Sage Journals: Discover world-class research

Abstract

PURPOSE:

Noxious sensory inputs from the neonatal Intensive Care Unit (NICU) and lack of placental support negatively impact neuronal organization which has implications later in life. Evidence regarding early interventions (EI) on preterm neonates (PN) at high risk for developmental motor disorders is limited and inconclusive. This study focuses on neuromotor changes following Multimodal stimulations (MMS) with sensory and motor interventions among stable hospitalized PNs.

METHODS:

This single-center, non-blinded pre-test post-test control group study will recruit 60 PNs admitted to the Level II and III NICU of a recognized tertiary care teaching hospital by convenience sampling method into two groups by block randomization. Group A (n = 30) will receive MMS trial lasting for 30 minutes per session for five days per week, until discharge of the neonate from the NICU; Group B (n = 30) will receive regular lifesaving care from the NICU. Anthropometric evaluation, physiological status, and Infant Neurological International Battery (INFANIB) will be the outcome measures used to analyze the neuromotor behavioral modifications among the hospitalized PNs. All the outcome measures will be recorded at baseline, after every five days (to compare trajectories of scores between the groups), and at the end of the intervention at the time of discharge of neonate from the NICU.

RESULTS:

Demographic and outcome measures will be assessed for their normality using the Shapiro-Wilk test. Within and between-group comparisons will be analyzed by the repeated measures analysis of variance/Friedman test and independent t-test/Mann-Whitney U test respectively.

CONCLUSION:

MMS, which includes both sensory and motor interventions, will, to the best of the authors’ knowledge, be the first trial for modifying the neuromotor behavior of hospitalized PNs. If successful, the clinical effects of this protocol could be revolutionary in mitigating developmental impairments of PNs.

Keywords

Early intervention multisensory stimulation newborn intensive care units preterm infants

1 Introduction

About 15 million premature births occur annually across the globe, and in India alone 3.5 million out of 27 million infants are born prematurely each year [1, 2]. Over 70% of these preterm neonates (PNs) need hospitalization in Neonatal Intensive Care Units (NICUs) for physiological support and developmental maturation [2, 3]. Most of the PNs have atypical maturation of the brain due to extra-uterine sensory experience and atypical sensory stimuli in the NICU [4]. Noxious sensory inputs that PNs experience in the NICU negatively impact neuronal organization, which typically occurs during the last trimester of pregnancy [5 –7]. The neonatal musculoskeletal system is fragile and vulnerable to injury [8] as cartilaginous joints have a high risk of developing osteopenia and bone mineral deficiency [6, 8]. Commonly used biochemical markers of bone metabolism such as blood calcium, phosphate levels, and plasma alkaline phosphatase levels can measure osteopenia and bone deficiency [8]. PNs cartilaginous joints are also vulnerable to the effect of gravity due to immature muscle fibers and reduced flexor tone. Tone development in PNs occurs in the caudo-cephalic direction resulting in hyperextended posture. PNs have limited endurance and an immature capacity to control more complex movements against gravitational forces [6].

The NICU is essential for the support and developmental maturation of neonates born preterm [3]. With their improving survival rates of preterm and increasing births of low-birth-weight infants, there is an increase in PNs with neuromotor impairments later in life which range from developmental coordination disorders to cerebral palsy (CP) [9]. Myelination begins during the second trimester and is most rapid in the first year of life; the process continues up to 30 years of age. Therefore, it is important that infants with motor dysfunction are identified early so that appropriate interventions can be implemented [10].

Due to the advancements in NICU equipment, as well as evidence-based diagnostic and treatment techniques, the survival rate of PNs has increased significantly [2 , 12], causing an increase in the developmental impairments and motor issues [9 , 14]. The disability of PNs has a major impact on family and society [15]. Multi-disciplinary Early Intervention (EI) care in the NICU that includes sensory and kinesthetic stimulations has made an immense contribution toward minimizing the morbidity and hospital stays of PNs. EI has prevented and helped to treat the possible respiratory, neurological, musculoskeletal, and stress-related complications of PNs, including delayed growth, and abnormal bone mineralization [8 , 16]. These interventions improve the quality of life and limit disabilities in later part of their life [8 , 16].

Evidence is limited and inconclusive regarding the effectiveness of EI in infants at high risk for developmental motor disorders due to the heterogeneity of these interventions [6 , 18]. There is a definite need to establish the effectiveness of a standardized protocol comprising Multimodal stimulation (MMS) in PNs to determine whether or not this intervention will have a significant effect on neuromotor outcomes among hospitalized PN. The aim of this study is to identify the effects of a standardized MMS protocol versus standard NICU care among stable hospitalized PN.

