Abstract
Objective –
To determine the association of surgical necrotizing enterocolitis (NEC) and its timing, with the development and timing of retinopathy of prematurity (ROP).
Study design –
This was a secondary data analysis of 7,483 preterm infants from the Postnatal Growth and Retinopathy of Prematurity Study. Associations between infants with surgical NEC, early-onset surgical NEC (8–28 days), and late-onset surgical NEC (over 28 days) with ROP were evaluated using multivariable logistic regression models, controlling for birth weight, gestational age, small for gestational age status, chronic lung disease, intraventricular hemorrhage, hydrocephalus, patent ductus arteriosus, and periventricular leukomalacia.
Results –
Three-hundred fifty-six (4.8%) infants had surgical NEC, with 56% having early surgical NEC. Infants with surgical NEC had a higher risk of any ROP and severe ROP (adjusted OR 2.7 (95% CI 1.9–3.7) and 2.5 (95% CI 1.9–3.3), respectively, p<0.001) compared to infants without surgical NEC. Infants with early surgical NEC were at the highest risk of developing ROP and severe ROP (adjusted OR 3.1, (95% CI 2.1–4.8), and 3.3, (95% CI 2.3–4.7) respectively, p<0.001). Infants with late surgical NEC were also at increased risk of developing ROP and severe ROP (adjusted OR 2.1 (95% CI 1.3–3.4) and 1.9 (95% CI 1.3–2.8) respectively, p<0.001) compared to infants without surgical NEC.
Conclusion –
Infants with surgical NEC, especially early surgical NEC, are at higher risk of ROP and severe ROP.
Introduction
Necrotizing enterocolitis (NEC) is an inflammatory bowel necrosis seen in premature and critically ill neonates, particularly those born prior to 32 weeks gestation. It is a life-threatening condition that places surviving infants at increased risk of feeding difficulties, poor growth, multiple re-hospitalizations, and neurodevelopmental delay.1–3 Prior studies have shown that infants with surgical NEC (Bell Stage 34,5) have worse prognosis than those with medical NEC, including increased mortality and post-NEC complications.3,6 The etiology of NEC remains unclear; epidemiological studies suggest the causation to be complex and multifactorial, but NEC clearly begins with gut mucosal injury and is associated with an exaggerated inflammatory response.7,8
Histopathological studies of NEC lesions show prominent ischemic changes and inflammation,9 and animal studies have also shown disruption of intestinal microvasculature is involved in NEC.10 Abnormal vasculature is also noted in the retinae of premature infants who develop retinopathy of prematurity (ROP), which can lead to a range of visual impairments, including blindness. The etiology of ROP is thought to be related to hyperoxia and changes in insulin-like growth factor-1 (IGF-1) and other growth factors such as vascular endothelial growth factor (VEGF).11,12 Several studies have reported an increase in ROP in infants with NEC. 1,6,13,14 Clinically, infants develop NEC before the detection of ROP, however, the timing of NEC varies with some infants developing the disease earlier than others. We speculate that the timing of NEC, early versus later-onset, alters exposure duration to inflammatory cascades and growth factor expression by weeks to months in relation to ROP detection, resulting in differences in development and severity of ROP. Furthermore, early suppression of IGF-1 in patients with NEC may affect the pre-clinical phase of ROP development, leading to increased risk and severity of ROP.
Whether the timing of NEC affects ROP risk has not been evaluated. In this study, we sought to evaluate the association between surgical NEC and ROP in preterm infants, and to determine whether the timing of NEC is associated with risk and severity of ROP. We hypothesized that the timing of NEC determines the risk and severity of ROP. We posited that infants with early-onset surgical NEC (onset between 8–28 days of life) have increased incidence and severity of ROP compared to those with later-onset surgical NEC (onset after 28 days of life).
Understanding these associations can help with risk stratification for development of ROP, parental counseling, and provide additional insight into plausible mechanisms underlying the connection between NEC and increased ROP risk.
