Birth-related retinal hemorrhages: The Soonchunhyang University Cheonan Hospital universal newborn eye screening (SUCH-NES) study.

PURPOSE: To report the prevalence, related factors, and characteristics of birth-related retinal hemorrhages (RHs) according to their severity in healthy newborns using a telemedicine network and wide-field digital retinal imaging (WFDRI).
METHODS: Newborns who underwent WFDRI at 61 obstetrics/gynecology hospitals between January 2017 and December 2019 were enrolled. Demographics and related factors were compared among newborns with and without RHs. The newborns' eyes were divided into the minimal, mild, moderate, and severe groups according to the number of RHs, and characteristics like bilaterality, laterality, involved retinal layer, involved zone, macular and/or optic nerve (ON) involvement were compared.
RESULTS: Among 56247 newborns, 13026 had birth-related RHs (23.2%). Normal spontaneous vaginal delivery (NSVD) showed the highest association with RHs (odds ratio, 19.774; 95% confidence interval, 18.277-21.393; P < 0.001) on multivariate analysis. Bilateral RHs (8414/13026; 64.59%) were more common than unilateral RHs (4612/13026; 35.41%); however, unilateral RHs (2383/4217; 56.51%) were more common than bilateral RHs (1834/4217; 43.49%) in the minimal group. RHs showed no laterality differences between the two eyes (P = 0.493). Most RHs were intraretinal (18678/21440; 87.12%), and 2328 (31.65%) eyes with preretinal hemorrhage were observed in the severe group. Zone I RHs were common in the minimal (7072/7090; 99.75%), mild (4953/4960; 99.86%), and moderate (2013/2035; 98.92%) groups; zone I and II RHs were common in the severe group (4843/7355; 65.85%); and RHs in zone III were rare (7/21440; 0.03%). Most RHs showed no macular and/or ON involvement in the minimal and mild group; however, this was common in the severe group (7111/7355; 96.68%).
CONCLUSIONS: Birth-related RHs were common in healthy newborns and were significantly associated with NSVD. RHs were usually bilateral, intraretinal, and distributed posterior to the retina, but severe RHs had unique characteristics. Future long-term and longitudinal studies are required to elucidate the prognosis of severe RHs.

Introduction

Birth-related retinal hemorrhages (RHs) are known to occur in healthy newborns [1-12]. The characteristics of these RHs have been reported by many researchers, but these vary widely and are inconclusive [1-12]. A study by Emerson et al. [11] reported that most RHs were intraretinal and primarily involved the posterior retina. However, a study by Callaway et al. [5] reported that most RHs were multilayered and involved the peripheral retina. These discrepancies may be due to the wide clinical spectrum of birth-related RHs, differences in the age at examination, and varying examination methods used in each study [5, 8, 9, 11–13]. Therefore, a study with a larger number of newborns undergoing objective examination at a similar age would be required to verify the results. Furthermore, the characteristics of birth-related RHs seem to depend on their severity. Severe RHs may persist for a longer duration and potentially result in visual disturbances, such as anisometropia and amblyopia, while mild RHs spontaneously disappear without clinical significance [3, 8, 9, 11, 12, 14]. However, only a few studies with limited sample sizes have reported the characteristics of RHs according to their severity, and a generalized agreement has not yet been established [3, 8, 9, 11]. Investigating the characteristics of RHs according to severity will also be meaningful.

Telemedicine combined with wide-field digital retinal imaging (WFDRI) may be an effective and feasible method for screening a large number of newborns with RHs at a similar examination age [3, 5, 15–17]. This strategy involves capturing retinal fundus images and transmitting the remote interpretations of pediatric ophthalmologists [17]. The images were captured by trained nursing staff as soon after birth as possible, and the interpretations were performed by analyzing the photographs. Therefore, the process was less labor- and time-intensive than conventional binocular indirect ophthalmoscopy (BIO) examination, which necessitated direct contact between the patients and clinicians [14]. Furthermore, more accurate and objective documentation of RHs is possible, because WFDRI has a wider field of view than conventional BIO and can provide digital records [3, 17].

The Soonchunhyang University Cheonan Hospital universal newborn eye screening (SUCH-NES) study is an institutional prospective cohort study that used the telemedicine system to determine the prevalence, characteristics of ocular problems, and the long-term visual outcomes of newborns with ocular abnormalities in healthy newborns. In this study, we enrolled newborns from the SUCH-NES study and investigated the prevalence, related factors, and characteristics of RHs according to their severity.

Materials and methods

Subjects

Newborns who were born at 61 obstetrics/gynecology (OB/GYN) hospitals (Fig 1) between January 2017 and December 2019 were asked to participate in this study. Since fundus photography was optional, only newborns whose parents gave written consent to the examination of their child were screened. Newborns with (1) gestational age (GA) less than 32 weeks and/or birth weight (BW) less than 2000 g, (2) maternal and fetal systemic diseases, (3) structural ocular anomalies, (4) a familial history of ocular congenital anomalies, and (5) those transferred to tertiary hospitals due to problems during delivery or (6) those undergoing the examination 7 days after birth were excluded from the study. Sex, mode of delivery (normal spontaneous vaginal delivery [NSVD] or cesarean section [CS]), GA, BW, and Apgar scores (1 and 5 min) of each newborn were recorded. The Institutional Review Board (2019-04-007) of Soonchunhyang University approved the study, and it adhered to the tenets of the Declaration of Helsinki.

Fig 1

Distribution of the participating obstetrics/gynecology hospitals.

The numbers in parentheses indicate the number of hospitals.

Photography protocols

External eye and retinal images were captured by adequately trained nursing staff at each OB/GYN hospitals using WFDRI (RetCam III; Clarity Medical Systems, Pleasanton, CA). The photography protocol was as follows: (1) dilatation of the pupil with a mixture of 0.5% tropicamide and 0.5% phenylephrine eye drops; (2) imaging of the eyelid and anterior segment of both the eyes; (3) topical anesthesia using 0.5% proparacaine hydrochloride eye drops; (4) insertion of an eye speculum to open the eye; (5) imaging of red reflex assessment using illumination from RetCam III (Clarity Medical Systems); and (6) imaging of the entire retina using five-directional photography with an inert lubricating jelly and RetCam 130° lens. The five-directional fundus photographs included the posterior pole, optic nerve (ON) centered, ON superior, ON inferior, and ON nasal views. All examinations were performed with close cardiac and respiratory monitoring. Topical antibiotic eye drops were administered at the end of the examination.

Telemedicine network

At the end of the working hours, the images of newborns that were captured at the 61 OB/GYN hospitals were uploaded to a virtual hard drive, which was accessible using laptops and smartphones. These images were then interpreted by one pediatric vitreoretinal specialist (SYK) within 24 h. If the captured images were of poor quality, the newborns were re-screened. Since the newborns were hospitalized for 48 h after NSVD and 72 h after CS, an effort was made to report the results of the newborn eye examination to the parents within 48 hours. If abnormal ocular findings were noticed, the newborns were referred to a nearby pediatric ophthalmologist immediately. In the case of newborns with severe RHs, monthly follow-up was recommended until the RHs disappeared.

Analysis of birth-related RHs

Retinal images from newborns with RHs were reviewed by two independent graders (SYK and IHC) in a masked fashion. If there was any discrepancy between the graders, consensus was reached by discussion. The following factors were collected and analyzed: bilateralities of RHs, lateralities of RHs, numbers of RHs, size of the largest RH, involved retinal layers, involved zone, involvement of the macula and/or ON, involvement of the fovea, accompanying vitreous hemorrhage (VH), and presence of Roth spots. As per the modified classification by Watts et al, newborns and eyes with RHs were divided into four groups according to the number of RHs affecting the eyes. Less than 10 RHs were defined as minimal, 10 to 30 RHs as mild, 30 to 50 RHs as moderate, and more than 50 RHs as severe (Fig 2). If the severity of RHs in both the eyes did not match, the groups of newborns were classified on the basis of the more severe eye [8].

