Study reference

Study characteristics

Patient characteristics ²

Intervention (I)

Comparison / control (C) ³

Follow-up

Outcome measures and effect size ⁴

Comments

Mirlashari, 2021

Type of study:

Double-blind randomized controlled trial

Setting and country:

Single-centre, Iran

Funding and conflicts of interest:

This project was funded by the School of

Nursing and Midwifery, Tehran University of

Medical Sciences, Tehran, Iran.

The authors declare that there is no conflict of

interest in this study.

Inclusion criteria:

preterm neonates with a gestational

age of ≤ 32 weeks and birth weight of ≤ 2,000 g

Exclusion criteria:

neonatal

need for cardiopulmonary resuscitation during

ROP examinations.

N total at baseline:

Intervention: 21

Control: 21

Important prognostic factors²:

Gestational age (week) ± SD:

Intervention: 30.3 ± 0.3

Control: 30.2 ± 0.3

Sex, male (%):

Intervention: 9 (42.9)

Control: 9 (42.9)

Groups comparable at baseline? Yes

Describe intervention:

0.5 ml/kg of breast milk 2 min before the examination

Describe control :

0.5 ml/kg of sucrose 2 min before the examination

Length of follow-up:

15 minutes

Loss-to-follow-up:

None

Incomplete outcome data:

None

Outcome measures and effect size (include 95%CI and p-value if available):

1. Heart rate

The mean heart rate was significantly

lower in the breast milk group in comparison to

those reported for the other two groups (P<0.05; figure 4)

2. Blood pressure

Not reported

3. Saturation

There was no significant difference between the mean SpO2 and respiratory rate in the three groups (P>0.05; figures 2)

4. PIPP, 15 min after examination, mean ± SD:

I: 0.73 ± 0.7

C: 1.00 ± 0.8

Author’s conclusion:

Breast milk was more effective in the reduction of pain and stress after ROP examinations, compared to sucrose or distilled water.

Turan, 2021

Type of study:

randomized controlled trial

Setting and country: single centre, Turkey

Funding and conflicts of interest:

No potential conflict of interest was reported by the authors.

Inclusion criteria:

preterm infants who were hospitalized in the neonatal intensive care unit and whose gestational week was <32 weeks and birth weight were <1500 g.

Exclusion criteria:

major congenital anomalies, chromosomal abnormality, intraventricular hemorrhage, and on ventilator support.

N total at baseline:

Intervention: 17

Control: 17

Important prognostic factors²:

Gestational age (weeks) ± SD:

I: 30.12 ± 2.20

C: 28.47 ± 2.21

Sex, female/male (n/%):

I: 9 (52.9)/8 (47.1)

C: 7 (41.2)/10 (58.2)

Groups comparable at baseline? yes

Describe intervention (treatment/procedure/test):

 proparacaine HCl ophthalmic solution 0.5% plus breast milk

Describe control (treatment/procedure/test):

 proparacaine HCl ophthalmic

solution 0.5% plus sucrose 24%.

Length of follow-up:

90 seconds

Loss-to-follow-up:

Not reported

Incomplete outcome data:

Not reported

Outcome measures and effect size (include 95%CI and p-value if available):

1. Heart rate, mean ± SD:

Before the examination

I: 143.8 ± 9.71

C: 140.7 ± 11.9

30^th s

I: 161.7 ± 12.4

C: 159.2 ± 14.3

60^th s

I: 169.8 ± 17.8

C: 165.6 ± 15.5

90^th s

I: 165.7 ± 18.6

C: 165.7 ± 18.3

30 s after examination

I: 159.6 ± 14.4

C: 160.8 ± 17.8

2. Blood pressure

Not reported

3. Saturation, mean ± SD:

Before the examination

I: 97.0 ± 1.1

C: 96.2 ± 3.0

30^th s

I: 90.9 ± 5.9

C: 91.1 ± 6.7

60^th s

I: 90.7 ± 5.4

C: 87.8 ± 6.6

90^th s

I: 91.3 ± 5.8

C: 87.1 ± 9.2

30 s after examination

I: 94.1 ± 5.6

C: 89.1 ± 9.5

4. NIPS, 15 mean ± SD:

Before the examination

I: 0.82 ± 0.6

C: 1.18 ± 0.80

30^th s

I: 5.88 ± 0.6

C: 6.18 ± 0.72

60^th s

I: 6.29 ± 0.5

C: 6.51 ± 0.47

90^th s

I: 4.94 ± 1.0

C: 6.00 ± 1.00

30 s after examination

I: 3.94 ± 0.7

C: 4.12 ± 1.26

Author’s conclusion:

The present study indicates that alterations may be seen in PI during the ROP

examination: in other words, peripheral tissue perfusion could be affected. We consider that eye examination is a very painful procedure, and administering breast milk, sucrose or local anesthetic is not sufficient for reducing pain.

