Analysis of pathogenic factors of retinopathy of prematurity in Heilongjiang Province

doi:10.21203/rs.3.rs-3757727/v1

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Research Article

Analysis of pathogenic factors of retinopathy of prematurity in Heilongjiang Province

https://doi.org/10.21203/rs.3.rs-3757727/v1

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Background and purpose

Retinopathy of prematurity is a vascular development disorder in immature retinas of premature infants, which is the leading cause of blindness in children worldwide. Because the screening delay may lead to the occurrence of blindness in children, it is particularly important to conduct timely screening for children with high risk factors. Currently, the pathogenesis of ROP may be related to multiple factors such as gestational age and birth weight of premature infants. In this study, the prevalence and risk factors of ROP in Heilongjiang Province were determined through screening for premature infants in the region, aiming to proceed early prevention of the disease.

Methods

Retrospectively analyzed 714 premature infants admitted to the Ophthalmology Clinic of the Second Affiliated Hospital of Harbin Medical University from January 2016 to February 2022. 12 related factors was recorded including patients’ gender, gestational age, birth weight, oxygen duration, blood transfusions, anemia, neonatal infections, respiratory distress syndrome, maternal feeding way, childbirth way, pregnancy age and parity. The prevalence of ROP and the differences in related factors between ROP patientsand non-ROP patients were found.

Results

Among 714 premature infants, 188 had ROP of which the incidence is 26.3%，and 61 patients received treatment. There were statistically significance(P<0.05) in gestational age, birth weight, oxygen duration, blood transfusion, anemia, neonatal infection, respiratory distress syndrome and childbirth way between the 188 ROP patients and non-ROP patients in univariate regression analysis. Variables with statistical significance for single factor were selected and conducted by multivariate regression analysis, which showed that gestational age, birth weight, and oxygen duration had remarkable statistical significance(P<0.05) with the occurrence of ROP. Gestational age and birth weight were the protective factors of disease (OR=0.43 and OR=0.8), while oxygen duration was the risk factor of disease (OR=1.02), and the diagnostic value of the model was high (AUC=0.776). five of the 61 patients who received treatment for ROP accepted two treatments, with gestational age < 32 weeks, birth weight < 1500g, and oxygen inhalation time > 20 days. The Kendall grade relative analysis of 188 patients with ROP showed that disease severity was significantly correlated with gestational age, birth weight, oxygen duration, anemia, blood transfusion and respiratory distress syndrome(P<0.05), in which the gestational age, birth weight, anemia, blood transfusion and respiratory distress syndrome were negatively correlated with the severity of the disease, while oxygen duration was positively correlated with severity of the disease. 507 children were screened from 2016 to December 31th in 2019, 138 of which were ROP patients, 36 children were treated (7.1%). Due to the spread of the COVID-19, 207 children were screened after January 1th in 2020, 50 children were ROP patients, and 25 of whom got treatment (12%), 21were treated after 8 weeks of birth or more than 37 weeks of corrected gestational age. Four out of five children who received the second treatment happened after the epidemic, and three of them missed treatment due to the epidemic.

Conclusions

The gestational age, birth weight and oxygen duration are significantly correlated with the incidence and severity of the disease in premature infants screening of Heilongjiang Province. Premature infants screening and subsequent visit were affected due to the spread of the COVID-19 in the past two years, the proportion of children needed to be cured augmented apparently, therefore, it matters a lot for premature infants to be screened standardly and timely.

Retinopathy of prematurity

Gestational age

Birth weight

Oxygen duration

Retinopathy of Prematurity (ROP) is a complex vascular confusion in immature retinas of preterm infants, which is currently the leading cause of blindness in children worldwide. As the survival rate of premature infants has been enhanced by the improvement of neonatal care, the incidence of ROP has also been enlarged^[1]. The attack of retinopathy of prematurity may be related to a variety of factors, simultaneously, the insufficient understanding of disease-related risk factors and the delay of screening may both result in the occurrence of the disease in children, so it is especially important for children with high risk factors to be timely screened^[2–3]. It remains to be further clarified whether cold weather and dry climate in Heilongjiang district have an impact on the morbidity of children and whether environmental factors will increase some risk factors. Therefore, in order to avoid missed diagnosis and reduce screening times for premature infants, further understandings of the risk factors related to diseases in Heilongjiang Province need to be proceeded. In this study, 714 premature infants admitted to our hospital are selected, and the incidence and disease-related risk factors of retinopathy of prematurity in Northeast China are retrospectively analyzed.