2 Methods

2.1 Ethical statement and protocol registration

The MMS trial will be a single-center, non-blinded pre-test post-test control group study, performed on stable hospitalized PNs in the NICU of Maharishi Markandeshwar hospital, Mullana, Haryana, India. The study protocol was approved by the institutional ethics committee of Maharishi Markandeshwar (Deemed to be University) (MMDU/IEC/1566) on 10^th December 2019 and is registered in the publicly open access protocol registration and results system, Clinicaltrials.gov, approved by WHO’s International Clinical Trials Registry Platform (ICTRP) and the International Committee of Medical Journal Editors (ICMJE) with unique Universal Trial Number (UTN), U1111-1236-9478 and unique registration no. NCT04247308 on 30^th January 2020 (https://clinicaltrials.gov/ct2/show/NCT04247308) [19]. The study will be performed according to the principles laid out by the Declaration of Helsinki (Revised 2013) and the Council for International Organizations of Medical Sciences (CIOMS) guidelines; namely, the International Ethical Guidelines for Health-related Research Involving Humans (2016), and the National Ethical Guidelines for Biomedical Research Involving Children (2017). Before recruiting the preterm neonates in this trial, signed informed consent will be obtained from the parents or legal guardians.

2.2 Study population

2.2.1 Sample size and power

Sample size for the study was calculated using G*Power ver. 3.1.9.7 software (Heinrich- Heine-Universität Düsseldorf, Düsseldorf, Germany; https://www.gpower.hhu.de/) [20] for the sample size calculations with Effect size (ES) = 0.978 (Control group = 59.16±3.23; Study group = 62.24±3.07; Effect size = Group difference / Pooled standard deviation; Effect size = 62.24 –59.16 / √(3.07)²+(3.23)² / 2; Effect size = 3.08 / 3.15) [21]. By substituting ES with the level of significance as 0.05 (αerror prob), 0.90 [Power (1-β err prob)] with 1:1 allocation ratio of a two-tailed test, it was be estimated that the sample size in each group has to be n = 23. In considering a 30% drop-out rate (n = 6.9), the final minimal required sample must be n = 30 (rounded off to the next whole number) in each group. Accordingly, the minimum sample size required for the study to attain 90% power (Type II error = 10%) with 5% level of significance (Type I error = 5%) is n = 60.

2.2.2 Recruitment

The selection criteria for recruited participants are presented in Table 1. Hospitalized PNs (target n = 60) who will meet all the selection criteria will be identified by the convenience sampling technique and a signed informed consent form will be obtained from the parents to ensure appropriate volunteer participation in the study.

Table 1
Selection criteria for MMS trial

Inclusion Criteria: Exclusion Criteria:

i. Infants born between 28 and 36 weeks of gestation i. A preterm infant with congenital anomalies, congenital infections, or central nervous system injury

ii. Birth weight ranging from 1,000–3,500 g. ii. Neonates undergoing corrective surgeries

iii. Medically stable preterm infants iii. Neonates on medications (corticosteroid)

iv. Not connected to oxygen or ventilator support iv. Severe cardio–respiratory anomaly

v. Not significantly ill (e.g., low SNAP scores, not on ventilators) v. Babies with congenital anomalies (such as microcephaly)

vi. Mothers have no significant prenatal complications and no history of drug abuse. vi. Out–born preterm infant

vii. Voluntary parent consent

Inclusion Criteria:	Exclusion Criteria:
i. Infants born between 28 and 36 weeks of gestation	i. A preterm infant with congenital anomalies, congenital infections, or central nervous system injury
ii. Birth weight ranging from 1,000–3,500 g.	ii. Neonates undergoing corrective surgeries
iii. Medically stable preterm infants	iii. Neonates on medications (corticosteroid)
iv. Not connected to oxygen or ventilator support	iv. Severe cardio–respiratory anomaly
v. Not significantly ill (e.g., low SNAP scores, not on ventilators)	v. Babies with congenital anomalies (such as microcephaly)
vi. Mothers have no significant prenatal complications and no history of drug abuse.	vi. Out–born preterm infant
vii. Voluntary parent consent

2.2.3 Randomization and stratification

After demographic information is collected, recruited PNs will be randomly divided into two groups, group A and group B, using block randomization. There will be four blocks with 15 rows each. Each row contains 4 chits (2 chits for each group), totaling 60. By the block randomization method, PNs will be randomly allocated using sequentially numbered, opaque, sealed envelopes (SNOSE). PNs will be allotted to a group based on the randomly chosen chit by their parents. A physiotherapist who is not involved in this research will perform the randomization. Once the first row of all the blocks are filled, the next row block will be opened for recruitment. Thus, an equal number of PNs will be assigned to each group over time.

2.2.4 Intervention description

Group A will receive MMS (Table 2) lasting for 30 minutes per session for five days per week, until discharge of neonate from the NICU [21]; Group B will receive standard NICU care. The study [22] flow chart describing the details of the study is displayed in Fig. 1.

