Breast milk as a topical eye drop reduces the

severity of ROP: A randomized placebo-controlled

trial.
Musa Silahli 
(

msilahli@gmail.com
)
Baskent University
Mehmet Tekin 
Baskent University
Ali Kal 
Baskent University
Zeynel Gökmen 
Baskent University
Melek Büyükeren 
Konya City Hospital
Beyza Ozcan 
Turkey
Fatma Yılmaz 
Dr.Ali Kemal Beliviranli Hospital for Obstetrics and Pediatrics
Kadir Yümlü 
Dr.Ali Kemal Beliviranli Hospital for Obstetrics and Pediatrics
Birgin Torer 
Baskent University Faculty of Medicine
Bilin Çetinkaya 
Baskent University School of Medicine

Article

Keywords: Breastmilk, retinopathy of prematurity, morbidity, eye drop

Posted Date: June 13th, 2022

DOI: https://doi.org/10.21203/rs.3.rs-1719363/v1

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Abstract
Objective
Retinopathy of prematurity (ROP) is the most common cause of visual impairment and disability in
preterm infants. Human breast milk contains stem cells which have the ability to differentiate into all
three germ layers. This study investigated whether breast milk used as an eye drop reduces severe ROP or
laser-requiring ROP in VLBWinfants.

Methods
A single-blinded, multicenter, prospective, randomized controlled trial was conducted from May 2021 to
December 2021 in four level 3 neonatal intensive care units in (hidden for reviewer) in preterm infants
younger than 32 weeks gestation. Participants were randomly assigned to use either breast milk eye
drops or a placebo (0.9% normal saline). The primary outcome was any stage of ROP. Secondary
outcomes were laser-requiring ROP and the highest stage of ROP during follow-up.

Results
For the final analysis, a total of 62 participants (28.6 (2) weeks) were included in the breast milk group
(BMG) and 39 participants (29.9 (2) weeks) were included in the placebo group (PG). Although risk
factors for the development of ROP and advanced stage ROP were consolidated in BMG, treatment with
breast milk reduced ROP progression in patients with ROP in the first examination (stage 2–3 ROP n = 9
(75%) in BMG vs. n = 3 (80%) in PG), RR = 0.93, 95% CI: [0.54–1.61]; p = 0.999). No serious adverse effects
were observed in either group.

Conclusion
The use of freshly expressed breast milk as eye drops reduced the advanced stage of ROP or laser-
required ROP in patients with ROP on initial examination.

Introduction
Retinopathy of prematurity (ROP) was first described in the 1940s as a result of intensive oxygen therapy
in preterm infants. In addition to oxygen therapy, the immaturity of retinal vessels also plays an important
role in its development. ROP is a vasoproliferative disorder and the leading cause of preventable
blindness in low-birth-weight infants (LBW), and affecting with 50,000 infants worldwide by this disease
(1). Improvements in neonatal intensive care and technology over the past 20 years, higher survival rates
of LBW, and VLBW infants have meant that late morbidities such as ROP continue to be commonly
observed in preterm infants and the expected incidence has not decreased (2). Early detection of ROP
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disease, peripheral retinal ablation, and anti-vascular endothelial growth factor (VEGF) injections may
prevent vision loss (3, 4). ROP is the leading cause of the preventable childhood blindness (1).

Currently, there is no factor to prevent ROP other than avoiding preterm birth. It is not possible to prevent
premature births. Also, as viability increases, ROP continues to be one of the most important morbidities
in preterm infants. Breast milk has a unique composition with its protective factors, cellular factors,
immunoglobulin content. It is known to be particularly rich in stem cells (5). These cells are of
hematologic origin and are derived from the maternal breast. It is known to contain leucocytes,
myoepithelial cells, progenitor cells and stem cells from the maternal breast, hematopoietic stem cells
from the blood, and cells of immunologic origin (neutrophil, lymphocytes, monocytes, NK cells, B and T
cells). Thousands of studies to date have shown that breast milk contains many protective factors and
protects babies. In the late 1960s, colostrum was found to contain many different cells (6, 7). Using
multicolor flow cytometric analysis, Trend et al. demonstrated that colostrum contained approximately
146,000 /mm3 cells (8). They found that this value varied during different phases of lactation. Although
the protective and nutritional properties of breast milk have been the subject of numerous studies, very
little is known about non-immune cells (stem cells). The existence of pluripotent stem cells in human
breast milk (hBSCs) was first reported by Hassiotou et al. in 2012 (10). The authors demonstrated that
hBSCs were capable of producing self-renewing stem cells that had differentiation potential for all three
germ layers: ectoderm, mesoderm, and endoderm.