3.1 General Information

3.1.1 Research Subjects

Children who visited the ophthalmology clinic of the Second Affiliated Hospital of Harbin Medical University from January 2016 to February 2022 were selected and divided into ROP group and non-ROP group according to the inclusion criteria. This study was approved by the Ethics Committee of the Second Affiliated Hospital of Harbin Medical University, all the parents of the children signed informed consent.

3.2 Research equipment

3.2.1 Retcam 3 Wide-angle fundus photography system for children

All enrolled patients accepted Retcam 3 fundus photography, and the inspection results were interpreted by the same experienced pediatric fundus physician. All preterm infants were placed in supine position, and water was fasted for 2 hours before examination. Compound topicamide eye liquid (each 1 drop, 15 minutes for each time, continuous 6 times) was employed, and use ocbucaine hydrochloride ere drops for patients to make surface anesthesia after pupil fully dilated, ophthalmologist fixed the head and body of the child, use a pediatric eyelid opener to work. Retcam 3 also was employed by the same experienced pediatric fundus physician to check fundus of children, first right eye and then left eye, the examiner held the head of the probe, vertically placed on the corneal surface of the children, adjusted the probe first, so that the fundus imaging was clear, then slightly moved the probe, successively from the posterior pole, nasal side, topside and other quadrants line fundus examination, and photograph preservation.

3.3 Research Methods

3.3.1 Data collection

Retcam 3 fundus photography was performed on all children and 12 related factors data were collected: patients’ gender, gestational age (GA), birth weight (BW), oxygen duration, blood transfusions, anemia, neonatal infections, respiratory distress syndrome, maternal feeding way, childbirth way, pregnancy age and parity. A total of 714 premature infants were collected, 188 infants in the ROP group and 526 infants in the non-ROP group.

3.3.2 Discharge criteria

Preterm infants were divided into ROP group and non-ROP according to the third international ROP classification standard. The initiation time, interval time, intervention time and termination conditions of screening for all children were conducted in accordance with the《Requirements of Chinese Screening Guidelines for Retinopathy of prematurity (2014)》.

Screening interval: (1) no ROP, stage 1 or 2 in zone I, stage 2 or 3 in zone II, weekly follow-up, (2) ROP regression in zone I, or stage 1 in zone II for 1-2 weeks follow-up, (3) no ROP or stage 1 in zone I, or stage 1 and 2 in zone III, 2-3 weeks follow-up.

Intervention time: threshold lesions or type 1 pre-threshold lesions should be treated as soon as possible.

Screening termination conditions: (1) retinal vascularization (nasal to serrated edge, temporal to serrated edge of 1 Optic papilla diameter), (2) corrected gestational age of 45 weeks, no pre-threshold or threshold lesions, retinal vascular development area, (3) retinopathy degeneration. Follow-up was terminated if one of the above conditions was met.

Due to the discrepancy of incidence rates in different regions, screening coverage has been modestly expanded according to guidelines based on the principle of no missed diagnosis. Inclusion criteria: (1) premature infants with gestational age < 37 weeks, (2) birth weight < 3200 g, (3) no other fundus diseases, (4) full clinical data, (5) patients whose all family members have signed the ROP screening consent.

Exclusion criteria: (1) congenital cataract, (2) refractive interstitial opacity, (3) patients with other fundus diseases, (4) patients with serious complications, (5) incomplete clinical data.

3.3.3 Statistical analysis

Data were analyzed using version 4.0.1 of R language, Median quartile spacing was used for numerical variables with Wilcox rank-sum test, and χ² test was used for categorical variables. Logistic regression analysis was used to build the diagnostic model and draw receiver operating characteristic curves (ROC) and area under the receiver operating characteristic curves (AUC) to evaluate the sensitivity and specificity of diagnostic models. Univariate logistic regression analysis of disease-related factors was carried out first, variables with statistical significance in univariate regression analysis were selected for multivariate logistic regression analysis, and then Kendall correlation analysis was used to build prediction models according to the severity of the disease. The parameter P coincident with statistical significance if it is < 0.05.

