age prior to Cerebrolysin therapy

Implementation of the early intervention program significantly decreased the number of infants initially diagnosed with failed motor developmental assessment form 30 (100%) at 2 months corrected post-natal age to 20 (67 %) and 19 (63 %) at 6 months corrected postnatal age in infants randomized to receive Cerebrolysin or continued routine interventional program (p = 0.0008 for both groups) respectively. Infants randomized to Cerebrolysin therapy had no difference in their baseline gross motor, fine motor, language or personal-social developmental assessments compared to infants randomized to continue routine interventional care at 6 months corrected postnatal age (Table 2).

Table 2
Developmental assessment before and after Cerebrolysin therapy

Characteristics Baseline assessment at 6 months Post-interventional assessment at 9 months Post-interventional assessment at 12 months

Cerebrolysin group Routine intervention group p value Cerebrolysin group Routine intervention p value Cerebrolysin group Routine intervention p value p^* value p^ value p^* value

(n = 30) (n = 30) (n = 30) (n = 30) (n = 30) (n = 30)

Gross motor

•Normal 8 (26%) 9 (30%) 0.98 9 (30%) 8 (26%) 0.99 11 (37%) 2 (7%) 0.01 0.98 0.78 0.57

•Questionable 2 (7%) 2 (7%) 1.0 5 (17%) 6 (20%) 0.99 9 (30%) 7 (23%) 0.76 0.42 0.36 0.04

•Failed 20 (67%) 19 (63%) 0.98 16 (53%) 16 (53%) 1.0 10 (33%) 21 (70%) 0.009 0.42 0.19 0.02

Fine motor-adaptive

•Normal 10 (33%) 10 (33%) 1.0 5 (17%) 2 (7%) 0.42 11 (37%) 4 (13%) 0.07 0.23 0.14 0.98

•Questionable 6 (20%) 5 (17%) 0.98 17 (57%) 17 (57%) 1.0 11 (37%) 6 (20%) 0.25 0.007 0.19 0.25

•Failed 14 (47%) 15 (50%) 0.98 8 (26%) 11 (37%) 0.57 8 (26%) 20 (67%) 0.004 0.18 1.0 0.18

Language

•Normal 14 (47%) 12 (40%) 0.79 11 (37%) 13 (43%) 0.79 6 (20%) 0 (0%) 0.02 0.60 0.25 0.06

•Questionable 13 (43%) 9 (30%) 0.42 9 (30%) 4 (13%) 0.21 10 (33%) 6 (20%) 0.38 0.42 0.98 0.59

•Failed 3 (10%) 9 (30%) 0.10 10 (33%) 13 (43%) 0.59 14 (47%) 24 (80%) 0.02 0.06 0.43 0.003

Personal-social

•Normal 13 (43%) 10 (33%) 0.59 2 (7%) 0 (0%) 0.49 6 (20%) 2 (7%) 0.25 0.002 0.25 0.09

•Questionable 12 (40%) 11 (37%) 0.98 17 (57%) 13 (43%) 0.43 20 (67%) 12 (40%) 0.07 0.30 0.59 0.07

•Failed 5 (17%) 9 (30%) 0.36 11 (37%) 17 (57%) 0.19 4 (13%) 16 (53%) 0.002 0.14 0.07 0.98