In the last 10–15 years, breast milk has been shown to contain stem and progenitor cells (9, 10). In their
study, Hosseini et al. demonstrated that stem cells in breast milk could differentiate into the neural
lineage, particularly because of their pluripotent properties, similar to those of embryonic and
mesenchymal stem cells (11). In the same in vitro study, cells exposed to breast milk expressed factors
belonging to all three neurogenic lineages (β-tubulin, O4 marker, GFAP marker) (11). In a small study of 16
infants by Keller et al. found that intranasal administration of breast milk to preterm infants reduced the
incidence of poor neuroeimaging outcomes early period of hospital duration in ELBW infants with
intracranial hemorrhage (12). They linked this effect to neuronal growth factors called stem cells and
neurotrophins. There are also cultural and reaginol practices which include appliying of breast milk to as
eye drops. Some publications studied the effects of applying breast milk to the eye in some eye diseases,
especially in newborns. In a study from India, the application of breast milk was found to be effective for
neonatal conjunctivitis without serious adverse effects (13). In another study conducted in Spain, breast
milk was found to be more effective than antibiotic eye drops in opening blocked tear ducts, and no
serious adverse effects were observed (14).

Studies in mice demonstrate the migration and integration of stem cells from breast milk into the organs
of the newborn. These cells have been shown to survive and cross the mucosa of the gastrointestinal
tract of suckled mouse pups in vivo, pass into the bloodstream, and continue to migrate to various
organs, where they integrate and differentiate into functional cells (17). This may represent human micro
chimerism. The retina is rich in neuronal tissue, which are important for all humans and are considered as
a continuation of our nervous system, human milk applied as eye drops may be beneficial especially for
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preterm infants who may experience frequent episodes of feeding intolerance. Breast milk is normally
considered inexpensive and safe and could play a crucial role tissue regeneration and somatic growth or
vasculogenesis due to the pluripotent stem cells and neurotrophic substances present in breast milk. The
aim of this study was to describe effect of breast milk as eye drops on degree or severeity of ROP in
preterm infants.

Material And Method

Patients
This study was planned as a multicenter, prospective, randomized controlled trial, conducted between
May 2021 and December 2021 at (hidden for reviewer) Application and Research Center, (hidden for
reviewer) City Hospital, (hidden for reviewer) Maternity and Children Hospital, and (hidden for reviewer)
Hospital. The study was approved by the Traditional and Complementary Medicine Ethics Committee of
(hidden for reviewer) (Date: 06/05/2021, Decision Number: 29). Infants less than 32 weeks or 1500 g
birth weight, were eligible for the study. Families were informed of the content of the study and signed
documents were obtained. After obtaining informed consent, parents of participants who accepted to
participate in the study were randomized in one of 2 arms. The medical records of infants who were less
than 32 weeks of age or weighed less than 1500 g were collected during their stay. For each infant,
variables collected; gestational age, birth weight, intrauterine growth centiles, antenatal steroid
administration, IVH, incidence and degree of necrotizing enterocolitis (NEC), bronchopulmonary dysplasia
(BPD), proven sepsis, duration of oxygen exposure, total parenteral nutrition (TPN) days, age at full
enteral nutrition, packed red blood cell (pRBCs) transfusions, ROP examination results, laser treatment
and anti-VEGF treatment, and length of hospital stay were recorded. Infants assigned to each group were
recorded as receiving topical breast milk or placebo twice daily. Use was discontinued with laser
requirement or upon discharge.
Study Design and Randomization