Materials and Methods
We performed a secondary analysis of data from the Postnatal Growth and Retinopathy of Prematurity (G-ROP) study. The G-ROP Study was a multicenter, retrospective cohort study of infants who underwent ROP screening at twenty-nine hospitals in North America. Detailed methods of the G-ROP study are published elsewhere, but a summary is provided here15. Briefly, screened infants were born between January 1, 2006 and December 31, 2011, underwent serial ROP examinations, and had a known ROP outcome. In general, infants had a birth weight less than 1501 grams, or were less than 30 weeks gestational age, although more mature infants were included in screening if they were considered at-risk for ROP by a neonatologist due to clinical instability. Data on demographic characteristics and hospital morbidities were collected for all screened infants including cranial imaging abnormalities, chronic lung disease (oxygen requirement at 36 weeks post-menstrual age, PMA), and patent ductus arteriosus. If applicable, a diagnosis of NEC and bowel surgery were recorded.
Patient population
Institutional Review Board approval for the G-ROP study was obtained at all study sites, with waiver of informed consent.
Included infants with surgical NEC were defined as those with a diagnosis of NEC and bowel surgery beyond the first week of life. Infants with bowel surgery prior to 8 days of age were excluded, regardless of diagnosis, as these children more likely had a spontaneous intestinal perforation (SIP). Because of variability in practice and diagnosis, information on medical NEC was not collected. Early surgical NEC was defined, for this study, as an onset of NEC that occurred from 8 to 28 days of age; late surgical NEC was defined by NEC onset occurring after 28 days of age. We chose the cut-off of 28 days to capture a period accounting for longer exposure duration between development of NEC and detection of ROP, and to overlap with the general timing of pre-clinical ROP development.
Data from all ophthalmologic examinations for ROP was documented until retinal vascular maturity or disease regression. A known ROP outcome was defined as development of Early Treatment of ROP Study type 1 or type 2 pre-threshold ROP16, or ROP treatment in either eye; or retinal vasculature maturity, immature vasculature extending into zone III without prior disease in zone I or II; or regression of ROP not reaching criteria for type 1 or 2 ROP, in both eyes. Severe ROP is defined as type 1 or 2 ROP in either eye.
Statistical Analysis
Comparison between infants with versus without surgical NEC were made using two-sample t-test for means and chi-square test for proportions. Univariable logistic regression models and multivariable logistic regression models were used to assess associations of surgical NEC with any ROP and severe ROP. The multivariable models were adjusted by birth weight, gestational age, small for gestational age (SGA) status, chronic lung disease (CLD), intraventricular hemorrhage, hydrocephalus, patent ductus arteriosus, and periventricular leukomalacia. We adjusted for these characteristics and co-morbidities because of their association with both with NEC and ROP.1,17–20 We chose CLD rather than other measures of respiratory status as it is a dichotomous measure with an accepted definition and could be reliably collected. The odds ratios (OR) and their 95% confidence intervals (CI) from logistic regression models were computed. Similar analyses were performed for associations of early surgical NEC and late surgical NEC with ROP and severe ROP. All statistical analyses were performed in SAS v9.4 (SAS Institute Inc., Cary, NC, USA), and two-sided p<0.05 was considered to be statistically significant.
Results
There were 7,483 infants in the G-ROP study, of which 7,372 infants were included in this analysis after excluding 110 infants with a diagnosis at less than 8 days of life and 1 infant with an unknown surgical NEC date. Out of the 7,372 infants in the analytic sample, 356 (4.8%) were recorded to have developed surgical NEC after the first week of life; 200 (56%) infants developed surgical NEC between 8 and 28 days of life (early surgical NEC), and 156 (44%) infants developed surgical NEC after 28 days of life (late surgical NEC). The mean (SD) PMA of infants at onset of surgical NEC was 29.8 (3.1) weeks (range 23–36 weeks).