Table 2
Preemies’ Neuro-motor Facilitation (PNMF) Protocol

Sr. no. Interventions Method Duration

1. Sensory Stimulation Auditory Stimulation Soft lullaby (between 30–40 dB) using a miniature speaker 3 min×1

Tactile Stimulation Gentle stroking massage for 3 min in a sequence of the chest, upper limbs, and lower limbs in the supine position in the cephalo–quadral direction 3 min×1

Visual Stimulation Black and white visual stimulation card hung at a distance of 8–10 inches from the neonate’s eye (eye open) 3 min×1

Vestibular Stimulation Gentle horizontal and vertical rocking 3 min×1

Oromotor stimulation Stroking cheeks, lips, jaw, and tongue, or rubbing the gum 3 min×1

2. Movement Therapy Passive Movements Guided flexion–extension movements of upper limb (shoulder, elbow, and wrist joints of both side) and lower limb (bicycle riding pattern for hip and knee joints, the hand should be placed around knee joint and ankle joint) with articular compression. Care must be taken as an infant has cartilaginous joints at the wrist and ankle. Flex–Ext /Shoulder Abd–Add (6 repetitions, 10 sec / rep)

Antigravity Movements In prone: Neonate positioned firmly at one or both sides of the trunk, distracting the neonate’s lower ribs down toward the pelvis and assisting in caudal weight transfer 3 min×1

Sitting (supported): Lift the infant from supine or prone into sitting relatively vertical while providing trunk to pelvic alignment and stability; pause during the movement and wait for the neonate’s emerging neck rotation or lateral flexion responses with the allowed free movements of extremities. 3 min×1

Upright Positioning Neonate kept upright facing away from the therapist. Neonate’s head and back are supported by the chest and chin, and the anterior trunk is by the hands of the therapist. 3 min×1

Sr. no.	Interventions	Method	Duration
1.	Sensory Stimulation	Auditory Stimulation	Soft lullaby (between 30–40 dB) using a miniature speaker	3 min×1
		Tactile Stimulation	Gentle stroking massage for 3 min in a sequence of the chest, upper limbs, and lower limbs in the supine position in the cephalo–quadral direction	3 min×1
		Visual Stimulation	Black and white visual stimulation card hung at a distance of 8–10 inches from the neonate’s eye (eye open)	3 min×1
		Vestibular Stimulation	Gentle horizontal and vertical rocking	3 min×1
		Oromotor stimulation	Stroking cheeks, lips, jaw, and tongue, or rubbing the gum	3 min×1
2.	Movement Therapy	Passive Movements	Guided flexion–extension movements of upper limb (shoulder, elbow, and wrist joints of both side) and lower limb (bicycle riding pattern for hip and knee joints, the hand should be placed around knee joint and ankle joint) with articular compression. Care must be taken as an infant has cartilaginous joints at the wrist and ankle.	Flex–Ext /Shoulder Abd–Add (6 repetitions, 10 sec / rep)
		Antigravity Movements	In prone: Neonate positioned firmly at one or both sides of the trunk, distracting the neonate’s lower ribs down toward the pelvis and assisting in caudal weight transfer	3 min×1
			Sitting (supported): Lift the infant from supine or prone into sitting relatively vertical while providing trunk to pelvic alignment and stability; pause during the movement and wait for the neonate’s emerging neck rotation or lateral flexion responses with the allowed free movements of extremities.	3 min×1
		Upright Positioning	Neonate kept upright facing away from the therapist. Neonate’s head and back are supported by the chest and chin, and the anterior trunk is by the hands of the therapist.	3 min×1

PNMF Protocol should be administered for 30 min, 5 times per week.

Fig. 1

Study flow diagram for the randomized controlled trial protocol.

2.3 Group A - MMS trial

2.3.1 Sensory stimulations

Sensory stimulations will consist of a soft lullaby using a miniature speaker, gentle stroking massage, visual stimulation with a black and white card, gentle rocking, and oral stimulation including stroking the cheeks, lips, jaw, and tongue as well as rubbing the gums [22]. Each stimulation will be given for three minutes [21].

2.3.2 Movement therapy

Movement therapy will be administered for three minutes each per the following interventions: guided range of motion (bicycle riding pattern), antigravity movements in prone position (neck and spinal extension), antigravity movements in sitting position (supported), and upright positioning. A multi-parameter NICU monitor will be used to record physiological stress during the intervention. Recruited PNs will be considered to be in physiological stress if heart rate (HR) >200 or < 100 bpm, respiratory rate (RR) >20 over baseline, or oxygen saturation (SpO2) <86% for more than 15 seconds [15]. Similarly, signs of behavioral stress will be monitored; if a recruited PN startles, tremors, yawns, finger splays, averts gaze, cries, hiccups, protrudes their tongue, or displays tone or state-related behavior changes during treatment session, the MMS intervention will be modified. The particular stimulation will be paused for 15 seconds and only resumed if parameters recover. The infant’s physiological and behavioral stress responses will be monitored to prevent overstimulation. This standardized MMS protocol was named as Preemies’ Neuro-motor Facilitation (PNMF) Protocol, tabulated in Table 2. The PNMF Protocol by the first author was copyrighted under the Copyright Office of the Government of India with unique registration no. L-89359/2020 dated 11th February, 2020 (copyright filed with diary no., 19789/2019-CO/L dated 10th December, 2019).