Fig 2

Representative fundus photographs of newborns with retinal hemorrhages.

(A) Minimal retinal hemorrhage. (B) Mild retinal hemorrhage. (C) Moderate retinal hemorrhages. (D) Severe retinal hemorrhages with vitreous hemorrhage. (E) Optic nerve involvement of the hemorrhages. (F) Macular involvement of the hemorrhages.

The zone of involvement was defined according to zones I, II, and III of retinopathy of prematurity [18]. Zone I was defined as the circle, the radius of which is twice the distance between the center of the optic disc and the center of the macula. Zone II extended centrifugally from the edge of zone I to the nasal ora serrata. Zone III was the residual crescent of the retina anterior to zone II. In addition, the severity of RHs was scored using a grading scale similar to that described by Binenbaum et al. (Table 1) [13, 19].

Table 1

Grading scales of retinal hemorrhages.

Retinal hemorrhage	Points
Type and size (only one category chosen)
Mild: Intraretinal hemorrhage only	1
Moderate: Subhyaloid hemorrhage present; all lesions less than two disc areas in size	2
Severe: Subhyaloid hemorrhage; vitreous hemorrhage or any lesion greater than two disc areas in size	3
Extent (sum of categories)
Any hemorrhage within the following areas
Macula (>1 DD from the disc; within 2 DD of the fovea)	1
Peripapillary (within 2 DD of the disc, excluding the macula)	1
Periphery (outside the above region)	1

DD: disc diameter.

aThe overall score is calculated by combining the total scores for each eye; the maximal score is 6 points per eye or 12 points overall.

Statistical analysis

The mean and standard deviation of each variable were calculated using IBM SPSS Statistics for Windows, Version 20.0 (IBM Corporation, Armonk, NY). Student’s t-test or analysis of variance was used for comparing continuous variables, and the chi-squared test was used for categorical variables. Scheffe’s post-hoc test was used to analyze the statistical differences among the groups. The factors related to RHs in newborns were assessed using univariate linear regression analysis. Variables selected for the univariate analysis were sex, BW, GA, Apgar scores at 1 and 5 min, delivery method, and age at examination. Predictors with a P less than 0.05 in the univariate analysis were entered into the multivariate regression analysis. The agreement of the severity between eyes was calculated using weighted kappa. A P less than 0.05 was considered to indicate statistical significance.

Results

Newborns with and without birth-related RHs

Among the screened newborns, newborns who met the inclusion criteria were enrolled. In total, 56247 newborns from 61 OB/GYN hospitals were examined over 3 years. Overall demographics of these newborns are described in Table 2.

Table 2

Demographics of newborns with and without retinal hemorrhages.

	Total	Newborns without RHs	Newborns with RHs	P-value
N (%)	56247 (100.0)	43221 (76.8)	13026 (23.2)
Sex, n (%)
0: Male	28894 (51.37)	22361 (51.74)	6533 (50.15)	0.002a
1: Female	27353 (48.63)	20860 (48.26)	6493 (49.85)
Delivery method, n (%)
NSVD	30826 (54.80)	18537 (42.89)	12289 (94.34)	<0.001a
CS	25421 (45.20)	24684 (57.11)	737 (5.66)
Gestational age (days), mean ± SD	273.10 ± 8.27	272.69 ± 8.40	274.47 ± 7.64	<0.001b
Birth weight (g), mean ± SD	3233.42 ± 405.13	3233.04 ± 414.32	3234.70 ± 373.02	0.665b
Agar score (1 min), mean ± SD	8.95 ± 0.65	8.94 ± 0.66	8.98 ± 0.62	<0.001b
Agar score (5 min), mean ± SD	9.79 ± 0.46	9.79 ± 0.47	9.82 ± 0.42	<0.001b
Age at examination (days), mean ± SD	2.00 ± 1.90	2.18 ± 2.04	1.38 ± 1.16	<0.001b

CS: Cesarean section; NSVD: normal spontaneous vaginal delivery; RHs: retinal hemorrhages; SD: standard deviation.

aChi-square test.

bStudent’s t-test.

Demographics were compared between newborns with and without birth-related RHs. Among the 56247 newborns, 13026 had RHs, and the prevalence was 23.2%. A significant difference existed in the mode of delivery between the two groups (P < 0.001). Newborns without RHs were mostly delivered via CS (24684/43221; 57.11%) rather than NSVD (18537/43221; 42.89%). However, newborns with RHs were more frequently delivered via NSVD (12289/13026; 94.34%) rather than CS (737/13026; 5.66%). Notably, 39.87% (12289/30826) of newborns delivered via NSVD developed RHs, whereas only 2.90% (737/25421) of newborns delivered via CS developed RHs. BW (3233.04 ± 414.32 vs 3234.70 ± 373.02 g; P = 0.665) was not significantly different between the two groups. However, GA (272.69 ± 8.40 vs 274.47 ± 7.64 days; P < 0.001) was significantly longer, Apgar scores at 1 minute (8.94 ± 0.66 vs 8.98 ± 0.62; P < 0.001) and 5 minutes (9.79 ± 0.47 vs 9.82 ± 0.42; P < 0.001) were significantly higher, and age at examination (2.18 ± 2.04 vs 1.38 ± 1.16; P < 0.001) was significantly lower in newborns with RHs than in those without RHs (Table 2).

Factors related to birth-related RHs in newborns

Univariate and multivariate analyses were performed to identify the predictors of birth-related RHs in newborns (Table 3). The univariate linear regression analysis showed that the following parameters were significantly associated with RHs: female sex (odds ratio [OR], 1.065; 95% confidence interval [CI], 1.024–1.108; P < 0.001), NSVD (OR, 22.204; 95% CI, 20.564–23.974; P < 0.001), GA (OR, 1.028; 95% CI, 1.025–1.030; P < 0.001), Apgar score at 1 minute (OR, 1.125; 95% CI, 1.091–1.160; P < 0.001), Apgar score at 5 min (OR, 1.194; 95% CI, 1.141–1.249; P < 0.001), and age at examination (OR, 0.631; 95% CI, 0.619–0.644; P < 0.001). Similarly, the multivariate analysis revealed that female sex (OR, 1.050; 95% CI, 1.005–1.098; P = 0.029), NSVD (OR, 19.774; 95% CI, 18.277–21.393; P < 0.001), and age at examination (OR, 0.797; 95% CI, 0.782–0.812; P < 0.001) was significantly associated with RHs (Table 3).

Table 3

Univariate and multivariate analyses of factors related to retinal hemorrhages.

		Univariate analysis		Multivariate analysis
		OR (95% CI)	P-value	OR (95% CI)	P-value
Sex, n (%)
Male	1		1
Female	1.065 (1.024–1.108)	0.002	1.050 (1.005–1.098)	0.029
Delivery method
NSVD	22.204 (20.564–23.974)	<0.001	19.774 (18.277–21.393)	<0.001
CS	1		1
Birth weight (g)	1.000 (1.000–1.000)	0.627
Gestational age (days)	1.028 (1.025–1.030)	<0.001	0.994 (0.992–0.997)	0.241
Apgar score (1 min)	1.125 (1.091–1.160)	<0.001	1.018 (0.963–1.076)	0.541
Apgar score (5 min)	1.194 (1.141–1.249)	<0.001	1.078 (0.996–1.168)	0.063
Age at examination (days)	0.631 (0.619–0.644)	<0.001	0.797 (0.782–0.812)	<0.001

CS: Cesarean section; CI: confidence interval; NSVD: normal spontaneous vaginal delivery; OR: odds ratio.

