Abstract
Aim
To investigate the association between retinopathy of prematurity and autism spectrum disorder in extremely preterm children.
Methods
Data in children born extremely preterm at <28 weeks’ gestational age in the Region Västra Götaland, 2013–2017, were analysed for association between retinopathy of prematurity and neurodevelopmental disorders. We focussed on autism spectrum disorder and excluded children with perinatal brain injuries or genetic disorders.
Results
Of 266 children with neurodevelopmental evaluation, 143 had no documented brain injury or genetic disorders. Of these 143, autism spectrum disorder was diagnosed in 18%, attention deficit hyperactivity disorder in 15% and intellectual disability in 7%. Of the 72/143 children with a history of no or mild retinopathy of prematurity (stage <1), 10% were diagnosed with autism spectrum disorder compared to 27% of 71/143 with prior moderate‐to‐severe retinopathy of prematurity (stages ≥2), (p = 0.008). A history of retinopathy of prematurity stages ≥2 was associated with a threefold increased likelihood of later autism spectrum disorder even when adjusting for gestational age and sex (p = 0.011).
Conclusion
Moderate‐to‐severe retinopathy of prematurity associated with a higher likelihood of later autism spectrum disorder diagnosis in extremely preterm children without documented brain injuries or genetic disorders.
Keywords: autism spectrum disorder, extremely preterm, neurodevelopmental disorders, perinatal brain injury, retinopathy of prematurity
Abbreviations
- ADHD
attention deficit hyperactivity disorder
- Anti‐VEGF
anti‐vascular endothelial growth factor
- ASD
autism
- CI
confidence interval
- GA
gestational age
- MRI
magnetic resonance imaging
- OR
odds ratio
- ROP
retinopathy of prematurity
Key points.
We evaluated the association between retinopathy of prematurity and autism spectrum disorders in extremely preterm infants.
Prior moderate‐to‐severe retinopathy of prematurity was associated with a tripled likelihood of a later autism spectrum disorder diagnosis in extremely preterm children without documented brain injuries or genetic disorders.
We emphasise the importance of early screening and assessment of autism spectrum disorder in extremely preterm children with a history of retinopathy of prematurity.
1. BACKGROUND
Autism spectrum disorder (ASD) is a neurodevelopmental condition characterised by deficits in social interaction and stereotypical and repetitive behaviour. 1 A combination of underlying vulnerability (genetics) and exogenous stress factors (pre and postnatal) during a critical period of brain development is suggested to contribute to the pathophysiology of ASD. 2 ASD is linked to both macroscopic and microscopic structural brain damage, and other neuropsychiatric comorbidities such as intellectual disabilities and attention‐deficit hyperactivity disorder (ADHD) are common, particularly in preterm infants. 3 , 4 , 5 , 6 , 7 , 8 , 9 Worldwide, ~1% of children are diagnosed with ASD, and some research suggest that the prevalence is rising. 10
Children born extremely preterm have a markedly increased risk for ASD and other neurodevelopmental disorders. A recent review reported ASD in 6%–20% of preterm children, 8 and of the children born before 24 weeks’ gestational age (GA), about one‐third had an ASD diagnosis. 4 Poor and abnormal brain development in extremely preterm children can be identified well before the onset of ASD. 3 , 9 This supports the notion of a vulnerable period in preterm infants during the third trimester of gestation when the brain undergoes rapid neuron development and growth. 11
Retinopathy of prematurity (ROP) is a developmental neurovascular disease of the eye, which primarily affects the most immature preterm infants. An early postnatal arrest and later abnormal growth of retinal blood vessels characterises ROP. In severe ROP, retinal neovascularisations may result in retinal detachment and blindness if not treated. Milder forms of ROP can regress spontaneously, usually around term‐equivalent age. 12 The retina is an extension of the central nervous system, sharing the same neuroectodermal embryological origin, development, functionality and immunology. 13 , 14 , 15 Structural changes in the retina and brain can be observed in children with previous ROP and are linked to neurodevelopmental impairments, indicating a shared origin of developmental issues. 14 , 15
In 1956, Keeler described autistic‐like patterns in five children who were blind due to ROP. 16 Since then, scattered reports have been published about the association between ROP and ASD. 3 , 9 , 17 This retrospective population‐based study comprises children born at <28 weeks’ GA in the Västra Götalands region in Sweden from 2013 to 2017. We aimed to evaluate an association between ROP and neurodevelopmental outcomes, such as ASD, ADHD and intellectual disabilities in extremely preterm children without documented brain injuries or genetic disorders, focussing on ASD.