2.3.3 Group B - Control group

The control group will receive standard life-saving NICU care from the medical team and daily maternal care, such as being held in the mother’s arms [23].

Though both the groups may not be identical, they differ only by MMS intervention and thereby pre-post intervention changes due to the full attribute of the MMS intervention could be verified. Hence, this design could be considered as the acceptable scientific standard for establishing a cause-and-effect relationship in clinical research [24].

2.4 Study measures

2.4.1 Demographic and clinical information

Date of birth, prematurity, type of delivery, APGAR scores [25], and the New Ballard score will be obtained from hospital records, whereas length (cm), head circumference (cm), and weight (grams) will be measured before the interventions.

3 Outcomes

3.1 Primary outcome

Infant Neurological International Battery: The Infant Neurological International Battery (INFANIB), which is easy and efficient to administer [25 –28], will be used as the primary outcome measure to assess the neuromotor development of the preterm neonate using corrected gestational age [21]. INFANIB has excellent reliability of ICC = 0.9 with 90% sensitivity and 83% specificity and acceptable predictive validity in detecting developmental delay [28, 29]. It can be successfully used among preterm infants to detect the short-term effect of multisensory interventions on the neuromotor development of preterm neonates [21]. INFANIB consists of a total of 20 items to be evaluated in five positions: supine, prone, sitting, standing, and suspended [25]. Among them, only 14 items are able to be administered at birth. The 14 included items are: 10 items in supine position - hands closed/open, scarf sign, heel to ear, popliteal angle, leg abduction, dorsiflexion of the foot, foot grasp, tonic labyrinthine, asymmetric tonic neck reflex and pull to sitting; two items in prone position –all fours and tonic labyrinthine; one item in sitting position –sitting; and one item in standing position –weight-bearing. Thus, a total score of 70 will be used instead of 100 [30]. The neurological cut-off scores proposed by the developer, Patricia H. Ellison (1986), are as follows: Abnormal:≤48, Transient: 49–65 and Normal:≥66 [30]. Following interpretation, these scores will be used to describe the characteristic of recruited PNs. Pre-post MMS intervention changes of INFANIB will be recorded at baseline and considered for the data analysis, after every five days (to compare trajectories of scores between the groups,) and at the end of the intervention at the time of discharge of neonate from the NICU.

3.2 Secondary outcomes

Bone minerals (serum calcium, serum phosphate, and bone specific alkaline phosphate) will be measured at baseline, after every five days, and at the end of the intervention (discharge of the neonate from the NICU) [26, 28] to compare the trajectories of scores between the groups.

Parathyroid hormone (serum level) will be measured at the onset and the end of the intervention (discharge of neonate from the NICU) [23].

3.3 Anthropometric parameters

Weight (g) of the neonate will be further stratified into normal birth weight (NBW) from 2500 g to 3999 g, low birth weight (LBW) which is considered less than 2500 g [31], appropriate for gestational age (AGA), small for gestational age (SGA), length (cm), cephalic perimeter (cm), and type of delivery (normal vaginal delivery [NVD] or Lower segment Caesarean section [LSCS]) [26].

Physiological parameters including HR, RR, body temperature (BT), and BP will be obtained from a multi-parameter NICU monitor before and after every session. In addition to this, the length of hospital stay will be noted. Both the primary and secondary outcomes with anthropometric parameters will be recorded at baseline, after every five days, and at the end of the intervention at the time of discharge of the neonate from the NICU to compare the trajectories of scores between the groups. The recommended content for the schedule of enrolment, interventions, and assessments of the MMS trial is displayed in Fig. 2.

Fig. 2

Recommended content for the schedule of enrolment, interventions, and assessments of MMS trial.

3.4 Fidelity

3.4.1 Fidelity of therapist

The application of the MMS trial and outcomes will be assessed by a pediatric physiotherapist practicing in NICU with five years’ experience in handling the neonates. This therapist will be known as the Investigating Therapist (IT).