Demographics of newborns according to the severity of RHs

Newborns with birth-related RHs (13026; 100%) were divided into the minimal (4217; 32.37%), mild (3002; 23.05%), moderate (1348; 10.35%), and severe (4459; 34.23%) groups according to the number of RHs. Overall, bilateral RHs (8414/13,026; 64.59%) were more common than unilateral RHs (4612/13026; 35.41%). However, a difference in bilaterality was observed according to the severity of RHs. Bilateral RHs were more common than unilateral RHs in the mild (1728/3002; 57.56% vs 1274/3002; 42.44%), moderate (925/1348; 68.62% vs 423/1348; 31.38%), and severe (3927/4459; 88.07% vs 532/4459; 11.93%) groups. In the minimal group, unilateral RHs (2383/4217; 56.51%) were more common than bilateral RHs (1834/4217; 43.49%) (Table 4). The severity of bilateral RHs was usually consistent between the eyes, and the percentage of agreement was 71.4% (P < 0.01) (Table 5).

Table 4

Demographics of newborns according to the severity of retinal hemorrhages.

	Total	Minimal	Mild	Moderate	Severe	P-value
Newborns, n (%)	13026 (100.00)	4217 (32.37)	3002 (23.05)	1348 (10.35)	4459 (34.23)
Bilateral RHs, n (%)	8414 (64.59)	1834 (43.49)	1728 (57.56)	925 (68.62)	3927 (88.07)	<0.001a
Unilateral RHs, n (%)	4612 (35.41)	2383 (56.51)	1274 (42.44)	423 (31.38)	532 (11.93)
Sex, n (%)
Male	6537 (50.18)	2109 (50.01)	1531 (51.00)	695 (51.56)	2202 (49.38)	0.358
Female	6489 (49.82)	2108 (49.99)	1471 (49.00)	653 (48.44)	2257 (50.62)
Delivery method
NSVD	12289 (94.34)	3863 (91.61)	2826 (94.14)	1263 (93.69)	4337 (97.26)	<0.001b
CS	737 (5.66)	354 (8.39)	176 (5.86)	85 (6.31)	122 (2.74)
Gestational age (days), mean ± SD	274.47 ± 7.64	274.56 ± 7.76	274.06 ± 7.79	274.10 ± 7.45	274.76 ± 7.44	0.471
Birth weight (g), mean ± SD	3234.70 ± 373.02	3235.33 ± 372.75	3233.38 ± 374.25	3239.88 ± 371.70	3232.06 ± 373.09	0.916
Agar score (1 min), mean ± SD	8.98 ± 0.62	8.97 ± 0.62	8.99 ± 0.63	8.96 ± 0.61	9.00 ± 0.62	0.058
Agar score (5 min), mean ± SD	9.82 ± 0.42	9.82 ± 0.42	9.82 ± 0.42	9.82 ± 0.43	9.83 ± 0.40	0.632
Age at examination (days), mean ± SD	1.38 ± 1.16	1.50 ± 1.38	1.41 ± 1.14	1.37 ± 1.27	1.24 ± 0.85	<0.001c

CS: Cesarean section; NSVD: normal spontaneous vaginal delivery; RHs: retinal hemorrhages; SD: standard deviation.

aBilateral RHs vs unilateral RHs.

bNSVD vs CS.

cThe severe group is significantly different from the minimal (P < 0.001), mild (P < 0.001), and moderate (P = 0.002) groups (Scheffe’s post-hoc analysis).

Table 5

Agreement of the inter-eye severity of retinal hemorrhages.

Right eyeLeft eye	Minimal	Mild	Moderate	Severe	Total
Minimal	1834 (80.09)	144 (7.89)	133 (16.16)	306 (8.80)	2417 (28.73)
Mild	134 (5.85)	1450 (79.50)	21 (2.55)	257 (7.39)	1862 (22.13)
Moderate	104 (4.54)	15 (0.82)	652 (79.22)	18 (0.52)	789 (9.38)
Severe	218 (9.52)	215 (11.79)	17 (2.07)	2896 (83.29)	3346 (39.77)
Total	2290 (100.00)	1824 (100.00)	823 (100.00)	3477 (100.00)	8414 (100.00)

No significant differences existed among the groups in terms of the sex ratio (P = 0.358), GA (P = 0.471), BW (P = 0.916), Apgar score at 1 min (P = 0.058), and Apgar score at 5 min (P = 0.632). The mode of delivery (P < 0.001) and age at examination (P < 0.001) were significantly different among the groups. NSVD was more common than CS in the minimal (3863/4217; 91.61% vs 354/4217, 8.39%), mild (2826/3002; 94.14% vs 176/3002; 5.86%), moderate (1263/1348; 93.69% vs 85/1348; 6.31%), and severe (4337/4459; 97.26% vs 122/4459; 2.74%) groups. In the post-hoc analysis, age at examination of the severe group (1.24 ± 0.85 days) was significantly lower than that of the minimal (1.50 ± 1.38; P < 0.001), mild (1.41 ± 1.14; P < 0.001), and moderate (1.37 ± 1.27; P = 0.002) groups (Table 4).

Characteristics of eyes with RHs according to their severity

Since 8414 newborns had bilateral birth-related RHs, 21440 newborn eyes were included in the analysis of characteristics according to the severity of RHs. Newborn eyes with RHs were also divided into the minimal (7090; 33.07%), mild (4960; 23.13%), moderate (2035; 9.49%), and severe (7355; 34.31%) groups according to the number of RHs. There was no laterality difference in RHs between the eyes, and it was not significantly different among the groups (P = 0.493) (Table 6).

Table 6

Characteristics of eyes with retinal hemorrhages according to severity.