2. PATIENTS AND METHODS
2.1. Study population and data retrieval
The study comprised of a Swedish cohort of children born at <28 weeks GA from January 2013 to December 2017 in the Västra Götalands region, Sweden. Children had completed screening for ROP close to term equivalent age. ROP outcomes and birth characteristics were retrieved from the Swedish National Register for Retinopathy of Prematurity. Swedish national guidelines recommend neurodevelopmental evaluation and follow‐up at 2 years of corrected age and 5.5 years for all children born <28 weeks’ GA. 18 The medical charts of all children were scrutinised with respect to neonatal characteristics, morbidities and neurodevelopmental assessments and diagnoses. Children with brain injuries, brain malformations or documented genetic disorders were excluded. We defined brain injuries as any grade of intraventricular haemorrhage, focal brain lesions (periventricular leukomalacia, hemorrhagic infarctions or cysts) or post‐hemorrhagic hydrocephalus detected by repeated ultrasound examinations or by magnetic resonance imaging (MRI) examination around term‐equivalent age.
2.2. Background characteristics and neonatal morbidities
Birthweight, sex and GA were recorded. GA was determined by ultrasound assessment at 17–18 weeks of gestation. Registered neonatal morbidities included bronchopulmonary dysplasia, defined as the need for supplemental oxygen at 36 weeks of postmenstrual age and necrotising enterocolitis stages 2–3 according to Bell et al. Perinatal brain injuries were recorded as listed above. Days with supplemental oxygen, as well as days with parenteral nutrition, were also recorded.
ROP screening was performed according to national guidelines and consisted of dilated ocular fundus examinations. All infants were examined repeatedly until complete retinal vascularisation or until spontaneous or post‐treatment regression of ROP. The revised International Classification of Retinopathy of Prematurity was used for classification, and the Early Treatment for Retinopathy of Prematurity Cooperative Group recommendations were followed for treatment. 19 , 20 We categorised ROP severity as ‘no or mild ROP’ when maximum was no ROP or ROP stage 1, ‘moderate ROP’ when maximum ROP was stage 2, and ‘severe ROP’ when maximum ROP was stages ≥3 and/or treated ROP. ROP treatments were laser and intravitreal injections with anti‐vascular endothelial growth factor (anti‐VEGF).
2.3. Neurodevelopmental disorders
Cerebral palsy was recorded based on International Classification of Diseases, Tenth Revision (ICD‐10) codes of G80.0‐G80.9 and epilepsy if codes G40.1–40.9 were used. Diagnosis of intellectual disability was based on ICD.10 codes (F70.0–72.9, 79.0–1 and 79.9) or on intelligence quotient <70 using the Wechsler Preschool and Primary Scale of Intelligence IV at 5.5 years of age. Diagnoses of neurobehavioral disorders ASD (F84.0) and ADHD (F90.0–90.9) were recorded.
2.4. Statistics
Numbers and percentages were given for categorical variables, and medians and ranges were used for continuous variables. Between‐group tests were performed using Fisher's exact tests, and Mantel–Haenszel's chi‐squared trend test for dichotomous and ordered categorical variables. The Mann–Whitney U‐test was used for continuous variables. The Hosmer–Lemeshow test tested goodness‐of‐fit for the logistic regression models and was found satisfactory. Binary logistic regression models were used to calculate the probability values for morbidities as odds ratios (OR) reported with a 95% confidence interval (CI). GA at birth and sex were included in a multivariable logistic regression as these factors strongly influence outcomes in preterm children. 5 Moreover, days of oxygen support was added to the list of adjustment variables due to its association with ROP and ASD. 12 , 21 , 22 , 23 Additionally, the association of oxygen support on ASD was studied stratified by no or mild ROP, moderate ROP and severe ROP. A p‐value <0.05 was considered statistically significant (two‐sided tests). All analyses were done with IBM SPSS Statistics for Windows, Version 25.0 (Armonk, NY, IBM Corp.) and SAS software version 9.4 (SAS Institute Inc., Cary, NC, USA).
2.5. Ethics
The Swedish Ethics Review Authority approved the study (D. nr 2021‐04926). The ethical review board granted a waiver of consent because parents were informed at their child's birth that data on ROP, neonatal and neurodevelopmental follow‐up would be collected and registered in the national registers and possibly used for research. Parents can have their child's data removed from the registers at any time.
3. RESULTS
Of the 287 children with completed ROP screening, 266 had a neurodevelopmental evaluation available. We found that 143/266 children had no brain injury, brain malformation or documented genetic disorder, and these were included in our main analyses regarding associations between ROP and neurodevelopmental outcomes. Of the 123 children excluded, 118 were diagnosed with intraventricular haemorrhage of any grade, 18 had hydrocephalus, 11 had a focal brain lesion, and five had a documented genetic disorder (Figure 1). Multiple children were diagnosed with more than one condition as the cause of their exclusion.
FIGURE 1.
Flow chart. *Multiple children had more than one diagnosis for exclusion.