Characteristics	Baseline assessment at 6 months	Post-interventional assessment at 9 months	Post-interventional assessment at 12 months
Gross motor
•Normal	8 (26%)	9 (30%)	0.98	9 (30%)	8 (26%)	0.99	11 (37%)	2 (7%)	0.01	0.98	0.78	0.57
•Questionable	2 (7%)	2 (7%)	1.0	5 (17%)	6 (20%)	0.99	9 (30%)	7 (23%)	0.76	0.42	0.36	0.04
•Failed	20 (67%)	19 (63%)	0.98	16 (53%)	16 (53%)	1.0	10 (33%)	21 (70%)	0.009	0.42	0.19	0.02
Fine motor-adaptive
•Normal	10 (33%)	10 (33%)	1.0	5 (17%)	2 (7%)	0.42	11 (37%)	4 (13%)	0.07	0.23	0.14	0.98
•Questionable	6 (20%)	5 (17%)	0.98	17 (57%)	17 (57%)	1.0	11 (37%)	6 (20%)	0.25	0.007	0.19	0.25
•Failed	14 (47%)	15 (50%)	0.98	8 (26%)	11 (37%)	0.57	8 (26%)	20 (67%)	0.004	0.18	1.0	0.18
Language
•Normal	14 (47%)	12 (40%)	0.79	11 (37%)	13 (43%)	0.79	6 (20%)	0 (0%)	0.02	0.60	0.25	0.06
•Questionable	13 (43%)	9 (30%)	0.42	9 (30%)	4 (13%)	0.21	10 (33%)	6 (20%)	0.38	0.42	0.98	0.59
•Failed	3 (10%)	9 (30%)	0.10	10 (33%)	13 (43%)	0.59	14 (47%)	24 (80%)	0.02	0.06	0.43	0.003
Personal-social
•Normal	13 (43%)	10 (33%)	0.59	2 (7%)	0 (0%)	0.49	6 (20%)	2 (7%)	0.25	0.002	0.25	0.09
•Questionable	12 (40%)	11 (37%)	0.98	17 (57%)	13 (43%)	0.43	20 (67%)	12 (40%)	0.07	0.30	0.59	0.07
•Failed	5 (17%)	9 (30%)	0.36	11 (37%)	17 (57%)	0.19	4 (13%)	16 (53%)	0.002	0.14	0.07	0.98

Data expressed as number (percentage). p comparing Cerebrolysin group to routine intervention group at each point of time. p^* comparing infants within the Cerebrolysin group at 6 months versus 9 months corrected post-natal age. p^** comparing infants within the Cerebrolysin group at 9 months versus 12 months corrected post-natal age. p^*** comparing infants within the Cerebrolysin group at 6 months versus 12 months corrected post-natal age.

3.2 Effect of Cerebrolysin versus routine interventional program on developmental outcome at 9 months corrected postnatal age

Infants in the Cerebrolysin group were not different at any of the gross motor, fine motor, language or personal-social domains compared to infants in the routine interventional program.

3.3 Effect of Cerebrolysin versus routine interventional program on developmental outcome at 12 months corrected postnatal age

Cerebrolysin group had a significant lower number of infants diagnosed with failed gross motor development and a significant higher number of infants diagnosed with normal gross motor development compared to infants in the routine intervention group [10 (33%) versus 21 (70%), p = 0.009; 11 (37% versus 2 (7%), p = 0.01 respectively] (Table 2).

Cerebrolysin group had a significant lower number of infants diagnosed with failed fine motor development compared to infants in the routine intervention group [8 (26%) versus 20 (67%), p = 0.004] (Table 2).

Cerebrolysin group had a significant lower number of infants diagnosed with failed language development and a significant higher number of infants diagnosed with normal language development compared to infants in the routine intervention group [14 (47%) versus 24 (80%), p = 0.02; 6 (20%) versus 0 (0%), p = 0.02 respectively] (Table 2).

Cerebrolysin group had a significant lower number of infants diagnosed with failed personal-social development compared to infants in the routine intervention group [4 (13%) versus 16 (53%), p = 0.002] (Table 2).

3.4 Effect of Cerebrolysin over time

Cerebrolysin therapy significantly lowered the number of infants diagnosed with failed gross motor development from 20 (67%) infants at 6 months corrected postnatal age to 10 (33%) infants at 12 months corrected post-natal age (p = 0.02) with no effect at 9 months corrected postnatal age (Table 2).

Infants with failed language development were significantly higher after Cerebrolysin therapy compared to before Cerebrolysin therapy [14 (47%) versus 3 (10%), p = 0.003) (Table 2).