	Total	Minimal	Mild	Moderate	Severe	P-value
Eyes with RHs, n (%)	21440 (100.00)	7090 (33.07)	4960 (23.13)	2035 (9.49)	7355 (34.31)
Right eye, n (%)	10871 (50.70)	3571 (50.37)	2508 (50.56)	1013 (49.78)	3779 (51.38)	0.493a
Left eye, n (%)	10569 (49.30)	3519 (49.63)	2452 (49.44)	1022 (50.22)	3576 (48.62)
Number of RHs, n (%)	14.75 ± 12.97	4.75 ± 2.38	18.41 ± 5.00	40.68 ± 5.46	>50	<0.001b
Size of the largest spot, DD (%), mean ± SD	0.79 ± 0.93	0.22 ± 0.19	0.39 ± 0.29	0.56 ± 0.35	1.66 ± 1.10	<0.001c
RH grading score (each eye), mean ± SD	2.30 ± 1.61	1.05 ± 0.24	1.34 ± 0.53	1.94 ± 0.59	4.25 ± 1.11	<0.001d
Involved layer, n (%)
Preretinal	2463 (11.49)	37 (0.52)	58 (1.17)	40 (1.97)	2328 (31.65)	<0.001
Intraretinal	18678 (87.12)	7043 (99.34)	4893 (98.65)	1990 (97.79)	4752 (64.61)
Subretinal	19 (0.09)	0 (0.00)	1 (0.02)	2 (0.10)	16 (0.22)
All layers	280 (1.31)	10 (0.14)	8 (0.16)	3 (0.15)	259 (3.52)
Involved zone, n (%)
Zone I	16545 (77.17)	7072 (99.75)	4953 (99.86)	2013 (98.92)	2507 (34.09)	<0.001
Zone II	28 (0.13)	15 (0.21)	5 (0.10)	7 (0.34)	1 (0.01)
Zones I and II	4860 (22.67)	3 (0.04)	2 (0.04)	12 (0.59)	4843 (65.85)
Zone III	7 (0.03)	0 (0.00)	0 (0.00)	3 (0.10)	4 (0.05)
Macular and/or ON involvement, n (%)
No involvement	10558 (49.24)	6770 (95.49)	3380 (68.15)	401 (19.71)	7 (0.10)	<0.001
Macula only	530 (2.47)	40 (0.56)	207 (4.17)	239 (11.74)	44 (0.60)
ON only	2978 (13.89)	278 (3.92)	1318 (26.57)	1189 (58.43)	193 (2.62)
Macula and ON	7374 (34.39)	2 (0.03)	55 (1.11)	206 (10.12)	7111 (96.68)
Foveal involvement, n (%)
Yes	416 (1.94)	8 (0.11)	11 (0.22)	23 (1.13)	374 (5.08)	<0.001
No	21024 (98.06)	7082 (99.89)	4949 (99.78)	2012 (98.87)	6981 (94.92)
Vitreous hemorrhage, n (%)
Yes	285 (1.33)	11 (0.16)	10 (0.20)	8 (0.39)	256 (3.48)	<0.001
No	21,155 (98.67)	7,079 (99.84)	4,950 (99.80)	2,027 (99.61)	7,099 (96.52)
Roth spot
Yes	10319 (48.13)	466 (6.57)	1491 (30.06)	1299 (63.83)	7063 (96.03)	<0.001
No	11121 (51.87)	6624 (93.43)	3469 (69.94)	736 (36.17)	292 (3.97)

DD: Disc diameter; ON: optic nerve; RHs: retinal hemorrhages; SD: standard deviation.

a: Right eyes vs left eyes.

b: The severe group is significantly different from the minimal (P < 0.001), mild (P < 0.001), and moderate (P < 0.001) groups (Scheffe’s post-hoc analysis).

c: The severe group is significantly different from the minimal (P < 0.001), mild (P < 0.001), and moderate (P < 0.001) groups (Scheffe’s post-hoc analysis).

d: The severe group is significantly different from the minimal (P < 0.001), mild (P < 0.001), and moderate (P < 0.001) groups (Scheffe’s post-hoc analysis).

A significant difference was observed among the groups in terms of the number of RHs, size of the largest spot, and RH grading score (all P < 0.001). In the post-hoc analysis, the number of RHs (>50) in the severe group was significantly higher than that in the minimal (4.75 ± 2.38; P < 0.001), mild (18.41 ± 5.00; P < 0.001), and moderate (40.68 ± 5.46; P < 0.001) groups. The size of the largest spot (1.66 ± 1.10 disc diameter) in the severe group was significantly greater than that in the minimal (0.22 ± 0.19; P < 0.001), mild (0.39 ± 0.29; P < 0.001), and moderate (0.56 ± 0.35; P < 0.001) groups. RH grading score (4.25 ± 1.10) in the severe group was significantly higher than that in the minimal (1.05 ± 0.24; P < 0.001), mild (1.34 ± 0.53; P < 0.001), and moderate (1.94 ± 0.59; P < 0.001) groups (Table 6).

The prevalence distribution of the involved layer, involved zone, involvement of the macula and/or ON, involvement of the fovea, accompanying VH, and presence of Roth spots was significantly different among the groups (all P < 0.001). Overall, most RHs were intraretinal hemorrhages (18678/21440; 87.12%), including those in the minimal (7043/7090; 99.34%), mild (4893/4960; 98.65%), moderate (1990/2035; 97.79%), and severe (4752/7355; 64.61%) groups. Notably, in the severe group, 2328 eyes (31.65%) showed preretinal hemorrhages, and RHs involved all the retinal layers in 259 eyes (3.52%). RHs were mainly distributed only in zone I (16545/21440; 77.17%), including those in the minimal (7072/7090; 99.75%), mild (4953/4960; 99.86%), and moderate (2013/2035; 98.92%) groups. However, RHs were mainly distributed in zones I and II in the severe group (4843/7355; 65.85%). RHs solely in zone III were rarely found, and included only 3 eyes (0.10%) in the moderate group and 4 eyes (0.05%) in the severe group. Most RHs did not involve the ON or macula in the minimal (6770/7090; 95.49%) and mild (3380/4960; 68.15%) groups. However, only ON involvement showed a high percentage in the moderate (1189/2035; 58.43%) group, and both macular and ON involvement showed a high percentage in the severe (7111/7355; 96.68%) group. Most of the RHs did not involve the fovea, but 374 (5.08%) eyes with severe RHs showed foveal involvement. Accompanying VH (256/7355; 3.48%) and Roth spots (7063/7355; 96.03%) were most commonly detected in the severe group (Table 6). Atypical features of RHs, such as subhyaloid hemorrhages with tortuous retinal vessels, RHs with vessel anomaly, VH with ON involvement, and sectoral RHs, were also observed (Fig 3).

Fig 3

Atypical features of newborns with retinal hemorrhages.

(A) Subhyaloid hemorrhages with tortuous retinal vessels. (B) Retinal hemorrhages with vessel anomalies. (C) Vitreous hemorrhage with optic nerve involvement. (D) Sectoral retinal hemorrhages. (E) Subretinal hemorrhages. (F) Dense vitreous hemorrhage with macular involvement.

Follow-up of severe RHs

Among the 7355 eyes with severe RHs, 2859 (38.87%) eyes were re-examined monthly after birth at our ophthalmology department. Of these, most of the RHs disappeared; however, 126 (4.40%) eyes showed persistent RHs until 2 months after birth (Fig 4).

Fig 4

Representative fundus photographs of eyes with persistent retinal hemorrhages during follow-up.

(A1-D1) Fundus photographs of RHs at birth. (A2-D2) Photographs from the follow-up examination at 1 month after birth. (A3-D3) Photographs from the follow-up examination at 2 months after birth. RH: retinal hemorrhages.

Discussion

In the present study, we successfully screened a large number of newborns from 61 OB/GYN hospitals using a telemedicine network combined with WFDRI. To the best of our knowledge, this is the largest study investigating the characteristics of newborns with RHs. In our study, the prevalence of birth-related RHs was 23.2%. This value is comparable with those reported in previous studies by Chen et al. (22%) [3], Li et al. (19% and 21.52%, respectively) [4, 9], Callaway et al. (20.3%) [5], and Zhao et al. (24.5%) [6]. However, it is higher than those reported by Ma et al. (6.7%) [1], Goyal et al. (13.2%) [2], and Vinekar et al. (2.4%) [7]. These discrepancies may be due to the differences in the age at examination [1, 2] and demographics of the newborns [7].