3.4.2 Fidelity of data management

The gathered data will be then overseen by the Data and Safety Monitoring Committee (DSMC) of the University. The DSMC operates independently from the IT and has a key role in surveilling the outcome of the trial, monitoring adverse effects, and supervising IT. After at least 50% of neonates have been randomized, an interim analysis will be done by the DSMC to check the expected or other unintended effects of the MMS trial. Twice per month, the DSMC will conduct a surprise audit of the MMS trial.

3.4.3 Confidentiality

Each recruited PN will be given a serial code. (Example: C1 for the first PN of the control group and M1 for the first PI of the MMS trial group). Only the IT will hold the key to the code matching demographic details of the PNs. An encrypted user password will be used to secure the collected data in the Microsoft® Office Excel 2019 and stored in a personal desktop of the IT to prevent unauthorized data access and data theft. All the encrypted user passwords will be shared only between the IT and the data analyst. Data will be archived for future reference without the names of PNs or any other features which can reveal the identities of PNs.

3.5 Data analysis

Qualitative variables (nominal and ordinal scales) of the demographic dimensions collected will be reported in frequency rounded off to one decimal with percentages. An example of a qualitative variable is type of delivery. For quantitative variables (interval and ratio scales) such as, demographic, physiological parameters including HR, RR, Body Temperature (BT), and BP and outcome measures (Primary: INFANIB and secondary: Bone minerals and parathyroid hormone), “goodness of fit” will be determined by Shapiro-Wilk (SW) test [32]. The SW test will be applied to assess for their normality, as the sample size of an individual group is less than 50 (n < 50) [33 –35]. The normality test can be sub-classified into descriptive statistics and theory-driven methods which use both graphical and numerical methods [34, 36]. The normality will be verified by numerical methods, skewness, and kurtosis for descriptive statistics and SW test for the theory-driven method. If skewness approaches zero (0) and kurtosis approaches three (3), then according to the descriptive statistics method, the data will be considered normal [36]. Similarly, if SW test is not significant (p > 0.05), then the distribution will be considered normal [32]. The descriptive statistics of the normally distributed data will be expressed in mean±standard deviation. A paired t-test will be adopted to find out the differences within Group-A and group-B for pre-post intervention changes. If PNs continue to stay longer than five days duration, repeated measures ANOVA/Friedman test will be used to compare the intervention changes at regular intervals till the time of discharge of neonate from the NICU within the groups. Independent t-test will be used to compare the changes in mean values of the outcome measures between Group A and Group B at baseline, after every five days, and at the end of the intervention at the time of discharge of neonate from the NICU, thereby allowing for comparison of the trajectories of scores between the groups. If the data does not follow a normal distribution, then the descriptive statistics will be reported in medians with interquartile ranges (IQR). Wilcoxon signed-rank test will be adopted to find out the differences within Group A and Group B for pre-post intervention changes and to compare the intervention changes at regular intervals till the time of discharge of neonate from the NICU, Friedman test will be used. A Mann-Whitney U test will be used to compare the changes in median values of the outcome measures between Group A and Group B at baseline, after every five days (to record trajectories of scores between the groups), and at the end of the intervention at the time of discharge of neonate from the NICU in order to compare the trajectories of scores between the groups. In this design, type of intervention (MMS and control) is the independent variable, neuromotor outcome measured by INFANIB and bone minerals are the dependent variable, and categories of preterm [extremely preterm (less than 28 weeks), very preterm (28 to 32 weeks), and moderate to late preterm (32 to 37 weeks)] are covariates, the potential confounding variables for which to control. Hence, analysis of covariance (ANCOVA)/Quade’s test for non-parametric Analysis Of Covariance (ANCOVA) will be used to make adjustments in the dependent variable. In addition to the above objective measurements, subjective visual observation method will be used to describe the status of the PNs. Both the primary (INFANIB) and secondary (bone minerals) outcomes with anthropometric parameters will be recorded at baseline, after every five days, and at the end of the intervention at the time of discharge of neonate from the NICU. All the data will be analyzed using, the statistical package for the social sciences (SPSS), IBM SPSS version 20.0 (Armonk, NY: IBM Corp.). For all the analyses, p < 0.05 will be considered as statistically significant.

4 Discussion

The long-term developmental sequelae associated with prematurity includes developmental delay in the acquisition of age-appropriate motor skills; this may be precipitated by noxious stimuli within the NICU [4–6 , 37]. The maturing PN brain is highly sensitive and rapidly-changing and thus EI and a pleasant environment of NICU is required for optimal brain development [5]. Although EI is an umbrella term describing a variety of multi-disciplinary care delivered to children up to five years of age [38, 39], in the current study, it refers to the specific EI MMS protocol.

Various physiotherapy interventions, namely, positioning [40], hydrotherapy [41, 42], motor physical therapies, tactile or massage, vestibular stimulation, and sensory interventions, have been tested independently for their effects on neuromotor outcomes of PNs. The effects of multisensory and tactile-kinesthetic stimulations EI have previously been evaluated in combinations [43, 44].