Dolgun, 2017

Type of study:

randomized controlled trial

Setting and country: single centre, Turkey

Funding and conflicts of interest:

The authors report no con- flict of interest or relevant financial relationships.

Inclusion criteria:

gestational age less than 32 weeks and body weight less than 1,500 g, parent approval on the consent form, no requirement for invasive or noninvasive mechanical ventilator support during the procedure, no intake of analgesic or sedative drug in the past 24 hours, no contra- indications to oral feeding, and no congenital abnormalities.

Exclusion criteria:

Not reported

N total at baseline:

Intervention: 29

Control: 29

Important prognostic factors²:

Gestational age, weeks ± SD:

I: 30.2 ± 1.6

C: 29.9 ± 2.1

Birth weight, grams ± SD:

I: 1048.3 ± 293.9

C: 1045.8 ± 372.6

Groups comparable at baseline? Yes

Describe intervention (treatment/procedure/test):

Swaddling with orally administered breast milk

Describe control (treatment/procedure/test):

Swaddling with orally administered 0.2 ml of 24% sucrose

Length of follow-up:

Not reported

Loss-to-follow-up:

Not reported

Outcome measures and effect size (include 95%CI and p-value if available):

1. Heart rate

Not reported

2. Blood pressure

Not reported

3. Saturation

Not reported

4. PIPP

Before the examination

I: 3.41 ± 0.63

C: 3.00 ± 1.10

During examination

I: 8.45 ± 1.38

C: 9.10 ± 1.82

After examination

I: 4.86 ± 1.27

C: 4.59 ± 1.64

Author’s conclusion:

Infant swaddlings with oral administration of sucrose or breast milk were no more effective than swaddling with oral administration of distilled water to reduce pain in premature infants during ROP examinations.

Sun. 2020

Type of study:

randomized controlled trial

Setting and country: single centre, China

Funding and conflicts of interest:

This work was supported by the Project of Nanjing Special Fund for Health Science and Technology Development (grant no. 201723007). The Foundation only provided experimental financial support and does not interfere with experimental conduct and data.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Inclusion criteria:

pre-mature birth with a gestational age of ≤34 weeks or a birth weight of ≤2,000g, no prior history of fundus screening, and screening at 4–6 weeks of age after birth or a corrected gestational age of 31–32 weeks.

Exclusion criteria:

administration of non-steroidal anti- inflammatory drugs or sedative and anti-epileptic drugs such as chloral hydrate, phenobarbital, and diazepam within 24h before ROP screening; intolerance to screening because of critical conditions such as severe respiratory diseases, central nervous system infections, sepsis, and other organic diseases such as severe congenital heart malformation and pulmonary insufficiency.

N total at baseline:

Intervention: 41

Control: 41

Important prognostic factors²:

Gestational age, weeks ± SD:

I: 29.88 ± 0.40

C: 30.03 ± 0.40

Sex ratio m/f:

I: 20/18

C: 14/14

Groups comparable at baseline? Yes

Describe intervention (treatment/procedure/test):

Receiving Gentle Human Touch during screening

Describe control (treatment/procedure/test):

screened according to the routine procedure.

Length of follow-up:

Not reported

Loss-to-follow-up:

Intervention:

13 (37.7%)

Reasons (describe)

Withdrew consent (n=9)

Withdrew due to intolerance of examination

Control:

3 (7.3%)

Reasons (describe)

Withdrew consent (n=3)

Incomplete outcome data:

Not reported

Outcome measures and effect size (include 95%CI and p-value if available):

1. Heart rate changes before and after examination, time/min:

I: 170.80 ± 3.50

C: 182.60 ± 3.50

2. Blood pressure

Not reported

3. Saturation during examination:

I: 85.68 ± 8.31

C: 1.89 ± 6.43

4. PIPP:

Reduction from baseline

I: 6.29 ± 2.98

C: 11.82 ± 3.47

During screening

I: 9.29 ± 2.89

C: 14.82 ± 3.22

Authors conclusion:

In conclusion, the findings of this study suggest that Gentle
Human Touch can effectively alleviate pain during ROP
screening in pre-mature infants.