Table 1 shows a comparison of demographic and clinical characteristics between infants with surgical NEC versus those without surgical NEC and those with early versus late surgical NEC. Infants with surgical NEC were more likely to have a lower birth weight, younger gestational age, be male, be outborn than those without surgical NEC (all p<0.001). There was no significant difference between the two groups in SGA status, defined as birth weight less than 10th percentile. Co-morbidities including chronic lung disease, severe intraventricular hemorrhage (Grades III or IV), hydrocephalus, patent ductus arteriosus, and periventricular leukomalacia occurred more frequently among those with surgical NEC than those without surgical NEC (all p<0.001). Infants with early surgical NEC were more likely to be of higher birth weight and gestational age than those with late surgical NEC. There was no difference in co-morbidities between the early and late surgical NEC groups.
Table 1:
Demographic and clinical characteristics of infants with vs. without surgical NEC and with early vs. late surgical NEC.
| Without surgical NEC (N=7016) | With surgical NEC (N=356) | P-valuea | Early surgical NEC (N=200) | Late surgical NEC (N=156) | P-valueb | |
|---|---|---|---|---|---|---|
|
| ||||||
| Birth weight (grams) | <0.001 | 0.02 | ||||
| Mean (SD) | 1114 (363) | 870 (284) | 902 (292) | 829 (268) | ||
| Range | 364–3000 | 370–1846 | 387–1846 | 370–1716 | ||
| Gestational age (weeks) | <0.001 | 0.005 | ||||
| Mean (SD) | 28.2 (2.6) | 26.1 (2.3) | 26.4 (2.5) | 25.7 (1.9) | ||
| Range | 22–35 | 22–34 | 22–34 | 22–30 | ||
| Gender: Female (%) | 3405 (48.5%) | 134 (37.6%) | <0.001 | 70 (35.0%) | 64 (41.0%) | 0.24 |
| Maternal ethnicity: Hispanic or Latino (%) | 524 (7.5%) | 33 (9.3%) | <0.001 | 16 (8.0%) | 17 (10.9%) | 0.57 |
| Maternal race: n (%) | <0.001 | 0.72 | ||||
| White/Caucasian | 3426 (48.8%) | 145 (40.7%) | 84 (42.0%) | 61 (39.1%) | ||
| Black/African American | 2160 (30.8%) | 112 (31.5%) | 62 (31.0%) | 50 (32.1%) | ||
| Asian/Asian American | 222 (3.2%) | 8 (2.2%) | 4 (2.0%) | 4 (2.6%) | ||
| American Indian/Alaskan Native | 37 (0.5%) | 3 (0.8%) | 1 (0.5%) | 2 (1.3%) | ||
| Native Hawaiian/Other Pacific Islander | 90 (1.3%) | 3 (0.8%) | 3 (1.5%) | 0 (0.0%) | ||
| Other | 471 (6.8%) | 42 (11.8%) | 22 (11.0%) | 20 (12.8%) | ||
| Unknown | 610 (8.7%) | 43 (12.1%) | 24 (12.0%) | 19 (12.2%) | ||
| Birth location: Inborn (%) | 5310 (75.7%) | 151 (42.4%) | <0.001 | 91 (45.5%) | 60 (38.5%) | 0.18 |
| Small for gestational age: Yes (%) | 938 (13.4%) | 40 (11.2%) | 0.25 | 25 (12.5%) | 15 (9.6%) | 0.39 |
| Chronic lung disease: Yes (%) | 2400 (34.2%) | 223 (62.6%) | <0.001 | 116 (58.0%) | 107 (68.6%) | 0.12 |
| Intraventricular hemorrhage (Grade III or IV): Yes (%) | 556 (7.9%) | 76 (21.3%) | <0.001 | 43 (21.5%) | 33 (21.2%) | 0.73 |
| Hydrocephalus: Yes (%) | 342 (4.9%) | 33 (9.3%) | <0.001 | 21 (10.5%) | 12 (7.7%) | 0.65 |
| PDA: Yes (%) | 3053 (43.5%) | 223 (62.6%) | <0.001 | 120 (60.0%) | 103 (66.0%) | 0.49 |
| PVL: Yes (%) | 297 (4.2%) | 39 (11.0%) | <0.001 | 24 (12.0%) | 15 (9.6%) | 0.75 |
| PMA at NEC (weeks) | <0.001 | |||||
| Mean (SD) | 29.8 (3.1) | 28.3 (2.8) | 31.8 (2.2) | |||
| Range | 23–36 | 23–36 | 27–36 | |||
From two-sample t-test for comparison of means and chi-square test for comparison of percentages.