4.1 General situation of patients

748 preterm infants were screened totally in this study, and 714 preterm infants were brought into this study, including 188 cases in the ROP group and 526 cases in the non-ROP. There were 392 males, 111 cases (15.5%) in the ROP group, and 322 females, 77 cases (10.8%) in the ROP group. Gestational age was in 25-36 weeks, gestational age < 28 weeks were 30 cases, 27 cases (3.8%) in the ROP group, 28-32 weeks were 428 cases, 132 cases (18.5%) in the ROP group, > 32 weeks were 256 cases, 29 cases (4%) in the ROP group. Birth weight was in 650g-3100g, < 1500g were 270 cases, 126 cases (17.6%) in the ROP group, 1500g-2000g were 292 cases, 45 cases (6.3%) in the ROP group, > 2000g were 152 cases, 17 cases (2.4%) in the ROP group. Method of delivery included vaginal delivery and cesarean section, including 262 cases were in vaginal delivery, 86 cases (12%) in the ROP group. There were 452 cases of cesarean section, 102 cases (14.3%) in the ROP group. The oxygen duration was in 0-120 days, < 7 days were 161 cases, 19 cases (2.7%) in the ROP group, 7-28 days were 360 cases, 74 cases (10.3%) in the ROP group, > 28 days were 193 cases, 95 cases (13.3%) in the ROP group. There were 381 premature infants with respiratory distress syndrome, 125 cases (17.5%) in the ROP group. Premature infants with anemia were 389 cases, 136 cases (19%) in the ROP group. 379 premature infants were treated by blood transfusion, 135 cases (18.9%) in the ROP group. There were 112 premature infants with neonatal injection, 45 cases (6.3%) in the ROP group. Feeding methods covered artificial feeding, breast feeding and mixed feeding, 182 premature infants were breast feeding, 43 cases (6.1%) in the ROP group, 357 premature infants were artificial feeding, 106 cases (14.8%) in the ROP group, 175 premature infants were mixed feeding, 39 cases (5.5%) in the ROP group. Pregnancy age was 19-45 years old, < 35 years old were 526 cases, 134 cases (18.8%) in the ROP group; > 35 years old was 188 cases,54 cases (7.6%) in the ROP group. The parities ranged from 1-7, < 2 parities was 357 cases, 80 cases (11.2%) in the ROP group. > 2 parities was 357 cases, 108 cases (15.1%) in the ROP group. The results were showed in Table 1.

Table 1. Basic information of the research object

		ROP		Non-ROP
		Number	Account	Number	Account
Gender	male	111	15.5%	281	39.4%
Gender	female	77	10.8%	245	34.3%
Gestational age (weeks)	＜28	27	3.8%	3	0.4%
	28-32	132	18.5%	296	41.5%
	＞32	29	4%	227	31.8%
Birth weight (g)	＜1500	126	17.6%	144	20.2%
	1500-2000	45	6.3%	247	34.6%
	＞2000	17	2.4%	135	18.9%
Childbirth way	eutocia	86	12%	176	24.6%
Childbirth way	cesarean section	102	14.3%	350	49.1%
Oxygen duration (days)	＜7	19	2.7%	142	19.9%
	7-28	74	10.3%	286	40.1%
	＞28	95	13.3%	98	13.7%
Respiratory distress syndrome		125	17.5%	256	35.9%
anemia		136	19%	253	35.4%
blood transfusions		135	18.9%	244	34.2%
neonatal infections		45	6.3%	67	9.3%
Feeding way	Breast-fed	43	6.1%	139	19.5%
	Artificial-fed	106	14.8%	251	35.2%
	Mixed-fed	39	5.5%	136	19%
Pregnancy age	＜35	134	18.8%	392	54.9%
Pregnancy age	≥35	54	7.6%	134	18.8%
Parity (time)	＜2	80	11.2%	277	38.8%
Parity (time)	≥2	108	15.1%	249	34.9%

4.2 Univariate and multivariate regression analysis of disease

The selected relative factors were analyzed by univariate Logistic analysis, and gestational age, birth weight, oxygen duration, delivery mode, repiratory distress syndrome, anemia, blood transfusion, infection were correlated with retinopathy of prematurity, with statistically significant differences (P<0.05). There were no significant correlation between gender, gestational age, feeding mode, parity and retinopathy of prematurity (P>0.05). The results were showed in Table 2.