Kristoffersen, 2019

Type of study:

randomized controlled trial

Setting and country: single centre, Norway

Funding and conflicts of interest:

This study was funded by the Liaison Committee between the Central Norway Regional Health Authority and the Norwegian University of Science and Technology.

None of the authors have any conflicts of interest to disclose.

Inclusion criteria:

preterm infants with a GA of less than 32 weeks who were eligible for ROP screening and admitted to St Olavs University Hospital, Trondheim, Norway, between January 2014 and June 2016

Exclusion criteria:

- They were given any sedative or analgesic medication at the time of the ROP screening or had a severe intraventricular haemor- rhage (grade 3–4)

- examined only with an indirect ophthalmoscopy and not with digital imaging by RetCam

- Infants with insufficient data recordings

N total at baseline:

Intervention: 21

Control:25

Important prognostic factors²:

Gestational age, median ± SD:

28+6weeks

Groups comparable at baseline? Unknown

Describe intervention (treatment/procedure/test):

Skin-to-skin with one of the parents

Describe control (treatment/procedure/test):

standard care with supportive positioning by parents

Length of follow-up:

Up to 17 days

Loss-to-follow-up:

Intervention:

5 (23.8%)

Reasons:

Not assessable (n=5)

Control:

6 (24%)

Reasons:

Withdrew consent after first eye-examination (n=1)

Not assessable (n=5)

Incomplete outcome data:

Not reported

Outcome measures and effect size (include 95%CI and p-value if available):

1. Heart rate:

Not reported

2. Blood pressure

Not reported

3. Saturation:

Not reported

4. PIPP, mean:

During screening

I: 10.2

C: 10.3

mean difference of 0.1 and a 95% confidence interval (95% CI) of 1.568 to 1.396, p = 0.91

After screening

I: 7.0

C: 6.8

mean difference 0.2, 95% CI: 1.09 to 1.49, p = 0.76

Authors conclusion:

Skin-to-skin contact during ROP examination did not give additional pain relief compared to standard care with parental support in preterm infants. The pain scores were lower than in comparable studies, and we speculate whether active parental involvement had a pain reducing effect in both groups. Further studies are needed to determine the most efficient multidimensional approach to reduce pain in preterm infants undergoing ROP screen- ing.

Naik, 2021

Type of study:

randomized controlled trial

Setting and country: single centre, India

Funding and conflicts of interest:

Financial support and sponsorship

Nil.

There are no conflicts of interest.

Inclusion criteria:

gestational age (assessed using New Ballard Score) <34 weeks and/or birth weight <1500 gm

Exclusion criteria:

Infants requiring mechanical ventilation at the time of ROP screening or receiving sedatives or narcotics, neonates not receiving oral feeds, and neonates with congenital anomalies

N total at baseline:

Intervention: 31

Control: 30

Important prognostic factors²:

Gestational age (weeks) ± SD:

I: 33.35 ± 2.12

C:33.46 ± 2.11

Sex:

I: 54.8% M

C: 56.7% M

Groups comparable at baseline? Yes

Describe intervention (treatment/procedure/test):

2 ml expressed breast milk (EBM) through a sterile syringe orally 2 min prior to procedure

Describe control (treatment/procedure/test):

syrup paracetamol, 15 mg/kg 30 min prior to procedure and EBM

Length of follow-up:

Not reported

Loss-to-follow-up:

None

Incomplete outcome data:

Not reported

Outcome measures and effect size (include 95%CI and p-value if available):

1. Heart rate:

Not reported

2. Blood pressure

Not reported

3. Saturation:

Not reported

4. PIPP, mean:

Before screening

I: 3.25 ± 1.71

C: 3.45 ± 2.20

After screening

I: 15.44 ± 2.05

C: 15.83 ± 1.36

Authors conclusion:

The procedure of ROP screening causes significant pain in premature neonates which is demonstrated by PIPP scores of >12 across all groups.

There were no significant statistical differences noted in the PIPP scores between the control groups and the intervention groups, Group B and Group C. This indicates that breastmilk alone or in combination with paracetamol is inadequate to relieve the severe pain associated with the procedure of ROP screening.

The PIPP score following the procedure in all the three groups was >7, and this indicates that there was the persistence of slight to moderate pain which lasted for up to 2 min following the procedure.