Many of the reported intervention protocols were started at least a week after birth [5]. In contrast, the MMS trial will be implemented a day after the birth. Also, the majority of studies assessed only cognitive outcomes, with fewer studies assessing motor and behavioral long-term outcomes, and thus providing inconclusive evidence about the effect of early intervention across multiple developmental domains [5, 45]. Hence, neuromotor development of PNs (INFANIB) along with anthropometrics (weight, length, and head circumference) and bone minerals (serum calcium, serum phosphate, and bone-specific alkaline phosphate) will be used to determine the efficacy of the MMS trial. The current study describes the MMS trial which is a uniquely customized early intervention trial to promote sensory and motor maturation among the PNs.

The effects of MMS will be studied systematically by using a standardized MMS protocol with randomized controlled study design where the control group has no intervention except standard medical and maternal care [5].

Like other reported trials this study also might minimize parental stress, improve quality of life, lead to early discharge from the NICU, and provide other hidden benefits to PNs and their families [46]. Furthermore, the study could be extended to document the neurological outcomes of preterm infants at 3, 7, and 10 months as recommended by Liao et al. [28].

Footnotes

Acknowledgments

The authors express their sincere thanks to Dr. Asir John Samuel, PhD (Physiotherapy), Professor, Department of Pediatric and Neonatal Physiotherapy, Maharishi Markandeshwar Institute of Physiotherapy and Rehabilitation, Maharishi Markandeshwar (Deemed to be University), Mullana, Haryana, India, for his assistance in writing sample size and data analysis section. This study protocol forms the partial fulfillment for the completion of structured Doctorate of Philosophy / Philosophiae Doctor (PhD) programme by the first author, Mrs. Vencita Priyanka Aranha (Roll No. 2019001 / Regn No. 14-PCM-076).

Clinical trial registration

NCT04247308 on 30^th January 2020

Conflict of interest

The authors have no conflict of interest to report

Funding

Mrs. Vencita Priyanka Aranha, first author, was supported by a three year PhD Research Fellowship (MMDU/Ph.D/19/2108 dated 5^th Febrauary 2019) from Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala District, Haryana, India during the study period.

References

Kuppusamy

, Vidhyadevi

. Prevalence of Preterm Admissions and the Risk Factors of Preterm Labor in Rural Medical College Hospital, Int J Sci Study 2016;4(9):125–8. doi: 10.17354/ijss/2016/629.

March of Dimes, PMNCH, Save the Children, WHO. Born Too Soon: The Global Action Report on Preterm Birth. Howson CP, Kinney MV, Lawn JE, editors. Geneva: World Health Organization; 2012. Available from: http://apps.who.int/iris/bitstream/handle/10665/44864/9789241503433eng.pdf;jsessionid=87BD8BA1E181E0E2F115E1C2838E9FD6?sequence=1.

Alvarez-Garcia

, Fornieles-Deu

, Costas-Moragas

, Botet-Mussons

, Maturational changes associated with neonatal stress in preterm infants hospitalised in the NICU, J Reprod Infant Psychol 2014;32(4):412–22. doi: 10.1080/02646838.2014.937411.

Neel

, Yoder

, Matusz

, Murray

, Miller

, Burkhardt

, et al., Randomized controlled trial protocol to improve multisensory neural processing, language and motor outcomes in preterm infants, BMC Pediatr 2019;19(1):81. doi: 10.1186/s12887-019-1455-1.

Spittle

, Treyvaud

. The role of early developmental intervention to influence neurobehavioral outcomes of children born preterm, Semin Perinatol 2016;40(8):542–8. doi: 10.1053/j.semperi.2016.09.006.

Byrne

, Garber

, Physical therapy intervention in the neonatal intensive care unit, Phys Occup Ther Pediatr 2013;33(1):75–110. doi: 10.3109/01942638.2012.750870.

Mathur

, Inder

, Magnetic resonance imaging–insights into brain injury and outcomes in premature infants, J Commun Disord 2009;42(4):248–55. doi: 10.1016/j.jcomdis.2009.03.007.

Schulzke

, Kaempfen

, Trachsel

, Patole

. Physical activity programs for promoting bone mineralization andgrowth in preterm infants, Cochrane Database Syst Rev 2014;4):CD870053. doi: 10.1002/14651858.CD005387.pub3.

Bracewell

, Marlow

. Patterns of motor disability in very preterm children, Ment Retard Dev Disabil Res Rev 2002;8(4):241–8. doi: 10.1002/mrdd.10049.

10.

Hughes

, Redsell

, Glazebrook

, Motor development interventions for preterm infants: A systematic review and meta-analysis, Pediatrics 2016;138(4):e0147. doi: 10.1542/peds.2016-0147.

11.