Table 2. Univariate Logistic regression analysis of ROP related risk factors

indicators	parameter	Standard deviation	Z	P	OR [95% CI]
Gestational age	-0.4492	0.0448	-10.024	<0.0001	0.64[0.58-0.70]
Birght weight	-2.2627	0.2451	-9.2307	<0.0001	0.10[0.06-0.17]
Oxygen duration	0.0501	0.0054	9.3443	<0.0001	1.05[1.04-1.06]
Pregnancy age	0.0235	0.0189	1.246	0.2128	1.02[0.99-1.06]
Parity	0.1216	0.0802	1.5164	0.1294	1.13[0.96-1.32]
Gender	-0.2507	0.1724	-1.4539	0.146	0.78[0.55-1.09]
Childbirth way	-0.5039	0.1733	-2.9076	0.0036	0.60[0.43-0.85]
Respiratory distress Syndrome	-0.7451	0.1769	-4.211	<0.0001	0.47[0.33-0.67]
Anemia	-1.0339	0.1841	-5.6156	<0.0001	0.36[0.25-0.51]
Blood Transfusions	-1.0842	0.1834	-5.9109	<0.0001	0.34[0.23-0.48]
Neonatal infections	-0.8205	0.2168	-3.7845	0.0002	0.44[0.29-0.68]
Feeding way	0.3416	0.2094	1.6317	0.1027	1.41[0.94-2.14]

Statistically significant variables that selected in univariate Logistic analysis were made multivariable Logistic regression analysis to construct diagnosis model including gestational age, birth weight, oxygen duration, delivery mode, respiratory distress syndrome, anemia, blood transfusion, neonatal infection, the results shows that gestational age, birth weight, and oxygen duration are independent risk factors for disease (P<0.05). The childbirth way, respiratory distress syndrome, anemia, blood transfusion and infection were not independent risk factors. Gestational age and birth weight were protective factors (OR=0.8 and OR=0.43), and oxygen duration was the risk factor (OR=1.02) (Table 3). The gestational age, birth weight and oxygen duration that were significant in multivariate analysis were compared among the groups. The results showed that the gestational age was 27 cases (90%) in the ROP group (<28 weeks), 132 cases (30.8%) in the ROP group (28-32 weeks), and 29 cases (11.3%) in the ROP group (>32 weeks). It can be seen that the younger the gestational age, the higher the incidence of the children. 126 cases (46.7%) of BW< 1500g in the ROP group. There were 45 cases (15.4%) in the ROP group (1500-2000g) and 17 cases (11.2%) in the ROP group (>2000g), indicating that the lower the BW was, the higher the incidence was. The oxygen duration inhalation ranged from 0 to 120 days, among which 19 patients (11.8%) were in ROP group less than 7 days. 74 cases (20.6%) in ROP group (7-28 days), 95 cases (49.2%) in ROP group (>28 days), it can be seen that the longer the oxygen duration, the higher the incidence of children (Table 4). ROC and AUC were calculated according to the diagnostic model, and the model had high diagnostic value (AUC=0.776), as shown in Figure 1.

Table 3. Multivariate logistic regression analysis of risk factors associated with ROP

indicators	Number	标准误	Z	P	OR[95% CI]
gestational age	-0.2203	0.0642	-3.43	0.0006	0.80[0.71-0.91]
birth weight	-0.8550	0.3320	-2.58	0.0100	0.43[0.22-0.81]
oxygen duration	0.0236	0.0064	3.70	0.0002	1.02[1.01-1.04]

Table 4. Incidence rates within the three risk factors

		Number	ROP		non-ROP
		Number	Number	Account	Number	Account
Gestational age	＜28	30	27	90%	3	10%
	28-32	428	132	30.8%	296	69.1%
	＞32	256	29	11.3%	227	88.7%
Birth weight	＜1500	270	126	46.7%	144	53.3%
	1500-2000	292	45	15.4%	247	84.6%
	＞2000	152	17	11.2%	135	88.8%
Oxygen duration	＜7	161	19	11.8%	142	88.2%
	7-28	360	74	20.6%	286	79.4%
	＞28	193	95	49.2%	98	50.8%

4.3 Correlation analysis of disease severity

Among the 714 preterm infants, 188 cases were ROP, of which 10 cases (5.3%) were in Zone I, 60 patients (31.9%) in Zone II and 118 patients (62.8%) in zone III. 57 patients (30.3%) were in stage 1, 67 cases (35.6%) in stage 2, 60 cases (31.9%) in stage 3, and 4 cases (2.2%) in stage 4, including 127 cases with natural degeneration of untreated disease, 61 cases with anti-VEGF treatment, 56 cases with degeneration after treatment, and 5 patients with no degeneration and accept two times anti-VEGF treatment, respectively GA< 32 weeks, BW< 1500g, and oxygen duration was > 20 days, as shown in Table 5. Kendall grade correlation analysis was conducted according to the disease severity of 188 ROP children, and the results showed that gestational age, birth weight, oxygen duration, respiratory distress syndrome, anemia, blood transfusion and disease severity were significant (P<0.05). Gestational age, birth weight, respiratory distress syndrome, anemia, blood transfusion were negatively correlated with the severity of the disease, while oxygen duration was positively correlated with the severity of the disease (Table 6).