3.5 Adverse effects of Cerebrolysin

Three infants in the Cerebrolysin group developed single episodes of irritability which was not recurrent. No other Cerebrolysin related side effects were reported in the Cerebrolysin group and Cerebrolysin was not discontinued at any time in any of the treated infants secondary to reported side effects.

4 Discussion

Postnatal care represents an important complementary service to the antenatal and neonatal unit cares in optimizing the developmental outcomes of high-risk preterm neonates. The available interventions to improve the developmental outcome of high-risk preterm infants during the post-natal period are limited compared to the options provided during the antenatal and neonatal period. In the current randomized controlled trial; we aimed to study the efficacy and safety of Cerebrolysin as an adjuvant post-natal therapy on the developmental outcome of high-risk preterm infants. The main finding of our study is that Cerebrolysin, as an adjuvant therapy to the routine interventional physiotherapy, independently improves the gross motor development of preterm infants at high-risk for developmental delay without reported side effects.

The proposed mechanisms of Cerebrolysin neuro-protective action include: inhibition of brain cells apoptosis, improvement of synaptic plasticity, induction of neurogenesis and augmenting the proliferation and differentiation of neural progenitor cells [18, 19]. Cerebrolysin has shown a neurotrophic effects similar to those of endogenous neurotrophic factors, which play an important role in the maintenance of neuronal function [20]. In a case control study, Govorin and colleagues correlated the improvement of motor functions specific for mental development delay in 24 children aged 4 to 6 years with positive dynamics of lipid peroxidation, immune status, hormonal shifts and parameters of neurodegeneration-neuroprotection processes [21]. In pediatric patients aged 18 to 75 months and diagnosed with spastic diplegic and quadriplegic cerebral palsy, Nasiri and Safavifar found that their gross motor function improved significantly when Cerebrolysin was administered as a single daily dose of 0.1 cc/kg for 10 days and then continued weekly for 4 months in addition to their routine rehabilitation therapy [22].

We found that Cerebrolysin decreased the proportions of infants with fine motor delay, language delay and personal-social delay at 12 months corrected postnatal age compared to the baseline 6 months assessment.

In children with specific language impairment, Chutko and colleagues found that Cerebrolysin therapy was associated with improved language skills in 73% of the treated children in both receptive and expressive language [23]. However, the age group of these children were 5 to 7 years compared to the younger infants we included. Moreover, children in Chutko’s study had isolated language disorders and no other associated brain insults.

Hassanein and colleagues randomized 120 infants aged 6 to 21 months and diagnosed with neonatal asphyxia and perinatal brain insult to receive either Cerebrolysin therapy at a dose of 0.1 mL/kg body weight twice weekly by intramuscular injection for 5 weeks or placebo. They assessed their score of Communication and Symbolic Behavior Scale-Developmental Profile and the percentage of change from concern to no concern after 3 months. They found a significant improvement in infants’ social and speech composite scores but not symbolic composite score or the total score after 3 months of enrollment in the study. They also found a significant decrease in the proportion of those diagnosed with communication and symbolic behavior concerns from 71.6% to 28.3% after 3 months of enrollment in the study [15]. Compared to the results of Hassanein and colleagues study, the improvement in gross motor, fine motor, language or personal social developments were not achieved immediately after the three months duration of Cerebrolysin therapy (at 9 months corrected post-natal age) rather progressed to be achieved after six months of initial Cerebrolysin therapy. This difference can be attributed to the nature of our included infants being preterm with variable pathogenesis to brain insult and whom require longer time to achieve responses to any interventions compared to the term infants with hypoxic ischemic insult in Hassanein’s study.

We did not find significant side effects to Cerebrolysin in our treated infants apart from mild single episode of irritability which did not persist. However, we have to acknowledge that we excluded infants with seizure activity who represents a significant proportion in infants with developmental delay. In the study by Hassanein and colleagues which included infants with seizure activity, Cerebrolysin therapy was not associated with changes in seizure frequency, duration, severity, or antiepileptic drug doses during the study except for two infants in whom Cerebrolysin was discontinued because of intractable seizures that were controlled by discontinuation of therapy [15].