Melnyk

, Alpert-Gillis

, Feinstein

, Fairbanks

, Schultz-Czarniak

, Hust

, et al., Improving cognitive development of low-birth-weight premature infants with the COPE program: a pilot study of the benefit of early NICU intervention with mothers, Res Nurs Health 2001;24(5):373–89. doi: 10.1002/nur.1038.

12.

Borges Nery

, Snider

, Camelo Junior

, Zachary

, Fatima

, Jessica

, et al., The Role of Rehabilitation Specialists in Canadian NICUs: A 21st Century Perspective, Phys Occup Ther Pediatr 2019;39(1):33–47. doi: 10.1080/01942638.2018.1490846.

13.

Sizun

, Westrup

, Early developmental care for preterm neonates: a call for more research, Arch Dis Child Fetal Neonatal Ed 2004;89(5):F384–8. doi: 10.1136/adc.2002.025114.

14.

Ustad

, Evensen

KAI

, Campbell

, Girolami

, Helbostad

, Jørgensen

, et al., Early Parent-Administered Physical Therapy for Preterm Infants: A Randomized Controlled Trial, Pediatrics 2016;138(2):e0271. doi: 10.1542/peds.2016-0271.

15.

Silveira

, Mendes

, Fuentefria

, Valentini

, Procianoy

. Early intervention program for very low birth weight preterm infants and their parents: a study protocol, BMC Pediatr 2018;18(1):268. doi: 10.1186/s12887-018-1240-6.

16.

Liberali

, Davidson

, dos Santos

AMN

, [Availability of physical therapy assistance in neonatal intensive careunits in the city of São Paulo, Brazil], Rev Bras Ter Intensiva 2014;26(1):57–64. doi: 10.5935/0103-507x.20140009.

17.

Dirks

, Blauw-Hospers

, Hulshof

, Hadders-Algra

, Differences between the family-centered “COPCA” program and traditional infant physical therapy based on neurodevelopmental treatment principles, Phys Ther 2011;91(9):1303–22. doi: 10.2522/ptj.20100207.

18.

Blauw-Hospers

, Dirks

, Hulshof

, Bos

, Hadders-Algra

, Pediatric physical therapy in infancy: from nightmare to dream? A two-arm randomized trial, Phys Ther 2011;91(9):1323–38. doi: 10.2522/ptj.20100205.

19.

ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2020 Oct 1 –2021 Dec 13. Identifier NCT04247308, Multi Modal Stimulations in Pre-term Neonates; 2022 Jan 20 [cited 2021 Mar 26]. Available from: https://clinicaltrials.gov/ct2/show/NCT04247308.

20.

Peacock

, Kerry

, Balise

Writing a research protocol. In: Presenting Medical Statistics from Proposal to Publication. 2nd ed. Oxford, United Kingdom: Oxford University Press; 2017, pp. 32–4.

21.

Kanagasabai

, Mohan

, Lewis

, Kamath

, Rao

, Effect of multisensory stimulation on neuromotor development in preterm infants, Indian J Pediatr 2013;80(6):460–4. doi: 10.1007/s12098-012-0945-z.

22.

Bala

, Kaur

, Mukhopadhyay

, Kaur

, Oromotor Stimulation for Transition from Gavage to Full Oral Feeding inPreterm Neonates: A Randomized controlled trial, Indian Pediatr 2016;53(1):36–8. doi: 10.1007/s13312-016-0786-3.

23.

Vignochi

, Miura

, Canani

, Effects of motor physical therapy on bone mineralization in premature infants: a randomized controlled study, J Perinatol 2008;28(9):624–31. doi: 10.1038/j2008.60.

24.

Portney

Experimental designs. In: Foundations of Clinical Research: Applications to Evidence-Based Practice. 4th ed. Philadelphia, USA: FA Davis Company; 2020, pp. 228.

25.

Ellison

, Horn

, Browning

, Construction of an Infant Neurological International Battery (Infanib) for the assessment of neurological integrity in infancy, Phys Ther 1985;65(9):1326–31. doi: 10.1093/ptj/65.9.1326.

26.

Soleimani

, Dadkhah

, Validity and reliability of Infant Neurological International Battery for detection ofgross motor developmental delay in Iran, Child Care Health Dev 2007;33(3):262–5. doi: 10.1111/j.1365-2214.2006.00704.x.

27.

Soleimani

, Infant Neurological International Battery (INFANIB): Validity and Reliability in Iran, Neuropediatrics 2006;37:MP10. doi: 10.1055/s-2006-943607.

28.

Liao

, Wen

E-Y

, Li

, Chang

, Lv

K-L

, Yang

, et al., Predicting neurodevelopmental outcomes for at-risk infants: reliability and predictive validity using a Chinese version of the INFANIB at 3, 7 and 10 months, BMC Pediatr 2012;12:72. doi: 10.1186/1471-2431-12-72.