The known incidence of ROP in infants less than 32 weeks is 66% (15). The open-access website
calculated that administration of breast milk in the form of eye drops would reduce ROP disease by 50%,
with a power of 80%, a confidence interval of 95%, and 35 cases per group (ratio 1/1) (16). Mothers were
trained by a nurse experienced in expressing and storing breast milk in the neonatal intensive care unit
(NICU). Subjects participating in the study were randomized by flipping a coin for each center. The study
length was estimated to last from 6 -12 months . One-mL syringes were used to ensure standardization,
and 0.5 mL of breast milk (mother’s own milk) or normal saline was dripped at several times to prevent it
from slowly leaking from the eye. Beginning with the first topical administration of breast milk to babies
in the intervention group who participated in the study, fresh breast milk (no more than 6 hours after
pumping) was dripped into both eyes twice daily until discharge or laser therapy. Breast milk applications
to the eye was applied regardless of enteral tolerability, unless there were contraindicatios as mentioned
above or as long as the mother’s own milk was supplied. Enteral feeding via milk or formula were in
accordance with the local guidance of NICU. In the placebo group, 0.9% saline was instilled. Because of
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the nature of the study, the neonatologists caring for  the patients were not blinded, but the
ophthalmologists were. They did not know which baby belonged to which group. As neonatology
specialists, we provided general follow-up and treatment for the babies and continued their usual follow-
up. Eye findings were reviewed during daily visits for any adverse reactions by staff neonatologist. Eye
examinations for ROP were performed at the times specified in the American Academy of Pediatrics
(AAP) guidelines by a single ophthalmologist. Target saturation scores were ranged from 91-95 according
to clinical protocols at all centers, and the primary outcome was to assess whether any stage of ROP
developed. Secondary outcomes were assessed as severe and advanced stage of ROP. Examinations
continued until discharge or a stage of ROP requiring laser treatment. Before the first eye examination
(usually after the 4th or 31st week of gestation, whichever was later), infants who had died and parents
who did not accept the study are excluded from the study. Infants who had a contraindication to breast
milk use, such as active maternel HIV infection, active maternal tuberculosis, and known maternal CMV
infections, congenital eye development disorders such as agenesis, situations that do not allow retinal
examination, other congenital lethal malformations, and congenital infections affecting the retina, such
as TORCH infections were also excluded. There were no further exclusion criteria. 

Statistical analyses

When the numerical data conformed to normal distribution, they were expressed as mean ± standard
deviation (SD), and data that did not conform to normal distribution were expressed as median (min-
max). The Chi-square test or Fisher’s test was used for categorical variables. Student’s t-test was used to
compare parametric data between two independent groups, and the Mann-Whitney U test was used to
compare nonparametric data. For statistical significance, p < 0.05 was used. The SPSS ver. 25 statistical
program was used for all analyses.

Results
From May 2021 to December 2021, 359 infants were screened for eligibility, and 122 were enrolled and
randomized (Suppl.Figure 1). One hundred one patients were included in the study for statistical analysis,
62 were in the breast milk group (BMG) and 39 were in the placebo group (PG). In the BMG, breast milk
was administered to 62 infants at a median dose of 56 doses (interquartile range 26-106 doses), and in
the PG, physiologic saline was administered to 39 infants at a median dose of 72 doses (interquartile
range 56.5-97 doses). Although fewer doses were administered in the BMG, there were no significant
differences between the groups in the frequency of use as eye drops (p=0.111). The birth weight of the
BMG was lower PG, but this difference was not statistically significant (BMG:1217 g vs. PG:1309 g,
p=0.152). The gestational week was significantly lower in the BMG compared to PG (BMG: 28.6 vs. PG:
29.9 weeks, p=0.001), but the duration of oxygen exposure (BMG: 28.3 vs. PG: 17.7 days,p=0.063) and
TPN days (BMG:13.1 vs. PG: 10.2 days, p=0.035) were higher. There was no significant difference
between the groups in the reported number of pRBCs (BMG: 1.7 vs. PG: 0.9, p=0.302) (Table 1 and Suppl.
Table 16).