3.1. Children's characteristics and neonatal morbidities
Table 1 presents the birth characteristics and neonatal morbidities of the children included stratified by ROP severity. The birth characteristics and neonatal morbidities of children with brain injuries or genetic disorders stratified by ROP severity are described in Table S1.
TABLE 1.
Birth characteristics, neonatal morbidities and neurodevelopmental disorders in children without documented brain injuries or genetic disorders stratified by ROP severity.
| Variables | All children (n = 143) | No ROP and mild ROP stage 1 (n = 72) | Moderate ROP stage 2 (n = 34) | Severe ROP stages ≥3 and ROP treatment (n = 37) |
|---|---|---|---|---|
| Birth characteristics | ||||
| Gestational age, median, (range), weeks |
26.4 (22.7–27.9) |
27.0 (22.7–27.9) |
26.4 (23.0–27.9) |
25.6 (22.9–27.9) |
| Birthweight, median, (range), grams |
880 (440–2080) |
948 (560–2080) |
840 (450–1890) |
690 (440–1025) |
| Sex, boys, % (n) | 52% (75/143) | 56% (40/72) | 47% (16/34) | 51% (19/37) |
| Neonatal morbidities | ||||
| Bronchopulmonary dysplasia, % (n) | 61% (87/143) | 49% (35/72) | 74% (25/34) | 73% (27/37) |
| Necrotising enterocolitis, % (n) | 6% (8/143) | 3% (2/72) | 6% (2/34) | 11% (4/37) |
| Days of oxygen support, median (range) | 57 (1–267) | 41 (1–138) | 76 (2–172) | 88 (1–267) |
| Days parenteral nutrition, median (range) | 13 (4–190) | 9 (4–31) | 15 (4–114) | 22 (5–190) |
| Neurodevelopmental disorders | ||||
| ASD, % (n) | 18% (26/143) | 10% (7/72) | 24% (8/34) | 30% (11/37) |
| ADHD, % (n) | 15% (22/143) | 14% (10/72) | 9% (3/34) | 24% (9/37) |
| Intellectual disability, % (n) | 7% (10/143) | 4% (3/72) | 18% (6/34) | 3% (1/37) |
| ASD, ADHD or intellectual disability, % (n) | 32% (45/143) | 25% (18/72) | 32% (11/34) | 43% (16/37) |
| Cerebral palsy, % (n) | 1% (2/143) | 3% (2/72) | 0% | 0% |
| Epilepsy, % (n) | 1% (2/143) | 0% | 0% | 5% (2/37) |
Abbreviations: ADHD; attention‐deficit hyperactivity disorder, ASD; autism spectrum disorder system, ROP; retinopathy of prematurity.
Of the 143 included children, 61% had a history of prior ROP (24% had moderate ROP, stage 2, and 26% had severe ROP, stages ≥3 and/or ROP treatment) (Table 1).
3.2. Neurodevelopmental disorders
Of the 143 children, 32% were diagnosed with ASD, ADHD and/or intellectual disability, and 29% of those had more than one diagnosis. ASD was diagnosed in 18%, ADHD in 15%, and intellectual disability in 7% (Table 1). Fifteen (10%) of the 143 children had not been examined at 5.5 years according to national guidelines; parents had declined examination, medical files were unavailable, and some had moved abroad. Those 15 children were examined at 2 years of corrected age. Four children (3%) were still under investigation for neurodevelopmental disorders.
Figure 2A shows the association between ROP severity and ASD diagnosis.
FIGURE 2.
Percentage of children with autism spectrum disorder stratified by prior retinopathy of prematurity severity (p = 0.007).
In Table S1, we present the characteristics, neonatal morbidities and neurodevelopmental disorders in children with brain injuries or documented genetic disorders.
3.3. Associations with ASD
We found a significant association between ROP severity and ASD. In univariable logistic regression, ROP stage ≥2 were significantly associated with ASD (OR 3.39, CI 95% 1.33 to 8.69, p = 0.011). Following adjustment for GA at birth and sex, ROP stage ≥2 persisted as an independent association variable for ASD (aOR 3.76 CI 95% 1.36–10.40, p = 0.011) (Table 2). Other significant predictors following adjustment for GA and sex were birthweight, aOR 0.87 per 50 g increase (95% CI 0.76–1.00), p = 0.044, days with oxygen support, aOR 1.09 per 1‐week increase (95% CI 1.01–1.19), p = 0.037, and ROP severity with increased OR with increased severity. Days with oxygen support is a known risk factor for ROP; in this cohort, aOR for ROP ≥ stage 2 was 1.33 per 1‐week increase (95% CI 1.18–1.50), p < 0.0001 (data not shown in table). Adding this variable as an additional adjustment in the ASD logistic model, including ROP ≥ stage 2, the two variables reduced each other's aOR to non‐significance, aOR for ROP ≥ stage 2 was 2.67 (95% CI 0.87–8.17), p = 0.085, and aOR for days with oxygen was 1.06 per 1‐week increase (95% CI 0.97–1.16), p = 0.23 (data not shown in a table). There was a tendency towards interaction between the two variables in their association with ASD (p = 0.17) showing lower association between oxygen support and ASD among children with ROP ≥ stage 2 than for those with no or mild ROP. Graphic presentation of estimated probability is shown in Figure 3.