Table 5. Disease severity statistic

		Number	Account
Zone	I	10	5.3%
	II	60	31.9%
	III	118	62.8%
Stage	1	57	30.3%
	2	67	35.6%
	3	60	31.9%
	4	4	2.2%
Treatment		61	32.4%
Natural degradation		127	67.6%

Table 6. Correlation analysis of desease severity

Indicators	Cor Correlation coefficient R	p
Gestational age	-0.2304	0.0003
Birth weight	-0.2197	0.0003
Oxygen duration	0.1434	0.0186
Pregnancy age	0.0331	0.5915
Parity	-0.0796	0.2438
Gender	-0.0384	0.5993
Childbirth way	-0.0781	0.2857
Respiratory distress syndrome	-0.1622	0.0265
Anemia	-0.2070	0.0046
Blood transfusions	-0.2140	0.0034
Neonatal infections	-0.0106	0.8845
Feeding way	0.0866	0.2142

4.4 Correlation analysis between COVID-19 and disease

In addition, we also learned the proportion of children treated before and after the COVID-19. From 2016 to December 31th 2019,138 children were ROP among the 507 children screened, and 36 children (7.1%) were cured. There were 50 children with ROP in 207 children screened after January 1st 2020, and 25 children received treatment (12%), 21 patients were treated after 8 weeks of birth or more than 37 weeks of postmenstrual age. In this study, 4 out of 5 children who received the second treatment occurred after the epidemic, and 3 of them did not accept the treatment on time due to the epidemic.

In order to clarify the incidence of ROP in Heilongjiang Province where the climate is cold and dry, the screening scope was moderately expanded in this study under the principle of no missed diagnosis. Among the 714 premature infants, 188 developed ROP, with the 26.3% incidence rate, 127 had spontaneous regression of lesions, 61 received anti-VEGF therapy, 56 of them had regression after only one treatment, whereas 5 received second drug injection therapy.

5.1 Correlation between ROP and gestational age

In this study, the overall and intra-group incidence rates of different gestational ages were analyzed, Among the overall incidence rates, 30 cases were in GA < 28 weeks, whose 27 cases (3.8%) were in the ROP group, The gestational age ranged from 28 to 32 weeks were 428 patients, of which 132 (18.5%) cases in the ROP group, 29 (4%) out of 256 patients whose GA > 32 weeks belonged to the ROP group. The intra-group incidence was 90%, 30.8%, 11.3%. The difference between the two incidence rates may be due to the large gestational age of the hospitalized children and the small number of children. As can be seen from the incidence rate, the younger the gestational age was, the higher the incidence was, especially the incidence of children with GA < 28 weeks reaches 90%, which is similar to some previous studies^[4]. Because gestational age reflects the time of fetal development in utero, it indicates the immaturity degree of premature babies to certain extent. At 40 weeks, the peripheral retinal vessels of the embryo are fully developed, while the premature maturity of the vessels is low, and the immature retinal vessels are prone to atresia due to severe contraction, leading to the formation of ROP ^[5]. Moreover, the younger the gestational age, the retina is hyperoxygenated with the reduction of vascular endothelial growth factor (VEGF) and insulin-like growth factor1 (IGF-1) leads to the formation of the avascular region of the retina. With the increase of developmental metabolic requirements, hypoxia in the avascular region induces the secretion of VEGF and IGF-1, which further leads to the formation of neovascularization. The younger the gestational age, the worse the retinal development, the more prominent the unvascularized retinopathy, and the more likely it is to develop into severe retinopathy ^[6].