Birth-related RHs seem to occur because of the compression of the head during passage through the birth canal. An acute increase in intracranial pressure due to compression inhibits central retinal venous flow and subsequently results in an acute change in central retinal arterial pressure [5, 12, 13]. In other words, the retina of newborns becomes more vulnerable to hemorrhages during vaginal delivery. In our study, 94.34% of newborns with RHs were delivered via NSVD, and only 5.66% were delivered via CS. While 39.87% of newborns delivered via NSVD developed RHs, only 2.90% of newborns delivered via CS developed RHs. Furthermore, multivariate analysis confirmed that NSVD significantly increased the odds of RHs in newborns (OR, 19.774; 95% CI, 18.277–21.393; P < 0.001). These results are comparable with previous findings that the mode of delivery, including NSVD, forceps-assisted vaginal delivery, and vacuum-assisted vaginal delivery, are significantly associated with the occurrence of RHs in newborns [2, 3, 5, 6, 8, 10, 11, 20, 21]. A study by Goyal et al. [2] reported RHs in 47.6% of newborns delivered via NSVD but only 5.2% of those delivered via CS. A study by Callaway et al. [5] reported that NSVD significantly increased the odds of fundus hemorrhages than did CS (OR, 9.34; 95% CI, 2.5–33.97). A study by Zhao et al. [6] reported that NSVD was positively correlated (OR, 3.81; 95% CI, 2.65–5.48) and CS was negatively correlated (OR, 0.30; 95% CI, 0.14–0.63) with the occurrence of RHs. A study by Emerson et al. [11] reported that 75% of newborns delivered via vacuum-assisted vaginal delivery developed RHs, and a study by Williams et al. [21] reported that vacuum- and forceps-assisted vaginal deliveries were associated with the occurrence of severe RHs. Unfortunately, since none of the newborns included in our study were delivered via vacuum- or forceps-assisted vaginal delivery, we could not elucidate the differences in the occurrence of RHs according to the mode of delivery.

Other demographic factors, including sex ratio, GA, Apgar scores at 1 and 5 min, and age at examination, were significantly different between the newborns with or without RHs. However, as the magnitude of differences of GA and Apgar scores at 1 and 5 min were minimal between the newborns with and without RHs, the clinical significance of these factors might be ambiguous.

In the multivariate analysis, GA, BW, and Apgar scores were not significantly associated with the occurrence of RHs, and these results were consistent with those of previous studies [6, 11]. Female sex (OR, 1.050; 95% CI, 1.005–1.098; P = 0.029) was significantly associated with RHs. However, the OR was slightly higher than 1, and the clinical significance of female sex prevalence compared to male sex prevalence was ambiguous. Further studies are warranted to validate these results. Age at examination (OR, 0.797; 95% CI, 0.782–0.812; P < 0.001) was also significantly associated with RHs, and this was in agreement with the findings of previous studies [22, 23]. A study by Giles et al. [22] reported that the occurrence of RHs reduced from 40% at 1 h after birth to 20% at 72 h. A study by Sezen et al. [23] found that the prevalence of RHs was only 2.6% after 3 days of birth. Unfortunately, other related factors that have been known to be associated with the occurrence of RHs, such as maternal age [11], primiparous mothers [23], duration and difficulty of active labor [21], converting delivery methods from NSVD to CS, and head circumference [24] were not assessed in this study. Future studies to specify more detailed risk factors in relation to the occurrence of RHs should be planned.

RHs in newborns have varying severity [2, 8, 10, 11]. A study by Watts et al. [8] reported that the severity of RHs ranged from mild (22–56%) to severe (18–37%) in their review article. A study by Emerson et al. [11] reported that RHs varied from a single dot hemorrhage in one eye to bilateral widespread hemorrhages. Furthermore, the characteristics of RHs vary according to their severity. RHs in newborns usually spontaneously resolve within 2 weeks, but in cases of severe RHs, it may persist for a longer duration and obscure the visual axis [3, 8, 9, 11, 12, 14]. This may limit the development of normal visual function, potentially resulting in complications such as anisometropia and amblyopia [14]. Thus, we divided newborns’ eyes into the minimal, mild, moderate, and severe groups, and investigated the differences in characteristics according to the severity of RHs. Since no unified criteria are available for categorizing newborns and eyes with RHs, we used a newly developed criteria that further subdivided Watts et al.’s criteria [8]. This was possible because we could document the number of RHs more accurately by analyzing recorded retinal images obtained using WFDRI. Through a more detailed classification of the newborns’ eyes, we could recognize the differences in characteristics according to the severity of RHs.

We found that bilateral RHs were more common than unilateral RHs in all the groups, as shown in previous studies [3, 5, 6, 8–11, 20]. In particular, most newborns had bilateral RHs (88.07%) in the severe group, but unilateral RHs were more common in the minimal group (56.51%). These results suggest that RHs in newborns may initially occur bilaterally due to the compression of the head during passage through the birth canal, and the RHs in one eye may disappear more quickly in the minimal group than in the severe group because of their small numbers. In the case of bilateral RHs, the severity in one eye usually matched that of the fellow eye (percentage of agreement = 71.4%; P < 0.01). These results are inconsistent with those of studies by Emerson et al. [11]. They reported that the severity of RHs in one eye did not correlate with the presence or severity of RHs in the fellow eye [11]. No laterality differences in RHs were noted in our study. This result is comparable with that of Simkin et al. [20] but is inconsistent with that of Callaway et al. [5], who reported that left-sided hemorrhages were far more common than were right-sided hemorrhages. These discrepancies may be due to the differences in the demographics of the enrolled newborns. In addition, the age at examination was significantly shorter in the severe group than in the other groups (P < 0.001). This result suggested that the age at examination affected not only the occurrence of RHs but also their severity.

Most RHs were intraretinal hemorrhages in all the groups (18678/21440; 87.12%). This is consistent with previously published data [8, 10, 11], but is inconsistent with that of Callaway et al. [5], who reported that 71% of RHs involved multiple layers of the retina. We hypothesized that intraretinal hemorrhages were predominant in all the groups because the retinal capillary plexus, which is located intraretinally, is more vulnerable to acute changes in arterial pressure than other vessels are because of its small size. In addition, approximately one-third of severe RHs showed preretinal hemorrhages in our study. This result suggested that the preretinally located retinal artery or arterioles, which are larger than the retinal capillary plexus, might be damaged because the newborns’ heads would have been compressed by a stronger force during passage through the birth canal in the severe group than in the other groups.

RHs were mainly distributed in zone I in the minimal, mild, and moderate groups, and this result was comparable with that of Emerson et al. [11] RHs were mainly distributed in both zones I and II in the severe group, and RHs were rarely found in zone III. Chen et al. [3] found that all RHs were distributed in zone II, and Callaway et al. [5] reported that 95% of RHs involved the peripheral retina. These discrepancies may be due to the differences in the sample size and demographics of the enrolled newborns. Callaway et al. [5] also reported that RHs in newborns were most commonly ON flame hemorrhages (48.3%) and Roth spots (30.0%). Eighty-three percent of newborns with RHs had macular hemorrhages and 3.0% had foveal hemorrhages [5]. These characteristics seem to correspond to those of the severe group in our study. Most RHs did not involve the ON or macula, but both macular and ON involvement was high (7111/7355; 96.68%) in the severe group. Roth spots (7063/7355; 96.03%) were also commonly found in the severe group. Most of the RHs did not involve the fovea, but 374 (5.08%) eyes with severe RHs showed foveal involvement. These results suggest that newborns with RHs in the severe group had unique characteristics.

Notably, severe RHs in some newborns can be the result of nonaccidental trauma and Terson syndrome [13, 25–29] which is commonly associated with intracranial injury. As we have previously reported [13], RHs caused by abusive head trauma had a larger RH size, a higher percentage showed multilayer involvement and vitreous hemorrhage. Therefore, widespread severe RHs with multilayer involvement in the present study might have occurred in relation to the intracranial injuries. Unfortunately, we could not fully differentiate between RHs by birth canal compression and intracranial injury in the present study because of lack of information. Future studies about the pathophysiology of severe RHs should help provide an insight on this issue.