This study is strengthened by being the first to introduce Cerebrolysin therapy to high-risk preterm infants with motor developmental delay early in the first year of life. Thus, it opens the doors for the opportunity of early introduction of Cerebrolysin in this valuable period of brain growth and development to prevent further neuronal and motor impairment.

We acknowledge the study limitation of being non-blinded and not placebo controlled. We felt unethical to administer 12 placebo intramuscular injections to the routine interventional group. However, we minimized this bias by blinding the service providers of the routine interventional program and the assessor of developmental outcome to the group allocation. The study is also limited by using the Denver Developmental Screening Test II which is a screening tool rather than a diagnostic tool for detection of developmental delay in the first 12 months of life. However, it was previously shown that Denver Developmental Screening Test II at 6 months of life has a good sensitivity and specificity in predicting severe neurological outcome in infants with hypoxic ischemic insult [24].

In conclusion, Cerebrolysin represents a promising adjuvant therapy to routine interventional physiotherapy for improving the motor developmental outcome of preterm infants at high risk for developmental delay. Cerebrolysin gives a new hope for the future neuro-preventive and curative therapies in preterm infants with developmental dely. We recommend to use the findings of the study as pilot data for future large, placebo-controlled trial. Future study using more valid diagnostic tool for developmental delay and correlating the effect of Cerebrolysin on developmental outcome with brain magnetic resonance finding are warranted prior to generalizing the practice of Cerebrolysin therapy in preterm infants with developmental delay.

Footnotes

Acknowledgment

We would like to thank Miss Sakina Kamal for her effort in randomization and allocation of infants into study groups. We would like to thank the parents and families in the Neonatal Intensive Care Unit at Mansoura University Children’s Hospital.

Authors’ contribution

Aya Samir participated in design of the study, data collection and writing the manuscript. Nehad Nasef participated in formulating the hypothesis, design of the study, developmental assessment, data collection, data interpretation, statistical analysis, and writing of the manuscript. Khalid Fathy participated in neurological assessment, data interpretation and writing the manuscript, Abdel-Hady El-Gilany participated in data interpretation, statistical analysis and writing the manuscript. Sohier Yahia participated in formulating the hypothesis, design of the study, data interpretation, statistical analysis, and writing of the manuscript All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Trial Register Name:

Financial disclosure and funding

None declared.

Conflict of interest

None declared.

References

Agarwal

, Shi

, Rajadurai

, Zheng

, Yang

, Khoo

, et al. Factors affecting neurodevelopmental outcome at 2 years in very preterm infants below 1250 grams: A prospective study. J Perinatol. 2018;38(8):1093–100.

Asztalos

, Church

, Riley

, Fajardo

, Shah

. Neonatal factors associated with a good neurodevelopmental outcome in very preterm infants. Am J Perinatol. 2017;34(4):388–96.

Klebermass-Schrehof

, Czaba

, Olischar

, Fuiko

, Waldhoer

, Rona

, et al. Impact of low-grade intraventricular hemorrhage on long-term neurodevelopmental outcome in preterm infants. Childs Nerv Syst. 2012;28(12):2085–92.

Ylijoki

, Ekholm

, Ekblad

, Lehtonen

. Prenatal risk factors for adverse developmental outcome in preterm infants-systematic review. Front Psychol. 2019;10:595.

Chollat

, Sentilhes

, Marret

. Protection of brain development by antenatal magnesium sulphate for infants born preterm. Dev Med Child Neurol. 2019;61(1):25–30.

Nasef

, Shabaan

, Schurr

, Iaboni

, Choudhury

, Church

, et al. Effect of clinical and histological chorioamnionitis on the outcome of preterm infants. Am J Perinatol. 2013;30(1):59–68.

Neubauer

, Voss

, Wachtendorf

, Jungmann

. Erythropoietin improves neurodevelopmental outcome of extremely preterm infants. Ann Neurol. 2010;67(5):657–66.

Tarnow-Mordi

, Morris

, Kirby

, Robledo

, Askie

, Brown

, et al. Delayed versus immediate cord clamping in preterm infants. N Engl J Med. 2017;377(25):2445–55.