5.2 Correlation between ROP and birth weight

In this study, the overall morbidity and intra-group morbidity of different birth weights were analyzed. The overall morbidity in BW < 1500g were 270 cases, and 126 cases (17.6%) in the ROP group. There were 292 cases in 1500-2000g group, 45 cases (6.3%) in the ROP group, 152 cases (2.4%) in > 2000g group, 17 cases (2.4%) in the ROP group. The incidence rates of intra-group were 46.7%, 15.4%,11.2%. Both incidence rates showed that the lower the birth weight, the higher the incidence. Univariate and multivariate regression analysis showed that low birth weight was significantly correlated with the occurrence and severity of disease (P < 0.05). These results were consistent with some previous studies, indicating that birth weight was an important risk for disease occurrence^[7].What’s more, an analysis for low birth weight infants in Spain found that the incidence of premature infants weighting < 1501g reached 29.2%, and the number need treatment achieved 5.6%^[8]. In 2021, the hospital conducted another study on preterm infants under 1250g and found the rate was much higher, with the incidence and treatment rates reaching 41.1% and 10%^[9]. The significant correlation between birth weight and disease is mainly on account of the fact that in patients with low birth weight, the retina is not fully developed, and the incidence of ROP is apparently correlated with the size of the avascular-free area of the retina at birth, so that fetus with lower birth weight experience a higher incidence of ROP^[10].

5.3 Correlation between ROP and oxygen duration

In this study, we analyzed the overall morbidity and intra-group morbidity of oxygen duration, 161 cases in oxygen duration < 7 days, 19 cases (2.7%) in the ROP group. There was 360 cases between 7 days and 28 days, 74 cases (10.3%) in the ROP group, 95 cases (13.3%) were in the ROP group within 193 cases in oxygen duration > 28 days. The intra-group incidence rates were 11.8%, 20.6%, 49.2%. It appeared that the longer the duration of oxygen inhalation, the higher the incidence of the disease in both incidence rates. Furthermore, multivariate regression analysis showed that the oxygen duration was an independent risk factor for disease occurrence. In the early postnatal period, high oxygen can inhibit vascular growth, and then along with the occurrence of retinal hypoxia, vascular growth factor surges, leading to unregulated vascular proliferation^[11]. Many studies have shown that irregular oxygen inhalation may cause ROP^[12], including improper oxygen concentration, long oxygen duration and oxygen inhalation mode. Therefore, children should pay close attention to oxygen duration and oxygen concentration to ensure that oxygen partial pressure remains stable. Moreover, respiratory distress syndrome is closely related to oxygen duration. As the lung function of premature infants is not fully developed, it is easy to produce respiratory distress and apnea, and the decrease of arterial partial pressure of oxygen leads to the occurrence of hypoxia in children, so the oxygen inhalation treatment is required for children^[13]. However, ventilator-assisted therapy can promote the formation of many oxygen free radicals, studies have found that the antioxidant defense mechanism of human body can resist excessive oxygen free radicals, and retinal hypoxia can stimulate the release of vascular growth factor, which ultimately causes neovascularization and pathological changes^[14]. Our results showed that respiratory distress syndrome was significantly associated with disease occurrence in univariate regression analysis, but it was not an independent risk factor in multifactorial analysis. May be due to the cause of this changes in the way, but we did not focus on the research to the concentration of oxygen and oxygen inhalation mode in children with these two factors, because the research objects are who come to our hospital rather than born in our hospital, it is not clear for family members to tell the specific concentration and the mode about oxygen, so no good follow-up to these factors.

5.4 Correlation between ROP and other factors

It has been reported that anemia in premature infants is caused by insufficient Erythropoietin (EPO) secretion which results in impaired erythropoiesis and decreased hemoglobin concentration. EPO is an angiogenic factor associating with retinal vascular stability, Premature infants under hypoxia will stimulate the body to produce a large number of VEGF and also promote the release of EPO, and the two interactions generate retinal vascular hyperplasia^[15]. Lundgren found that the average EPO level with severe ROP was apparently higher on day 7 after birth than that of children with ROP who did not require treatment^[16]. Blood transfusion and anemia are closely related, there is a causal relationship between the two. Studies have shown that the increased incidence of ROP caused by blood transfusion may be due to the higher oxygen carrying capacity of adult hemoglobin than that of the fetus. Adult blood transfusion will generate more oxygen in the retina of the newborn, which is in a state of high oxygen. In addition, it will also lead to fluctuations in blood oxygen concentration, further cause the occurrence of ROP^[17]. Del.eg found that controlling the transfusion rate of premature infants can significantly reduce the occurrence of ROP^[18]. Our study showed that blood transfusion and anemia were significantly associated with disease occurrence and negatively correlated with disease severity in univariate regression analysis. Nevertheless, anemia and blood transfusion are not independent risk factors among the multiple factors, which may be due to the smaller data volume and the more accurate identification of factors with more significant effects, such as gestational age and birth weight. As a result, the correlation between anemia and blood transfusion and disease is reduced. However, screening for premature infants with a history of anemia and blood transfusion treatment cannot be neglected. In our subsequent studies, we will try to expand the sample size to further analyze these two factors.