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In the ROP exmainations and follow- ups, it was observed that there were smaller infants in the BM group
in term of gestational age and birth weight (Suppl. Table14, Suppl. Table 15). Rates of ROP detection
were slightly higher when first screened for ROP in the BMG, but the difference was not statistically
significant (BMG: 19.4% vs. PG:12.8%, p=0.393) whereas,  the maximum ROP stage observed during
hospitalization in the NICU was significantly higher in the BMG (p=0.008). In the BMG, 8 cases were
identified as stage 1, 18 as stage 2, and 4 as stage 3. There was no significant difference between groups
in terms of ROP requiring laser (n=5 (8.1%) vs. n=1 (2.6%), p=0.255) (Table 2). At the first examination,
there were 50 patients in the BMG and 34 in the PG. The gestational week of patients in which no ROP
was observed was significantly lower in the BMG than in the PG (28.6 vs. 30 weeks, p=0.002). Although
birth weight was not significant (1232 vs. 1326 g, p=0.201), there was a non-significant increase in the
duration of oxygen exposure (29.1 days vs. 17.4 days, p=0.082) (Table 3). There was a significant
difference between the BMG and PG in the maximum observed ROP level of patients whose ROP was not
observed at the first examination (p=0.001) (Table 4). While ROP progression was less observed in PG, we
found that stage 2 ROP observed more than expected.  In addition, as expected, there was a significant
difference between the maximum observed stage of ROP according to the gestational week (p<0.001),
birth weight (p<0.001), and duration of oxygen exposure (p<0.001) (Table 5). 

The maximum observed ROP stage increased with decreasing gestational week and birth weight, and the
ROP stage increased with increasing oxygen exposure. Although no ROP was observed in 18 patients in
the BMG, the maximum observed ROP was increased. Five of them progressed to stage 1, 11 progressed
to stage 2, and two progressed to stage 3. As can be seen in Table 5, the average gestational week of 50
patients who did not have ROP at the first examination and received breast milk was 28.6, the average
gestational week of those who progressed to stage 1 was 27.6, those who progressed to stage 2 was
26.8, and those who progressed to stage 3 was 25 on average. The use of breast milk failed to protect
against adverse progression as a function of the gestational week. Similarly, the protective effect of
breast milk was dependent on birth weight and total oxygen exposure. In patients in whom ROP was not
observed at the first examination and who had not progressed to ROP stages thereafter, the groups were
found to be similar concerning week of gestation, birth weight, and oxygen exposure times (Suppl. Table
6). These results suggest that breast milk does not affect the maximum ROP stage in patients with
similar birth characteristics and postpartum oxygen exposures in whom ROP was not observed at the
initial examination. 

When comparing the laser requirements of the group in which ROP was not observed at the first
examination, laser was required in four of 50 patients who did not have ROP (4 (8%) in BMG vs. 0 (0%) in
PG, p=0.091) (Suppl. Table 7). However, when examining the characteristics of participants in the BMG
who required laser, it was found that gestational week, birth weight, and oxygen exposure were
significantly higher, which was indicative of the development of ROP in this group (Suppl. Table 8). This
is thought to be due to the clustering of risk factors that favor the development of ROP in this group,
overshadowing the protective effect of breast milk. In addition, although there was a significantly lower
gestational age and a high rate of exposure to oxygen in the BMG (Suppl. Table 9), the high rate of non-
laser requiring infants without ROP at baseline suggests the effect of breast milk. There were 12 cases of
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ROP in the BMG at the first examination, whereas there were five in the placebo group (Suppl. Table 10).
Evaluating   at the progression of the ROP stage in these cases, it can be seen that especially the
progression of ROP stage 2 was significantly reduced in the BMG compared with the placebo group
(Suppl. Table 11). 