Rosali, 2015

Type of study:

randomized controlled trial

Setting and country: single centre, India

Funding and conflicts of interest:

Not reported

Inclusion criteria:

Babies with a gestational age of less than 35 weeks (as assessed by New Ballard Score), birth weight less than 2000g, requiring an ROP screening and who were on at least partial oral feeds

Exclusion criteria:

Newborns on opioid analgesics, sedatives, anticonvulsants or on mechanical ventilation

N total at baseline:

Intervention: 20

Control: 20

Important prognostic factors²:

Gestational age (weeks) ± SD:

I: 31.5 6 2.4

C: 30.3 6 1.89

Birth weight (grams) ± SD:

I: 1426 .7 6 366.7

C: 1285.2 6 245.6

Sex:

I: 35% M

C: 50% M

Groups comparable at baseline? Yes

Describe intervention (treatment/procedure/test):

2ml of EBM orally by paladai, (a small cup used to feed neonates) 2 min prior to the procedure along with standard practice.

Describe control (treatment/procedure/test):

nested, swaddled and received topical proparacaine which is the standard practice in the unit.

Length of follow-up:

5 min

Loss-to-follow-up:

None

Incomplete outcome data:

Not reported

Outcome measures and effect size (include 95%CI and p-value if available):

1. Heart rate:

Not reported

2. Blood pressure

Not reported

3. Saturation:

Not reported

4. PIPP, mean:

Baseline

I: 3.85 ± 1.9

C: 5.25 ± 2.3

During screening

I: 12.7 ± 1.7

C: 15.3 ± 1.78

1 min after screening

I: 6.2 ± 1.98

C: 12.4 ± 2.54

5 min after screening

I: 3.2 ± 1.58

C: 6.85 ± 2.41

Authors conclusion:

The severe pain of ROP screening is significantly reduced by the use of EBM. This analgesic effect lasts even at 5 min after the procedure.

Sener Taplak, 2017

Type of study:

randomized controlled trial

Setting and country: Single centre, Turkey

Funding and conflicts of interest:

No competing financial interests exist.

Inclusion criteria:

Preterm infants with a birth weight £1,500 g and gestational age of £32 weeks.

Exclusion criteria:

Preterm infants diagnosed with a congenital anomaly, hydrocephalus, necrotizan enterocolitis, indirect hyperbilirubinemia, and receiving ventilatory sup- port or analgesic drug treatment.

N total at baseline:

Intervention: 20

Control: 20

Important prognostic factors²:

Gestational age (weeks), n (%):

£ 27.6

I: 1 (5)

C: 5 (25)

>28

I: 19 (95)

C: 15 (75)

Sex:

I: 45% M

C: 30% M

Groups comparable at baseline? Yes

Describe intervention (treatment/procedure/test):

The preterm infants were provided with 1mL of breast milk before ROP examination.

Describe control (treatment/procedure/test):

The preterm infants were provided with 1mL of sucrose before ROP examination

Length of follow-up:

15 min

Loss-to-follow-up:

None

Incomplete outcome data:

Not reported

Outcome measures and effect size (include 95%CI and p-value if available):

1. Heart rate:

Before screening

I: 151.80 ± 11.76

C: 155.20 ± 16.72

During screening

I: 176.59 ± 18.18

C: 183.42 ± 21.71

After screening

I: 159.70 ± 12.86

C: 165.70 ± 9.99

2. Blood pressure

Not reported

3. Saturation:

Before screening

I: 91.10 ± 5.48

C: 91.55 ± 5.16

During screening

I: 89.88 ± 7.72

C: 88.93 ± 6.57

After screening

I: 91.05 ± 7.88

C: 88.30 ± 8.73

4. PIPP, mean:

Before screening

I: 2.10 ± 0.55

C: 2.05 ± 0.75

During screening

I: 16.06 ± 2.41

C: 15.58 ± 2.02

After screening

I: 3.20 ± 1.36

C: 3.65 ± 1.78

Authors conclusion: conclusion, based on the finding that the breast milk group recovered and reached their initial physiological and behavioral values more quickly after the ROP examination, and due to the superiority of breast milk as being a safe, effective, available, and natural analgesic at no cost, breast milk is better than sucrose during the ROP examination. It is recommended that similar studies should be conducted pro- viding repetitive doses of breast milk and sucrose due to the long and painful nature of the ROP examination.

Study reference

(first author, publication year)

Was the allocation sequence adequately generated? ^a

Definitely yes

Probably yes

Probably no

Definitely no

Was the allocation adequately concealed?^b

Definitely yes

Probably yes

Probably no

Definitely no

Blinding: Was knowledge of the allocated

interventions adequately prevented?^c

Were patients blinded?

Were healthcare providers blinded?

Were data collectors blinded?

Were outcome assessors blinded?

Were data analysts blinded?