Doyle

, Cheong

, Hunt

, Lee

, Thompson

, Davis

, et al. Caffeine and brain development in very preterm infants. Ann Neurol. 2010;68(5):734–42.

10.

Johnson

, Marlow

. Early and long-term outcome of infants born extremely preterm. Arch Dis Child. 2017;102(1):97–102.

11.

Bennet

, Van Den Heuij

, Dean

, Drury

, Wassink

, Gunn

. Neural plasticity and the Kennard principle: Does it work for the preterm brain? Clin Exp Pharmacol Physiol. 2013;40(11):774–84.

12.

Coviello

, Keunen

, Kersbergen

, Groenendaal

, Leemans

, Peels

, et al. Effects of early nutrition and growth on brain volumes, white matter microstructure, and neurodevelopmental outcome in preterm newborns. Pediatr Res. 2018;83(1-1):102–10.

13.

Oberg

, Campbell

, Girolami

, Ustad

, Jorgensen

, Kaaresen

. Study protocol: An early intervention program to improve motor outcome in preterm infants: A randomized controlled trial and a qualitative study of physiotherapy performance and parental experiences. BMC Pediatr. 2012;12:15.

14.

Petrukhin

, Pylaeva

. [Cerebrolysin in pediatric neurology practice]. Zh Nevrol Psikhiatr Im S S Korsakova. 2014;114(1 Pt 2):75–80.

15.

Hassanein

, Deifalla

, El-Houssinie

, Mokbel

. Safety and efficacy of cerebrolysin in infants with communication defects due to severe perinatal brain insult: A randomized controlled clinical trial. J Clin Neurol. 2016;12(1):79–84.

16.

Guekht

, Vester

, Heiss

, Gusev

, Hoemberg

, Rahlfs

, et al. Safety and efficacy of Cerebrolysin in motor function recovery after stroke: A meta-analysis of the CARS trials. Neurol Sci. 2017;38(10):1761–9.

17.

Sperhac

, Salzer

. A new developmental screening test. The Denver II. J Am Acad Nurse Pract. 1991;3(4):152–7.

18.

Alvarez

, Lombardi

, Fernandez-Novoa

, Garcia

, Sampedro

, Cagiao

, et al. Cerebrolysin reduces microglial activation in vivo and in vitro: A potential mechanism of neuroprotection. J Neural Transm Suppl. 2000;59:281–92.

19.

sadin

, Zhydomorov

, Gogoleva

, Demidov

, Grishina

, Gromova

. [A study of neuroregenerative action of cerebrolysin in brain trauma]. Zh Nevrol Psikhiatr Im S S Korsakova. 2013;113(4):57–60.

20.

Plosker

, Gauthier

. Cerebrolysin: A review of its use in dementia. Drugs Aging. 2009;26(11):893–915.

21.

Govorin

, Zlova

, Akhmetova

, Tarasova

. [The pathophysiological analysis of cerebrolysin therapy of children with mental developmental delay caused by ecological factors]. Zh Nevrol Psikhiatr Im S S Korsakova. 2008;108(5):51–5.

22.

Nasiri

, Safavifar

. Effect of cerebrolysin on gross motor function of children with cerebral palsy: A clinical trial. Acta Neurol Belg. 2017;117(2):501–5.

23.

Chutko

, Surushkina

, Yakovenko

, Sergeev

, Rozhkova

, Anosova

, et al. [Clinical and electroencephalographic characteristics of specific language impairment in children and an evaluation of the efficacy of cerebrolysin]. Zh Nevrol Psikhiatr Im S S Korsakova. 2015;115(7):98–102.

24.

Hallioglu

, Topaloglu

, Zenciroglu

, Duzovali

, Yilgor

, Saribas

. Denver developmental screening test II for early identification of the infants who will develop major neurological deficit as a sequalea of hypoxic-ischemic encephalopathy. Pediatr Int. 2001;43(4):400–4.