Although no significant difference was found between the two groups in terms of birth weight,
gestational week, and duration of oxygen exposure, a laser was required in one of 12 patients in the BMG,
whereas it was required in one of five patients in the PG (Suppl. Table 12). Although there was no
statistically significant difference between the BMG and the PG in birth weight, gestational week, and
duration of oxygen exposure, the clustering of these risk factors in the BMG in a manner that increased
ROP and the decrease in laser requirement in the BMG suggested that breast milk reduced laser
requirement (RR=0.41, 95% CI: [0.03-5.43], control event rate (CER)=0.2, experimental event rate
(EER)=0.08, absolute risk reduction (ARR)=0.11, number needed to treat (NNT)=8.57, p=0.463). In
addition, the progression of patients with ROP detected at the first examination to maximum stage 2 or 3
was nine (75%) patients in the BMG, whereas four cases (80%) were observed in the PG (RR=0.93 95% CI:
[0.54-1.61], ARR =0.05, NNT=20, p=0.999). The duration of oxygen exposure increased in the BMG group,
but not significantly (20.5 days in the BMG group vs. 12 days in the PG, p=0.063). However, the duration
of TPN (11 days vs. 10 days, p=0.035) and day of full enteral transition (14 days vs. 11 days, p=0.016)
were significantly higher in BMG. Hospital length of stay (49 days vs. 38 days, p=0.003), rate of antenatal
steroid administration (36 (58%) vs. 14 (35%), p=0.030), and rate of BPD at any stage (24 (38%) vs. 7
(17%), p=0.028) were significantly higher in the BMG; no statistically significant differences were found
between the groups with respect to other important clinical outcomes (stage 1 NEC, proven sepsis, HsPda,
severe IVH (grades 3-4)) (Supp. Table 13).

Discussion
Given the high prevalence of retinopathy of prematurity worldwide and its significant impact on quality of
life, there is great interest in discovering safe and effective means to prevent this morbidity in preterm
infants. Prevention strategies for ROP, which is one of the most important morbidities in preterm infants,
remain among the problems that need to be solved and further developed. Because breast milk contains
living and humoral factors, it is unique, too complex to be produced in a laboratory, and therefore cheap.
We know that the pluripotent stem cells and growth factors found in breast milk can differentiate into all
three germ layers and may play a regulatory role in angiogenesis. In this study, we found that the use of
breast milk as an eye drop resulted in a reduction in the severity of ROP and the need for laser-requiring
treatment of ROP.

Many studies have been conducted to investigate the association between ROP and breast milk as a
protective factor. The focus of studies on breast milk in ROP has been on nutritional volume and
comparison of breast milk, the composition of breast milk, and formulas. Some studies that examined
the relationship between breast milk and ROP concluded that infants who required ROP surgery received
less breast milk, especially during the second week after birth. They claimed that ROP requiring surgery
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decreased as the amount of breast milk increased (18, 19). In contrast to these studies, some studies
state that the amount of breast milk does not affect ROP (20). In our study, we did not compare breast
milk volume and nutrient intake through breast milk, but we found that the day of transition to complete
enteral nutrition and the duration of TPN administration were significantly higher in patients with
advanced-stage ROP and laser-requiring ROP. This finding suggests that there is a relationship between
advanced-stage ROP and nutrition. Studies suggesting that breast milk is protective in ROP have
discussed this protective effect on antioxidant properties, growth factors, and fatty acids.

There are few reports of topical application of breast milk as an effective treatment for diaper rash, atopic
eczema, diaper dermatitis, or umbilical cord separation that do not involve an application to the eye (23–
25). When examining studies investigating the association between topical eye drops and ROP, this is the
first study to investigate whether the use of breast milk as an eye drop has a protective effect on ROP in
preterm infants. Other topical applications of breast milk have been studied, particularly in the eye. In a
retrospective study, Akdogan et al. investigated the effect of a combination of topical coenzyme Q10 and
vitamin E eye drops in patients with ROP and found that fewer laser photocoagulations were performed
in the intervention group (26). When we reviewed the study, the study was not clearly understood due to
the lack of ROP risk factors. Although the duration or percentage of drug application and the duration of
oxygen consumption were not elucidated, they claimed that topical application of CoQ10 and vitamin E
reduced the need for laser therapy.