In terms of feeding methods, our data have not found a remarkable correlation with disease, but some studies have shown that children who are breast-fed have a lower incidence than those who are formula fed. Because the absorption of taurine, vitamins and trace elements in breast milk is better than that of formula milk, immune proteins in breast milk can reduce the probability of infection and the occurrence of complications^[19].

5.5 Impact of COVID-19 on screening of children

ROP screening faced challenges during the 2020 coronavirus pandemic, such as preventing cross-infection, ensuring accuracy and timeliness for screening, and better communication with families. Our results show that 507 children were screened, 138 cases suffered from ROP, and 36 cases (7.1%) were treated from December 31 in 2016 to December 31 in 2019. A total of 207 preterm infants were screened after January1 in 2020, including 50 infants with ROP and 25 infants (12%) receiving treatment, of which 36 infants were treated after 8 weeks of birth or more than 37 weeks of corrected gestational age. The proportion of treatment increased from pre-pandemic 7.1–12%, among which 4 out of the 5 children receiving second treatment were all after the epidemic, and 3 of them could not accept treatment on time due to the epidemic, so timely screening is very important for premature infants. This also suggests that whether can use artificial intelligence auxiliary means, such as image analysis system, early diagnosis model and telemedicine, to provide convenient diagnosis and treatment conditions for those who cannot come to the hospital for screening due to objective factors, so as to guarantee that children can be screened on schedule, especially those with high risk factors. Since the outbreak of COVID-19, studies have shown that telemedicine has significant advantages in ophthalmology applications^[20]. In the future, we should also gradually use various artificial intelligence-assisted means to screen children, not only ensure timely diagnosis and treatment of children but also avoid cross-infection between doctors and patients.

5.6 Limitations

There are some limitations in this study. Firstly, Retcam 3 was officially introduced into our hospital in 2016. The overall screening time has just been over 6 years. Although it is the largest ROP screening and treatment institution in Heilongjiang Province, yet due to the constraints of overall regional economy and residents’ cognition, comprehensive and timely diagnosis or treatment has not been carried out in the whole region, and the number of premature infants included in the study is limited. Moreover, we included few risk factors, so we will further strengthen communication with neonatologists and fellow physicians in other hospitals in the future to record detailed information as far as possible. Gradually realize multi-center joint research, including more premature infants and related risk factors to improve research results and draw more comprehensive conclusions.

5.7 Summary

The 714 premature infants in this study had a high incidence of ROP, so timely screening of patients with high risk factors is particularly important. birth weight, gestational age and oxygen duration are closely related to the mobidity, and preterm infants with these three risk factors should be focused emphatically in future screening. While strengthening the propaganda work of disease screening and timely communicating with neonatologists, a comprehensive understanding of the related risk factors, for pediatricians think that newborn children with serious illness can appropriately expand the scope of screening, children with lower risk factors reduce the screening numbers, alleviate the pressure for the medical staff, remit the economic and psychological burden of patients and their families. Under the influence of COVID-19, we strive to provide convenient diagnosis and treatment conditions for children with artificial intelligence assisted diagnosis, so as to guarantee timely screen for children, at the same time to avoid cross-infection between doctors and patients.

Author Contribution

G.Xiao and Y.Gao wrote the main manuscript text;D.Zhang and Y.Fu acquisition and analysis of data;S.H.Zhang and Y.Y.Li revised it critically for important intellectual content;

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No competing interests reported.

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Analysis of pathogenic factors of retinopathy of prematurity in Heilongjiang Province

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Abstract

Figures

Background

Data and Method

Results

Discussion

5.1 Correlation between ROP and gestational age

5.2 Correlation between ROP and birth weight

5.3 Correlation between ROP and oxygen duration

5.4 Correlation between ROP and other factors

5.5 Impact of COVID-19 on screening of children

5.6 Limitations

5.7 Summary

Declarations

Author Contribution

References

Additional Declarations

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