SD: Standard deviation; PDA: Patent ductus arteriosus; PVL: periventricular leukomalacia; PMA: post-menstrual age.
The associations of history and timing of surgical NEC with ROP and severe ROP are shown in Table 2. Compared to infants without surgical NEC, infants with surgical NEC were more likely to develop any ROP (79.5% vs. 40.9%, p<0.001), severe ROP (39.3% vs. 10.9%, p<0.001), type 1 ROP (22.2% vs. 5.2%), and type 2 ROP (17.1% vs. 5.7%) (p<0.001). However, there were no significant difference between patients with early surgical NEC and late surgical NEC with regards to the incidence of ROP (p=0.43) or severe ROP (p=0.46). The infants with surgical NEC developed ROP slightly later than infants without surgical NEC in terms of both PMA (mean 35.7 vs. 35.2 weeks, p=0.006) and chronological age (mean 72.9 vs. 63.5 days of life, p<0.001). There was no significant difference in the timing of severe ROP between infants with versus without surgical NEC.
Table 2:
Association of surgical NEC and timing of surgical NEC with incidence, severity and timing of ROP.
| Surgical NEC | Timing of surgical NEC | |||||
|---|---|---|---|---|---|---|
|
|
||||||
| Without surgical NEC (N=7016) | With surgical NEC (N=356) | P-valuea | Early NEC (N=200) | Late NEC (N=156) | P-valuea | |
|
| ||||||
| ROP | <0.001 | 0.43 | ||||
| No | 4145 (59.1%) | 73 (20.5%) | 44 (22.0%) | 29 (18.6%) | ||
| Yes | 2871 (40.9%) | 283 (79.5%) | 156 (78.0%) | 127 (81.4%) | ||
| Severe ROP | <0.001 | 0.46 | ||||
| No | 6252 (89.1%) | 216 (60.7%) | 118 (59.0%) | 98 (62.8%) | ||
| Yes | 764 (10.9%) | 140 (39.3%) | 82 (41.0%) | 58 (37.2%) | ||
| Type of ROP | <0.001 | 0.58 | ||||
| Type I | 365 (5.2%) | 79 (22.2%) | 46 (23.0%) | 33 (21.2%) | ||
| Type II | 399 (5.7%) | 61 (17.1%) | 36 (18.0%) | 25 (16.0%) | ||
| ROP not Type I or II | 2107 (30.0%) | 143 (40.2%) | 74 (37.0%) | 69 (44.2%) | ||
| No ROP | 4145 (59.1%) | 73 (20.5%) | 44 (22.0%) | 29 (18.6%) | ||
| PMA at ROP (weeks) | 0.006 | 0.38 | ||||
| Mean (SD) | 35.2 (2.7) | 35.7 (2.8) | 35.8 (2.9) | 35.5 (2.7) | ||
| Range | 30–49 | 30–46 | 30–46 | 31–43 | ||
| Day of life at ROP | <0.001 | 0.99 | ||||
| Mean (SD) | 63.5 (21.6) | 72.9 (20.3) | 72.9 (21.3) | 72.9 (19.1) | ||
| Range | 12–160 | 24–135 | 29–135 | 24–129 | ||
| PMA at severe ROP (weeks) | 0.28 | 0.40 | ||||
| Mean (SD) | 36.8 (3.0) | 36.5 (2.9) | 36.7 (3.0) | 36.3 (2.8) | ||
| Range | 30–49 | 31–46 | 31–46 | 31–42 | ||
| Day of life at severe ROP | 0.86 | 0.91 | ||||
| Mean (SD) | 83.5 (20.3) | 83.8 (18.3) | 83.9 (18.8) | 83.6 (17.7) | ||
| Range | 31–160 | 53–135 | 54–135 | 53–129 | ||
From two-sample t-test for comparison of means and chi-square test for comparison of percentages.