Another concern is that the effect of topical eye drops on retinal disease may be limited. In a study of the
ophthalmic application of topical propranolol concerning transcorneal kinetic transmission and plasma
and retinal concentrations in New Zealand white rabbits, compared with oral propranolol, the authors
showed that plasma levels were in the safe range, and aqueous humor, vitreous, and retinal
concentrations were greater compared with oral propranolol (27). This study showed that a topical agent
applied to the eye could achieve an effective retinal concentration.

The issue of using breast milk for purposes other than nutrition has been studied in other premature
morbidities such as intraventricular hemorrhage. Keller et al. administered intranasal breast milk to
preterm infants less than 31 weeks of age with severe IVH (12). They were compared before discharge
regarding porencephalic defects. They showed that early intranasal administration of breast milk was
associated with a lower incidence of severe porencephalic defects. Similar to our study, they found that it
reduced the risk of severe porencephalic cysts by 2.5-fold, although they were unable to demonstrate
statistical significance in pairwise comparisons because the target outcome variables were few. The
authors used breast milk for 2 hours after milking in their study, our use was longer, up to 6 hours. It is not
clear, however, how long breast milk preserves the stability of cellular factors, immune system factors,
inflammatory factors, and growth factors.

In a Japanese study that investigated the reliability and efficacy of breast milk as eye drops in infants
younger than 6 months of age due to ocular discharge, no significant adverse effects were observed (21).
Although details about the collection, storage, and duration of breast milk were not reported in this study,

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we observed no serious adverse effects in our study. Breast milk banking is not yet active in our country.
All mothers were the biologic mothers of the infants, and we did not use any breast milk other than the
patients' own mother's milk. No processes were performed to isolate bacteria or viruses in breast milk. In
experimental mouse models in which dry eyes were produced using benzalconium hydrochloride, positive
effects on corneal thickness were shown and no serious adverse effects associated with the use of
breast milk on the eye were noted (22).

Limitation and strengths

This study had several limitations. The groups were not masked for the nurses and neonatologists.
However, the ophthalmologists did not know whether the infants received breast milk or a placebo.
Because we used fresh breast milk, the use in the BMG was lower than in the PG. The randomization
method was flipping a coin. This randomization method resulted in an uncontrolled distribution of
participants' weeks of gestation. Thus, infants who had a lower gestational age were accumulated in the
BMG. We should have designed this study with stratified block randomization by gestational age. This
resulted in more morbidities coinciding with lower gestational age and birth weight in the BMG. The
strengths of the study include its multicenter design and the fact that it is the first study to examine the
use of fresh breast milk as an eye drop and the association with ROP at gestational ages less than 32
weeks. Another strength is that although the risk factors associated with ROP are accumulated in BMG,
the preventive effects of breast milk on ROP are seen in this group. In assessing the weakness of the
results, especially concerning the relative risk values, we should assume that the same outcome rates are
maintained so that the confidence interval is less than 1, so each group should have at least nine patients
with laser-requiring ROP. Thus, to be able to say more precisely that breast milk reduces the need for laser
treatment and may play a protective role in the presence of ROP, studies with larger samples and more
patients requiring laser treatment are needed.

Conclusion
Breast milk as an eye drop may have a protective effect on ROP. Because this is the first study in this field,
we hope that it may promote further clinical investigation in this area. Administration of fresh breast milk
in the form of eye drops to preterm infants with a gestational age of fewer than 32 weeks had no
significant adverse effects and appears to be a promising intervention for sight-threatening ROP and
blindness. For more precise effects on ROP requiring laser treatment, well-designed prospective controlled
trials that treat larger patient groups with stratified randomization are needed. Studies focusing on breast
milk volume and freshness time may also be planned.

Declarations
Acknowlegments: I would like to thank all neonatal intensive care nurses who worked with all their
strength during this pandemic period, David Chapman for his support in language editing, and Mustafa
Semiz, who did not spare his help in statistical issues.