As mentioned above, the duration of RHs seems to depend on their severity, and severe RHs persist longer. We followed up newborns with severe RHs who visited our ophthalmology clinic and found that 126 (4.40%) eyes showed persistent RHs until 2 months after birth. Ma et al. [1] reported that all hemorrhages resolved spontaneously at the 3 months follow-up. Hughes et al. [10] found that 9 of 14 RHs resolved by 10 days, whereas dense foveal hemorrhages in 2 newborns persisted for a longer duration. Emerson et al. [11] reported that 85% of RHs resolved within 2 weeks, but a single subretinal hemorrhage persisted for longer than 4 weeks, and resolved only by 42 days.

In conclusion, this study confirmed that telemedicine combined with WFDRI was an effective and feasible method for investigating a large number of newborns with RHs. RHs commonly occur in healthy newborns and are significantly associated with NSVD. The characteristics of these newborns with RHs varied widely and seemed to depend on their severity. Severe RHs have unique characteristics, and future long-term longitudinal studies would be required to elucidate the prognosis of newborns with severe RHs.

6 Sep 2021

PONE-D-21-21462Birth-related retinal hemorrhages: The Soonchunhyang University Cheonan Hospital universal newborn eye screening (SUCH-NES) studyPLOS ONE

Dear Dr. Kim,

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ACADEMIC EDITOR: The manuscript is well-written and the number of included patients is quite impressive. I would suggest the authors highlight the difference between "clinical significance" and "statistical significance" in their study and discussion. The differences in gestational age and Apgar scores for example while might be statistically significant is too minute to be clinically significant.

==============================

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Reviewer #1: Great paper. Congratulations.

This paper would be very helpful in enhancing our understanding of RH in neonates.

I have no concerns regarding ethics on this paper.

Well written paper that is easy to understand.

Reviewer #2: • This was a prospective, observational study aimed at evaluating the prevalence and clinical factors related to birth-related retinal hemorrhages. The large number of eyes is impressive, and makes up for the relatively short follow-up period.

• The authors regularly mention the term "civil clinics" which I am not familiar with, and could not find adequate information on. Please elaborate on what they are and whether they are different from regular clinics.

• Methods:

o The authors determined a history of systemic illness as an exclusion criterion. Does this include both maternal and fetal illness? Were there records on maternal blood disorders or medications that may influence clotting and predispose to hemorrhages?

o The authors do not mention any details on the length and difficulty of the vaginal deliveries. Were there appliances used in any of them? Please elaborate and compare this data to the described ocular findings.

o The authors do not mention whether any of the CS deliveries attempted vaginal deliveries first before converting to CS. This may skew the results in the CS group. Please confirm.

o The data suggests some of these newborns' APGAR scores were low. Were any of them distressed? Did any require oxygenation, intubation or any other medical procedures that may have contributed to the development of hemorrhages?

o The authors mention in page 6, line 121 that eyes with abnormal ocular findings were referred to a pediatric ophthalmologist. Were these eyes removed from the total cohort of eyes?

o The authors divided the eyes by severity into 4 groups based on the number of retinal hemorrhages. Please elaborate on the rationale behind the specific thresholds used in this classification.

o The authors mention that the images were reviewed by a single grader. Why wasn't a double-grader analysis used? Was the grader masked to the clinical history of the newborns they were assessing? Methodology involving subjective analysis of data usually involves double-grading and blinding to ensure the absence of bias and error. Please explain.

o The quality of some of the images used is questionable. One might argue that panel D2 in figure 1 is too hazy to determine the quantify and localize all hemorrhages in this eye. Please expand on this issue.

• Results:

o P. 7, lines 165-172: these numbers are already mentioned in table 2. There is no need to repeat them.

• Tables:

o Almost all tables require editing. The numbers and parentheses are not properly spaced.

• Minor edits:

o P.6, line 115: Add "s" to "hour".

Reviewer #3: This is the largest study to date of newborn retinal hemorrhages. The size is impressive. The main conclusion is that 20-25% of healthy newborns have some degree of retinal hemorrhages, the vast majority of which will resolve over then ensuing few weeks. As has been extensively described previously, NSVB is the main risk factor for retinal hemorrhages, theoretically due to compression though this has not been proven. Thus, while the main findings reported in this paper are not novel, they are certainly sound given the astronomical sample size. The authors should be commended for undertaking such a task.

My only concern is that some of the other associations reported seem to be so minuscule in terms of the absolute value of the difference that the clinical relevance is questionable. The association to female sex has a clinically irrelevant O.R. and the difference is a single percentage point. The difference in gestational age is less than 2 days. The difference in Apgar score at 1 minute is 0.04! These things are so minuscule that it makes me wonder about the distribution of the data and whether there is some batch effect leading to spurious findings. I would request that the authors provide some additional analysis to investigate possible confounders (perhaps redoing the statistics several times, each time with a single hospital removed) to see if the results are robust. I would also switch to non-parametric testing (e.g. rank-sum for continuous variables).

The discussion could benefit from more speculation about why these minuscule differences exist. There should also be more discussion about the full differential for retinal hemorrhages in a newborn beyond cranial compression (i.e. things like Terson's, clotting disorders, etc). In addition (perhaps most importantly), there is NO discussion about non-accidental trauma (and this CAN occur in the hospital). Figure 1-C1, Figure 2-D are very concerning and there should be some acknowledgement of this and discussion about any further exam or inquiry that was done given the appearance of widespread hemorrhage in several layers.

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18 Oct 2021

October, 2021

The Editor,

PLOS ONE

Thank you for giving me the opportunity to submit a revised draft of my manuscript titled ‘Birth-related retinal hemorrhages: The Soonchunhyang University Cheonan Hospital universal newborn eye screening (SUCH-NES) study” to PLOS ONE. I appreciate the time and effort that you and the reviewers have dedicated in providing your valuable feedback on my manuscript. I am grateful to the reviewers for their insightful comments and suggestions which has helped me improve the quality of my submission. I have been able to incorporate changes to reflect most of the suggestions provided by the reviewers. Please note that I have highlighted the changes within the manuscript in red font.

Please find below the point-by-point response to the reviewers’ comments and concerns.

Comment : The manuscript is well-written and the number of included patients is quite impressive. I would suggest the authors highlight the difference between "clinical significance" and "statistical significance" in their study and discussion. The differences in gestational age and Apgar scores for example while might be statistically significant is too minute to be clinically significant.

Response : Thank you for your valuable comments. We completely agree with them. We think that gestational age and Apgar score showed statistical significance because the sample sizes were large. The magnitude of differences between groups might be too minimal to be clinically significant.

We have added the following sentences in the discussion section of our manuscript.

Modification : However, as the magnitude of differences of GA and Apgar scores at 1 and 5 min were minimal between the newborns with and without RHs, the clinical significance of these factors might be ambiguous (Page 25, Line 383-385).

Comment : Great paper. Congratulations. This paper would be very helpful in enhancing our understanding of RH in neonates. I have no concerns regarding ethics on this paper. Well written paper that is easy to understand.

Response : Thank you for your valuable comments and compliments.

Comment 1 : The authors regularly mention the term "civil clinics" which I am not familiar with, and could not find adequate information on. Please elaborate on what they are and whether they are different from regular clinics.

Response : Thank you for bringing this error to our notice. There was a mistake in the description of the term “civil clinics”. There are specialized obstetrics/gynecology (OB/GYN) hospitals in South Korea. These hospitals are responsible for the most of normal newborn deliveries. We collected data from these specialized OB/GYN hospitals via a telemedicine network. To reduce confusion, we used the term “OB/GYN hospitals” instead of “Civil OB/GYN clinics”.

Modification : Civil OB/GYN clinics -> OB/GYN hospitals

Please note that we have implemented this change throughout our revised manuscript.

Comment 2 : The authors determined a history of systemic illness as an exclusion criterion. Does this include both maternal and fetal illness? Were there records on maternal blood disorders or medications that may influence clotting and predispose to hemorrhages?