Definitely yes

Probably yes

Probably no

Definitely no

Was loss to follow-up (missing outcome data) infrequent?^d

Definitely yes

Probably yes

Probably no

Definitely no

Are reports of the study free of selective outcome reporting?^e

Definitely yes

Probably yes

Probably no

Definitely no

Was the study apparently free of other problems that could put it at a risk of bias?^f

Definitely yes

Probably yes

Probably no

Definitely no

Overall risk of bias

If applicable/necessary, per outcome measure^g

LOW

Some concerns

HIGH

Mirlashari, 2021

Probably yes;

Reason: Randomization was performed using closed letters. Accordingly, one of the letters was randomly selected and the infants were assigned to one of the three groups, namely breast milk, sucrose, or distilled water.

Definitely yes;

Reason: Randomization was performed using closed letters.

Definitely yes;

Reason: Double-blind RCT, videos evaluated by blinded video coders.

Definitely yes;

Reason: Loss to follow-up was infrequent in intervention and control group.

Definitely yes;

Reason: All relevant outcomes were reported

Definitely yes;

Reason: No other problems noted

LOW

Sener Taplak, 2017

Probably yes;

Reason: The preterm infants were randomly assigned to the breast milk, sucrose, and control groups.

Probably no:

Reason: Not reported

Definitely yes;

Reason: Double-blind RCT, videos were evaluated by three observers blinded to the study

Definitely yes;

Reason: Loss to follow-up was infrequent in intervention and control group.

Definitely yes

Reason: All relevant outcomes were reported;

Definitely yes;

Reason: No other problems noted

Some concerns

Turan, 2021

Probably yes;

Reason: The preterm infants who would undergo ROP examination were allocated to three groups according to simple randomization method

Probably no:

Reason: Not reported

Probably no:

Reason: Not reported

Definitely yes;

Reason: Loss to follow-up was infrequent in intervention and control group.

Definitely yes

Reason: All relevant outcomes were reported;

Definitely yes;

Reason: No other problems noted

Some concerns

Dolgun, 2017

Definitely yes;

Reason: For randomization, numbers 1 to 87 were ran-domized with no number repetition into three groups through the use of the Random Assignment computer program

Probably no:

Reason: Not reported

Probably yes:

Reason: Nurses were blinded to the group’s assignments of the infants

Definitely yes;

Reason: Loss to follow-up was infrequent in intervention and control group.

Definitely yes

Reason: All relevant outcomes were reported;

Definitely yes;

Reason: No other problems noted

Some concerns

Sun, 2020

Definitely yes;

Reason: Using the random number table, we assigned 41 pre-term infants to each group.

Probably no:

Reason: Not reported

Definitely no;

Reason: Not reported

Definitely yes;

Reason: Loss to follow-up was infrequent in intervention and control group.

Definitely yes

Reason: All relevant outcomes were reported;

Definitely yes;

Reason: No other problems noted

HIGH

Kristoffersens, 2019

Definitely yes;

Reason: For randomisation, we applied a web-based randomisa- tion and data collection system developed and adminis- tered by the Unit of Applied Clinical Research, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway.

Probably no:

Reason: Not reported

Definitely no;

Reason: Not reported

Definitely yes;

Reason: Loss to follow-up was infrequent in intervention and control group.

Definitely yes

Reason: All relevant outcomes were reported;

Definitely yes;

Reason: No other problems noted

HIGH

Naik, 2021

Definitely yes;

Reason: The neonates were allocated into three groups using a computer‐based randomization process according

to their ophthalmologic examination sequence using sealed opaque envelopes.

Definitely yes;

Reason: The neonates were allocated into three groups using a computer‐based randomization process according

to their ophthalmologic examination sequence using sealed opaque envelopes.

Probably yes;

Reason: The video recorder and analyzer were both blinded to the intervention.

Definitely yes;

Reason: Loss to follow-up was infrequent in intervention and control group.

Definitely yes

Reason: All relevant outcomes were reported;

Definitely yes;

Reason: No other problems noted

LOW

Rosali, 2015

Definitely yes;

Reason: The eligible babies were randomly allocated to the intervention and control groups using computer- generated random numbers.

Definitely yes;

Reason: Allocation concealment was done by using sequentially numbered opaque sealed envelopes containing the codes for interven- tion.

Probably yes;

Reason: Both these observers were blinded.

Definitely yes;

Reason: Loss to follow-up was infrequent in intervention and control group.

Definitely yes

Reason: All relevant outcomes were reported;

Definitely yes;

Reason: No other problems noted

LOW