29.

Luo

, Chen

, Ma

X-L

, Lin

H-J

, Bao

, Wang

C-H

, et al., [Infant Neurological International Battery predicts neurological outcomes of preterm infants discharged from the neonatal intensive care unit], Zhongguo Dang Dai Er Ke Za Zhi 2013;15(1):5–8.

30.

Ellison

, Scoring sheet for the infant neurological international battery (INFANIB), Suggestion from the field. Phys Ther 1986;66(4):548–50. doi: 10.1093/ptj/66.4.548.

31.

Tecklin

The Infant at High Risk for Developmental Delay. In: Pediatric Physical Therapy. 5th ed. Philadelphia, USA: Lippincott Williams & Wilkins; 2015, .

32.

Portney

Foundations of Statistical Inference. In: Foun-dations of Clinical Research: Applications to EvidenceBased Practice. 4th ed. Philadelphia, USA: FA Davis Company; 2020, pp. 349..

33.

Shapiro

, Wilk

, An Analysis of Variance Test for Normality (Complete Samples), Biometrika 1965;52(3-4):591–611. doi: 10.1093/biomet/52.3-4.591.

34.

Mohd Razali

, Wah

, Power comparisons of Shapiro-Wilk, Kolmogorov-Smirnov, Lilliefors and Anderson-Darling tests, J Stat Model Anal 2011;2(1):21–33.

35.

Yap

, Sim

, Comparisons of various types of normality tests, J Stat Comput Simul 2011;81(12):2141–55. doi: 10.1080/00949655.2010.520163.

36.

Park

Univariate Analysis and Normality Test Using SAS, STATA, and SPSS. Bloomington, Indiana: The University Information Technology Services (UITS) Center for Statistical and Mathematical Computing, Indiana University; 2008. Available from: https://scholarworks.iu.edu/dspace/bitstream/handle/2022/19742/Univariate%20Analysis%20and%20Normality%20Test%20Using%20SAS%2c%20Stata%2c%20and%20SPSS.pdf?sequence=1&isAllowed=y.

37.

McManus

, Capistran

, A case presentation of early intervention with dolichocephaly in the NICU: collaboration between the primary nursing team and the developmental care specialist, Neonatal Netw 2008;27(5):307–15. doi: 10.1891/0730-0832.27.5.307.

38.

Persha

, Rao

VRPS

Early intervention to IUGR Children at risk for developmental delays. Secunderabad: National Institute for the Mentally Handicapped; 2003.

39.

Roberts

, Howard

, Spittle

, Brown

, Anderson

, Doyle

, Rates of early intervention services in very preterm children with developmental disabilities at age 2 years, J Paediatr Child Health 2008;44(5):276–80. doi: 10.1111/j.1440-1754.2007.01251.x.

40.

Waitzman

, The Importance of Positioning the Near-term Infant for Sleep, Play, and Development, Newborn InfantNurs Rev 2007;7(2):76–81. doi: 10.1053/j.nainr.2007.05.004.

41.

Novakoski

KRM

, Valderramas

, Israel

, Yamaguchi

, Andreazza

, Back to the liquid environment: effects of aquatic physiotherapy intervention performed on preterm infants, Rev Bras Cineantropom Desempenho Hum 2018;20(6):566–75. doi: 10.5007/1980-0037.2018v20n6p566.

42.

Sweeney

, Neonatal Hydrotherapy: An Adjunct to Developmental Intervention in an Intensive Care Nursery Setting, Phys Occup Ther Pediatr 1983;3(1):39–52. doi: 10.1080/J006v03n01_03.

43.

Scafidi

, Field

, Schanberg

, Bauer

, Vega-Lahr

, Garcia

, et al., Effects of tactile/kinesthetic stimulation on the clinical course and sleep/wake behavior of preterm neonates, Infant Behav Dev 1986;9(1):91–105. doi: 10.1016/0163-6383(86)90041-X.

44.

Pepino

, Mezzacappa

, Application of tactile/kinesthetic stimulation in preterm infants: a systematic review, J Pediatr (Rio J) 2015;91(3):213–33. doi: 10.1016/j.jped.2014.10.005.

45.

Garcia

, Gephart

, The effectiveness of early intervention programs for NICU graduates, Adv Neonatal Care 2013;13(4):272–8. doi: 10.1097/ANC.0b013e31829d8c75.

46.

Cameron

, Maehle

, Reid

, The effects of an early physical therapy intervention for very preterm, very low birth weight infants: a randomized controlled clinical trial, Pediatr Phys Ther 2005;17(2):107–19. doi: 10.1097/01.PEP.0000163073.50852.58.

A randomized controlled trial protocol in modifying neuromotor behavior of hospitalized preterm neonates using multimodal stimulations: MMS trial