SD: Standard deviation; PMA: post-menstrual age.
Multivariable analyses for associations of history and timing of surgical NEC with ROP and severe ROP after adjusting for birth weight, gestational age, and significant comorbidities are shown in Table 3. Surgical NEC was associated with significantly increased risks of ROP (OR=2.7, 95% CI: 1.9–3.7) and severe ROP (OR=2.5, 95% CI: 1.9–3.3) compared to those without surgical NEC. Infants with early onset surgical NEC were at even higher risk of developing ROP (OR 3.1, 95%CI: 2.1–4.8) and severe ROP (OR=3.3, 95% CI: 2.3–4.7), but infants with late surgical NEC were also at increased risk of ROP (OR = 2.1, 95% CI: 1.3–3.4) and severe ROP (OR=1.9, 95% CI: 1.3–2.8) compared to those without surgical NEC.
Table 3:
Univariable and multivariable analysis for the association of surgical NEC with ROP and severe ROP
| Univariable analysis | Adjusted analysis a | |||||
| N | ROP (%) | OR (95% CI) | p-value | OR (95% CI) | p-value | |
|
| ||||||
| Surgical NEC | <0.001 | <0.001 | ||||
| No | 7016 | 2871 (40.9%) | ||||
| Yes | 356 | 283 (79.5%) | 5.60 (4.31, 7.27) | 2.65 (1.92, 3.65) | ||
| Time of surgical NEC | <0.001 | <0.001 | ||||
| No surgical NEC | 7016 | 2871 (40.9%) | ||||
| Early surgical NEC | 200 | 156 (78.0%) | 5.12 (3.65, 7.18) | 3.14 (2.05, 4.82) | ||
| Late surgical NEC | 156 | 127 (81.4%) | 6.32 (4.21, 9.49) | 2.11 (1.31, 3.39) | ||
|
|
||||||
| N | Severe ROP (%) | OR (95% CI) | p-value | OR (95% CI) | p-value | |
| Surgical NEC | <0.001 | <0.001 | ||||
| No | 7016 | 764 (10.9%) | ||||
| Yes | 356 | 140 (39.3%) | 5.31 (4.23, 6.65) | 2.52 (1.92, 3.31) | ||
| Time of Surgical NEC | <0.001 | <0.001 | ||||
| No surgical NEC | 7016 | 764 (10.9%) | ||||
| Early surgical NEC | 200 | 82 (41.0%) | 5.69 (4.25, 7.61) | 3.28 (2.28, 4.70) | ||
| Late surgical NEC | 156 | 58 (37.2%) | 4.84 (3.47, 6.76) | 1.86 (1.26, 2.75) | ||
Adjusted by birth weight, gestational age, small for gestational age, chronic lung disease, intraventricular hemorrhage, hydrocephalus, patent ductus arteriosus, and periventricular leukomalacia. OR: odds ratio; CI: confidence interval.
Discussion
We found an association between surgical NEC and ROP in a large multicenter cohort of over 7,300 preterm infants. Independent of birth weight, gestational age, and other significant comorbidities, infants with surgical NEC were at increased risk of both ROP and severe ROP. Moreover, infants with early-onset surgical NEC occurring between postnatal days 8–28 had the highest increased risk of ROP and severe ROP compared to infants without surgical NEC. Infants with late-onset NEC were also at an increased risk of ROP and severe ROP.