Response : Thank you for your pertinent observation. The history of systemic illness, both maternal and fetal, were collected. In addition, mothers with known blood disorders or medications that could influence the occurrence of retinal hemorrhages were excluded from our study. We have modified the exclusion criteria in the method section accordingly.

Modification :

-> (2) maternal and fetal systemic diseases, (3) structural ocular anomalies, (4) a familial history of ocular congenital anomalies, and (5) those transferred to tertiary hospitals due to problems during delivery or (6) those undergoing the examination 7 days after birth were excluded from the study (Page 5, line 89-92).

Comment 3 : The authors do not mention any details on the length and difficulty of the vaginal deliveries. Were there appliances used in any of them? Please elaborate and compare this data to the described ocular findings.

Response : Thank you for your valuable observation. We agree with your opinion that there is a possibility that the duration and difficulty of the vaginal delivery can affect the occurrence of retinal hemorrhages. Unfortunately, we could not collect this data from each of the OB/GYN hospitals in the present study because of cost and labor restrictions. We are planning to analyze more details of risk factors in relation to the occurrence of retinal hemorrhages in a future study.

In addition, these days, vacuum- or forceps- assisted vaginal delivery is not performed in South Korea. Relevant information regarding the same can be found in the discussion section and is as follows

Unfortunately, since none of the newborns included in our study were delivered via vacuum- or forceps-assisted vaginal delivery, we could not elucidate the differences in the occurrence of RHs according to the mode of delivery. ( Page 25, line 378-381)

Modification :

-> Unfortunately, other related factors that have been known to be associated with the occurrence of RHs, such as maternal age [11], primiparous mothers [23], duration and difficulty of active labor [21], converting delivery methods from NSVD to CS and head circumference [24], were not assessed in this study. Future studies to specify more detailed risk factors in relation to the occurrence of RHs should be planned (Page 25, line 395-400).

Comment 4 : The authors do not mention whether any of the CS deliveries attempted vaginal deliveries first before converting to CS. This may skew the results in the CS group. Please confirm.

Response : Thank you for the pertinent observation. Newborns with RHs in the CS group have a possibility that they were subject to attempted NSVD before converting to CS. Unfortunately, as we have mentioned above, these data could not be collected because of the cost and labor restrictions. We are planning to clarify these factors in a future study.

Modification :

-> Unfortunately, other related factors that have been known to be associated with the occurrence of RHs, such as maternal age [11], primiparous mothers [23], duration and difficulty of active labor [21], converting delivery methods from NSVD to CS and head circumference [24], were not assessed in this study. Future studies to specify more detailed risk factors in relation to the occurrence of RHs should be planned (Page 25, line 395-400).

Comment 5 : The data suggests some of these newborns' APGAR scores were low. Were any of them distressed? Did any require oxygenation, intubation or any other medical procedures that may have contributed to the development of hemorrhages?

Response : Thank you for your comments. Apgar score of 0 to 3 indicates a severely depressed neonate, whereas a score of 7 to 10 is considered normal. Here is the distribution of newborns according to the Apgar score at 1 min and 5 min from our study.

Apgar score at 1 min Apgar score at 5 min

0 0 (0 %) 0 (0 %)

1 0 (0 %) 0 (0 %)

2 0 (0 %) 0 (0 %)

3 3 (0.01 %) 0 (0 %)

4 4 (0.01 %) 0 (0 %)

5 12 (0.02 %) 2 (0 %)

6 96 (0.17 %) 1 (0 %)

7 1176 (2.09 %) 71 (0.12 %)

8 9257 (16.49 %) 964 (1.71 %)

9 36696 (65.16 %) 9389 (16.61 %)

10 9003 (16.01 %) 45820 (81.46 %)

Total 56247 56247

As you commented, there were distressed newborns at 1 min after birth and the act of trying to revive them might have affected the occurrence of retinal hemorrhages. However, we think that the number of distressed newborns were too small to affect the main results of our study. In addition, there were no distressed newborns after 5 min of birth.

Comment 6 : The authors mention in page 6, line 121 that eyes with abnormal ocular findings were referred to a pediatric ophthalmologist. Were these eyes removed from the total cohort of eyes?

Response : Thank you for pointing this out. Abnormal ocular findings include all kinds of ocular abnormalities such as retinal hemorrhages, congenital cataract, optic disc abnormalities, retinoblastoma, and coloboma. Newborns with retinal hemorrhages without other ocular abnormalities were included our study, however, newborns with other ocular abnormalities were excluded from the study as we have mentioned in the exclusion criteria.

Comment 7 : The authors divided the eyes by severity into 4 groups based on the number of retinal hemorrhages. Please elaborate on the rationale behind the specific thresholds used in this classification.

Response : Thank you for pointing this out. We determined specific thresholds of the number of retinal hemorrhages from the study by Watts et al.[1] after modification.

Since Watts et al. had determined the appropriate severity equivalent from previous numerous papers, [2-8] we think this can be a reasonable standard for dividing the groups. We have already commented about this in the discussion section. “Since no unified criteria are available for categorizing newborns and eyes with RHs, we used a newly developed criteria, that further subdivided Watts et al.’s criteria [8].”

The modification can be also found in the method section.

Modification : Newborns and eyes with RHs were divided into four groups according to the number of RHs. -> Newborns and eyes with RHs were divided into four groups according to the number of RHs referring to the work of Watts et al. [8] after modification (Page 7, line 133-135).

Comment 7 : The authors mention that the images were reviewed by a single grader. Why wasn't a double-grader analysis used? Was the grader masked to the clinical history of the newborns they were assessing? Methodology involving subjective analysis of data usually involves double-grading and blinding to ensure the absence of bias and error. Please explain.

Response : Thank you for your pertinent observation. In our telemedicine system, interpretation of images was done by a pediatric vitreoretinal specialist (SYK) who reported to the parents within 24 hours because of the cost and time constraints. However, during the preparation of the manuscript, we re-checked all the data by two independent graders (SYK and IHC) in a masked fashion. If there was any discrepancy between the graders, it was resolved by discussion. We apologize for missing this information in the method section.

The modification can be found in the method section.

Modification : Retinal images from newborns with RHs were reviewed, and the details were recorded -> Retinal images from newborns with RHs were reviewed by two independent graders (SYK and IHC) in a masked fashion. If there was any discrepancy between the graders, consensus was reached by discussion (Page 7, line 128-130).

Comment 8 : The quality of some of the images used is questionable. One might argue that panel D2 in figure 1 is too hazy to determine the quantify and localize all hemorrhages in this eye. Please expand on this issue.

Response : Thank you for your valuable insights. As we have mentioned in the method section, if the captured images were of poor quality, the newborns were re-screened. However, in our humble opinion, we feel that the image quality of panel D2 in figure 1 depicts the necessary information. There were no major problems in the interpretation of the retinal hemorrhages according to the involved retinal layers. The image can be interpreted as below.

Comment 9 : P. 7, lines 165-172: these numbers are already mentioned in table 2. There is no need to repeat them.

Response : Thank you for your suggestion. We have removed the numbers which were already mentioned in table 2.

Modification : Among the screened newborns, newborns who met inclusion criteria were enrolled. In total, 56247 newborns from 61 OB/GYN hospitals were examined over 3 years and included 28894 males (51.37%) and 27353 females (48.63%). Newborns delivered via NSVD were 30826 (54.80%), and the rest were delivered via CS (25421/56247; 45.20%). The mean GA and mean BW were 273.10 ± 8.27 days and 3233.42 ± 405.13 g, respectively. The mean Apgar score was 8.95 ± 0.65 at 1 minute and 9.79 ± 0.46 at 5 minutes, and the mean age at examination was 2.00 ± 1.90 days (Table 2).