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Tables
 Table 1: Distributions of the ROP risk factors between the groups 

  Breast Milk Placebo Statistics Sig.

  Mean Std. Deviation Mean Std. Deviation    

Gestational age (week) 28.6 1.9 29.9 1.5 Z= -3.252 0.001*

Birth weight (g) 1217 320 1309 299 t= -1.445 0.152

Days on oxygen  28.3 27.5 17.7 18.8 Z= -1.860 0.063

TPN (day) 13.06 8.24 10.2 6.6 Z= -2.111 0.035*

The number of pRBCs 1.7 2.6 0.94 1.6 Z= -1.031 0.302

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Table 2: ROP characteristics of the groups

    Groups  

ROP at the initial examination:    Breast Milk Placebo Total

Chi-square=0.730, p=0.393

Absent n (%) 50 (80.6) 34 (87.2) 84

Present n (%) 12 (19.4) 5 (12.8) 17

Maximum stage of ROP:   Breast Milk Placebo Total

Chi-square=11.904, p=0.008

None n (%) 32 (51.6) 33 (84.6) 65

Stage1 n (%) 8 (12.9) 2 (5.1) 10

Stage2 n (%) 18 (29.0) 4 (10.3) 22

Stage3 n (%) 4 (6.5) 0  4

Laser:   Breast Milk Placebo Total

Chi-square=1.296, p=0.255

No n (%) 57 (91.9) 38 (97.4) 95

Yes n (%) 5 (8.1) 1 (2.6) 6

Table 3: Distribution of patients who did not demonstrate ROP at the initial examination in terms of ROP
risk factors 

ROP at the initial Breast milk (n=50) Placebo (n=34) Statistics Sig.
examination: NONE

  Mean Std. Mean Std.    

Deviation Deviation

Gestational age (week) 28.68 1.99 30.0 1.57 t= -3.232 0.002*

Birth weight (g) 1232.4 342.8 1326.4 306.2 t= -1.288 0.201

O2 exposure (day) 29.1 29.53 17.4 19.9 Z= 0.082

-1.742

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Table 4: Patients in whom ROP was not observed at the initial examination but later progressed to
advanced stages

ROP at the initial examination: None   Groups  

Maximum stage of ROP:   Breast milk Placebo Total

Chi-square=13.110, p=0.001

None n (%) 32 (64.0) * 33 (97.1) * 65

Stage 1 n (%) 5 (10.0) 1 (2.9) 6

Stage2 n (%) 11(22.0) * 0* 11

Stage3 n (%) 2 (4.0) 0  2

Table 5: Distribution of patients in whom ROP was not observed at the initial examination but progressed
to advanced stages later in terms of ROP risk factors

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 ROP at the initial Maximum stage n Mean Std. Statistics Sig.
examination: None of ROP Dev.

Gestational age(week) None 32 29.7 (a) 1.35 F=18.127 <0.001*

  Stage1 5 27.6 (b) .89
  Stage2 11 26.8 (b) 1.72
  Stage3 2 25.0 (b) .00
  Total 50 28.6 1.99    

Birth weight(g) None 32 1410.8 247.64 F=17.884 <0.001*

(a)
 
Stage1 5 1102.0 223.65
  (b)
  Stage2 11 864.0 233.24
(b)
 
Stage3 2 730.0 113.13
(b)

Total 50 1232.4 342.80    

Days on oxygen None 32 14.1 (a) 12.52 F=13.418 <0.001*

  Stage1 5 54.2 (b) 24.60
  Stage2 11 55.6 (b) 38.88
  Stage3 2 60.0 (b) 19.79
  Total 50 29.1 29.53    

Supplementary Files
This is a list of supplementary files associated with this preprint. Click to download.

Suppl.Figure1.docx
Suppl.Table6.docx
Supp.Table7.docx
Suppl.Table8.docx
Suppl.Table9.docx
Suppl.Table10.docx
Suppl.Table11.docx

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Suppl.Table12.docx
Suppl.Table13.docx
Suppl.Table14.docx
Suppl.Table15.docx
Suppl.Table16.docx

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