Other studies have reported an increased risk of ROP in infants with NEC. Shah et al. evaluated neonatal outcomes after intestinal perforation in a retrospective study of infants admitted to Canadian neonatal intensive care units. Among their secondary outcomes, the authors reported an increased risk of severe ROP among infants with SIP (n=178) compared to infants without SIP or NEC (adjusted OR 3.14, 95% CI 1.88–5.26) and increased risk of severe ROP among infants with intestinal perforation from SIP or NEC (n=424) compared to infants without SIP or NEC (adjusted OR 2.92, 95% CI 2.03–4.18).6 However, the associations between severe ROP and surgical NEC, and the association between surgical NEC and any stage ROP were not reported. In another retrospective study evaluating neurodevelopmental outcomes in 449 infants with surgical NEC, Fullerton et al. reported that 32% of infants with surgical NEC had severe ROP compared to 21% of infants with medical NEC and 16% of infants without NEC.1 Our large study confirms the association of surgical NEC with both ROP and severe ROP, in addition to stratifying ROP risk based on timing of surgical NEC.
Infants with surgical NEC in our cohort were more likely to have been born at a younger gestational age and with smaller birth weight than those without surgical NEC, both of which are known risk factors for NEC and ROP.21–23 Interestingly, infants in our cohort who were SGA were not more likely to develop NEC, which is contrary to prior studies.24,25 This may be due to our comparatively larger cohort of preterm infants versus prior studies, or due to variability in the definition of SGA status among studies; for example, Wold et al. defined SGA as birth weight less than 5th percentile for gestational age.25 We did not collect data on intrauterine growth restriction and were unable to assess it as an independent predictor of surgical NEC or ROP in our study.
The mechanism for an increased risk of ROP in patients with NEC cannot be determined by this study. However, some mechanisms may be hypothesized. Infants with NEC are usually critically ill and might have needed more aggressive respiratory support including mechanical ventilation and higher exposure to oxygen and swings in oxygen tension, all of which may contribute to increased ROP risk. Infants with early-onset NEC may be more clinically ill from other complications of prematurity and may have additional supplemental oxygen exposure and respiratory requirements at time of diagnosis than infants with later-onset NEC. The timing of exposure and illness severity related to other factors besides NEC may have a role in ROP development, and we attempted to mitigate this by controlling for other co-morbidities of prematurity.
Other factors may also be at play; NEC often precedes the development or detection of ROP13,26, and it is plausible that inflammatory cascades driven by the underlying pathophysiology of NEC may have a role in the increased risk of ROP. Several inflammatory factors are involved in the causation of both NEC and ROP.27,28 Animal studies have also shown that several systemic inflammatory pathways can disrupt retinal vascular development.29,30 Another potential contributing mechanism may involve microvasculature injury in the gut mucosa and the retina. Growth factors such as VEGF and IGF-1, or nutritional factors may be altered in NEC, and such effects may increase the risk of ROP in these patients. In particular, decreased serum levels of IGF-1 are associated with the subsequent development of ROP, because IGF-1 plays a permissive role in VEGF-mediated retinal growth31,32, so NEC-associated suppression of IGF-1 is another plausible mechanism connecting NEC and ROP. Interestingly, when slow postnatal weight gain, which is a surrogate measure for low serum IGF-1, is included in multivariable models of ROP risk, many suspected risk factors for ROP including NEC lose their significance.33 Of note, there is evidence that feeding with human milk decreases the incidence of both ROP and NEC.34,35 In this study, we did not analyze feeding type as a confounder with respect to NEC, ROP, and the timing of the diseases.