-> Among the screened newborns, newborns who met the inclusion criteria were enrolled. In total, 56247 newborns from 61 OB/GYN hospitals were examined over 3 years. Overall demographics of these newborns are described in Table 2 (Page 9, line 170-172).

Comment 10 : Tables: Almost all tables require editing. The numbers and parentheses are not properly spaced.

Response : Thank you for your feedback. Please note that we have edited and modified all the tables.

Comment 11 : Minor edits: P.6, line 115: Add "s" to "hour".

Response : Thank you for pointing out this error. We have made the necessary modifications.

Modification : hour -> hours (Page 6, line 116)

Comment 1 : This is the largest study to date of newborn retinal hemorrhages. The size is impressive. The main conclusion is that 20-25% of healthy newborns have some degree of retinal hemorrhages, the vast majority of which will resolve over then ensuing few weeks. As has been extensively described previously, NSVB is the main risk factor for retinal hemorrhages, theoretically due to compression though this has not been proven. Thus, while the main findings reported in this paper are not novel, they are certainly sound given the astronomical sample size. The authors should be commended for undertaking such a task

Response : Thank you for your valuable comments and compliments.

Comment 2 : My only concern is that some of the other associations reported seem to be so minuscule in terms of the absolute value of the difference that the clinical relevance is questionable. The association to female sex has a clinically irrelevant O.R. and the difference is a single percentage point. The difference in gestational age is less than 2 days. The difference in Apgar score at 1 minute is 0.04! These things are so minuscule that it makes me wonder about the distribution of the data and whether there is some batch effect leading to spurious findings. I would request that the authors provide some additional analysis to investigate possible confounders (perhaps redoing the statistics several times, each time with a single hospital removed) to see if the results are robust. I would also switch to non-parametric testing (e.g. rank-sum for continuous variables). The discussion could benefit from more speculation about why these minuscule differences exist.

Response : Thank you for your valuable comments. We completely agree with your comment. The female sex showed significant association with the occurrence of retinal hemorrhage in multivariate analyses. However, as mentioned in the discussion section, the odds ratio was slightly higher than 1, and the clinical significance of female sex might be ambiguous compared to that of male sex. You can find following sentence in the discussion section. “Female sex (OR, 1.050; 95% CI, 1.005–1.098; P = 0.029) was significantly associated with RHs. However, the OR was slightly higher than 1, and the clinical significance of female sex compared to male sex was ambiguous. Future studies are warranted to validate this result.”

In case of gestational age and Apgar score, they were statistically significant because of large sample size. However, we think that the magnitude of differences between groups might be minimal to be clinically significant. We have added the following sentences in the discussion section of our manuscript. “But, because the magnitude of differences of gestational age and Apgar scores at 1 and 5 minutes were minimal between the newborns with and without RHs, clinical significance of these factors might be ambiguous.”

As you pointed out a statistical problem with our manuscript, we have revisited our statistical analysis. Statistical analyses were conducted using both parametric and non-parametric statistical methods in total and by year (2017, 2018, and 2019). The gestational age was significantly different between groups in both parametric and non-parametric statistical methods from 2017 to 2019. The Apgar score at 1 min was significantly different between groups in both parametric and non-parametric statistical method in 2018 and 2019. From these results, there seems to be no major problem with our statistical analysis. Kindly let us know in case we are missing something. We will be happy to look into it again.

Comment 3 : There should also be more discussion about the full differential for retinal hemorrhages in a newborn beyond cranial compression (i.e. things like Terson's, clotting disorders, etc). In addition (perhaps most importantly), there is NO discussion about non-accidental trauma (and this CAN occur in the hospital). Figure 1-C1, Figure 2-D are very concerning and there should be some acknowledgement of this and discussion about any further exam or inquiry that was done given the appearance of widespread hemorrhage in several layers.

Response : Thank you for your valuable comments. We completely agree with your comments. Since fundus photography was optional, only newborns whose parents wanted the examination were screened. However, it might be difficult to exclude nonaccidental trauma. We have added comments about widespread severe RHs with multiple layer involvement which might be related to nonaccidental trauma or Terson syndrome in the discussion section. Unfortunately, it was impossible for us to fully differentiate between RHs by birth canal compression and intracranial injury in the present study because of lack of information. Since we are preparing future studies related to severe RHs, we expect to get an insight on this topic.

The modification can be found in discussion section.

Modification : Notably, severe RHs in some newborns can be the result of nonaccidental trauma and Terson syndrome [13, 25-29] which is commonly associated with intracranial injury. As we have previously reported [13], RHs caused by abusive head trauma had a larger RH size, a higher percentage showed multilayer involvement and vitreous hemorrhage. Therefore, widespread severe RHs with multilayer involvement in the present study might have occurred in relation to the intracranial injuries. Unfortunately, we could not fully differentiate between RHs by birth canal compression and intracranial injury in the present study because of lack of information. Future studies about the pathophysiology of severe RHs should help provide an insight on this issue. (Page 28, line 457-465).

References

1. Watts P, Maguire S, Kwok T, Talabani B, Mann M, Wiener J, et al. Newborn retinal hemorrhages: a systematic review. J AAPOS. 2013;17(1):70-8. Epub 2013/02/01. doi: 10.1016/j.jaapos.2012.07.012. PubMed PMID: 23363882.

2. Berkus MD, Ramamurthy RS, O'connor PS, Brown K, Hayashi RHJO, gynecology. Cohort study of silastic obstetric vacuum cup deliveries: I. Safety of the instrument. 1985;66(4):503-9.

3. Emerson MV, Pieramici DJ, Stoessel KM, Berreen JP, Gariano RF. Incidence and rate of disappearance of retinal hemorrhage in newborns. Ophthalmology. 2001;108(1):36-9. Epub 2001/01/11. doi: 10.1016/s0161-6420(00)00474-7. PubMed PMID: 11150261.

4. Hughes LA, May K, Talbot JF, Parsons MA. Incidence, distribution, and duration of birth-related retinal hemorrhages: a prospective study. J AAPOS. 2006;10(2):102-6. Epub 2006/05/09. doi: 10.1016/j.jaapos.2005.12.005. PubMed PMID: 16678742.

5. Kuit JA, Eppinga HG, Wallenburg H, Huikeshoven FJO, gynecology. A randomized comparison of vacuum extraction delivery with a rigid and a pliable cup. 1993;82(2):280-4.

6. Schoenfeld A, Buckman G, Nissenkorn I, Cohen S, Ben-Sira I, Ovadia JJAoO. Retinal hemorrhages in the newborn following labor induced by oxytocin or dinoprostone. 1985;103(7):932-4.

7. Svenningsen L, Eidal KJAoegS. Lack of correlation between umbilical artery pH, retinal hemorrhages and Apgar score in the newborn. 1987;66(7):639-42.

8. Williams MC, Knuppel RA, O'Brien WF, Weiss A, Spellacy WN, Pietrantoni M. Obstetric correlates of neonatal retinal hemorrhage. Obstet Gynecol. 1993;81(5 ( Pt 1)):688-94. Epub 1993/05/01. PubMed PMID: 8469455.

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19 Oct 2021

Birth-related retinal hemorrhages: The Soonchunhyang University Cheonan Hospital universal newborn eye screening (SUCH-NES) study

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29 Oct 2021

PONE-D-21-21462R1

Birth-related retinal hemorrhages: The Soonchunhyang University Cheonan Hospital universal newborn eye screening (SUCH-NES) study

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