There was an overall increased risk of ROP including severe ROP in infants with early surgical NEC. This is interesting given that these infants were of slightly older gestational age than those with late NEC (26.4 vs. 25.7 weeks). Although these differences are likely multifactorial, the pathophysiology of early and late surgical NEC may differ. Perhaps there are differences in the inflammatory cascades of the two diseases reflecting prenatal and postnatal inflammation that contribute to the varying ROP risk. Alternatively, the increased risk with early surgical NEC may relate to the pathogenesis of ROP, which occurs in two phases: an early, pre-clinical phase of poor vascular growth due to hyperoxia and low serum IGF-1 levels, and a later clinically-visible phase of pathological vascular growth.36 In this model, suppression of retinal vascular development resulting from inflammatory mediators and decreased IGF-1 production, due to NEC, would be expected to have a greater effect in the first phase of ROP, while the second phase of ROP is driven primarily by hypoxia-induced VEGF production by the developing retina, which may be less affected by NEC-related changes.
Limitations of the current study include the definition of surgical NEC in our cohort, which may include infants who developed a SIP that required surgery after the first 7 days of life, rather than purely surgical NEC. Given that these are two separate conditions with different pathogenesis37,38, there may be a different association with ROP; however, it is likely that the included number of patients with SIP is small. Additionally, this study does not include patients with medical NEC who contribute significantly to the overall incidence of the disease in premature infants. It is unknown specifically how medical NEC and its timing is associated with ROP. Patients with medical NEC often require a lower number of medical interventions than those with surgical NEC, so this could change the relationship with ROP. However, given that patients with medical NEC are included in the comparison group of infants without surgical NEC in our study, excluding them would potentially make the relationship stronger between surgical NEC and ROP. Finally, the definition of early vs late-onset NEC was defined in our study using a cut-off of 28 days, and we felt this was reasonable in this study evaluating the association between NEC and ROP. However, we note other studies have defined this cut-off differently. For example, Yee et. al39 used a cut-off of 14 days to define early- and late-onset NEC in their study evaluating the incidence and timing of NEC.
Ultimately, infants who developed surgical NEC had an increased risk for development of any ROP and severe ROP compared to infants without surgical NEC, regardless of gestational age, birth weight, and multiple other factors. When evaluating infants with surgical NEC, those with early-onset surgical NEC were at the highest risk for developing ROP compared to those without surgical NEC. Early surgical NEC may serve as an additional predictor for the development of ROP in preterm infants and is important in parental counseling for patients recovering from surgical NEC. Future studies should address the mechanisms behind this differential risk, and ultimately the possibility of targeted therapies in these patients.
Key Points.
Infants with surgical NEC are at higher risk of ROP and severe ROP than those without surgical NEC.
Increased ROP risk is seen in infants with both early- or later-onset surgical NEC.
Early-onset surgical NEC is associated with a higher ROP risk compared to later-onset surgical NEC.
Acknowledgements
We would like to acknowledge Dr. Raul Chavez-Valdez for support in reviewing this manuscript.
Financial support:
Supported by NIH grants T32HD044355, 1R01EY021137-01A1 and 1R21EY029776-01, R01 HL133022, R01 HL124078 and the Richard Shafritz Chair in Ophthalmology Research.
Footnotes
The authors have no potential conflicts of interest to disclose.
Contributor Information
Jennifer B. Fundora, Division of Neonatology, Johns Hopkins University School of Medicine, Baltimore, MD.
Gil Binenbaum, Division of Ophthalmology, Children’s Hospital of Philadelphia, Philadelphia, PA.
Lauren Tomlinson, Division of Ophthalmology, Children’s Hospital of Philadelphia, Philadelphia, PA.
Yinxi Yu, Center for Preventative Ophthalmology and Biostatistics, Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.
Gui-shuang Ying, Center for Preventative Ophthalmology and Biostatistics, Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.
Akhil Maheshwari, Co-convener, Global Newborn Society.
Pamela Donohue, Division of Neonatology, Johns Hopkins University School of Medicine, Baltimore, MD and Department of Population, Family, and Reproductive Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
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