TABLE 2.
Univariable and multivariable logistic regression and risk factors for ASD (n = 26) in extremely preterm children without documented brain injuries or genetic disorders (n = 143).
| Univariable model | GA and sex‐adjusted model* | |||||
|---|---|---|---|---|---|---|
| Values | n (%) events | OR (95% CI) | p‐value | OR (95% CI) | p‐value | |
| Gestational age (by 1‐week increase) | ≤median |
11 (15%) |
Reference | Reference | ||
| >median |
15 (22%) |
0.89 (0.63–1.26) |
0.51 |
0.86 (0.61–1.21) |
0.39 | |
| Birthweight (by 50 g increase) | ≤median |
15 (21%) |
Reference | Reference | ||
| >median |
11 (16%) |
0.90 (0.80–1.00) |
0.055 |
0.87 (0.76–1.00) |
0.044 | |
| Sex | Girl |
9 (13%) |
Reference | Reference | ||
| Boy |
17 (23%) |
1.92 (0.79–4.66) |
0.15 |
2.03 (0.83–4.97) |
0.12 | |
| Bronchopulmonary dysplasia | No |
7 (12%) |
Reference | Reference | ||
| Yes |
19 (22%) |
1.96 (0.76–5.01) |
0.16 |
1.77 (0.68–4.62) |
0.25 | |
| Necrotising enterocolitis | No |
23 (17%) |
Reference | Reference | ||
| Yes |
3 (38%) |
2.92 (0.65–13.09) |
0.16 |
2.60 (0.56–11.98) |
0.22 | |
| Days with oxygen support (by 1‐week increase) | ≤median |
6 (8.6%) |
Reference | Reference | ||
| >median |
19 (27.1%) |
1.10 (1.02–1.20) |
0.016 |
1.09 (1.01–1.19) |
0.037 | |
| Days on parenteral nutrition (by 1‐week increase) | ≤median |
8 (11.6%) |
Reference | Reference | ||
| >median |
17 (23.9%) |
1.10 (0.99–1.23) |
0.09 |
1.08 (0.96–1.21) |
0.19 | |
| ROP severity | No or ROP stage 1 |
7 (9.7%) |
Reference | Reference | ||
| ROP stage 2 |
8 (23.5%) |
2.86 (0.94–8.68) |
0.06 |
3.21 (1.02–10.07) |
0.045 | |
| ROP stage 3 and treatment |
11 (29.7%) |
3.93 (1.37–11.24) |
0.011 |
4.63 (1.40–15.38) |
0.012 | |
| ROP stage ≥2 | No |
7 (9.7%) |
Reference | Reference | ||
| Yes |
19 (26.8%) |
3.39 (1.33–8.69) |
0.011 |
3.76 (1.36–10.40) |
0.011 | |
| ROP treatment | No |
19 (16.1%) |
Reference | Reference | ||
| Yes |
7 (28.0%) |
2.03 (0.74–5.52) |
0.17 |
1.92 (0.59–6.22) |
0.28 | |
Note: *For association with GA, adjustment only for sex was done. For association with sex adjustment only for GA was done. Otherwise for all other variables adjustment was done for GA and sex.
Bold values represent statistically significant results.
Abbreviations: ASD; autism spectrum disorder, GA; gestational age, ROP; retinopathy of prematurity.
FIGURE 3.
Estimated probability for autism spectrum disorder depending on days of oxygen support if no/mild retinopathy of prematurity and moderate/severe ROP (ROP ≥ stage 2).
When evaluating ROP development in relation to ADHD and intellectual disability, we found no associations in preterm children with or without brain injuries or documented genetic disorders (data not shown).
4. DISCUSSION
In this retrospective study, we report a significant association between ASD and moderate‐to‐severe ROP in extremely preterm children without brain injuries or documented genetic disorders. We believe our results strongly support the hypothesis that a history of prior ROP may increase the likelihood of infants developing ASD, as we excluded children with documented brain injury and genetic disorders (with a possible increased susceptibility to ASD). Our findings underline the necessity for early screening, assessment, and diagnosis of ASD in preterm children with a previous history of moderate‐to‐severe ROP, to support their developmental potential and promote better functioning and quality of life.
Studies indicate that the prevalence of ASD is rising globally. 24 Whether this increase is due to greater recognition and diagnosis rather than an actual rise in the occurrence of ASD is unclear. A recent review including 71 studies reports a global median ASD prevalence of 1% (range 1%–4%), with males more often affected than girls (median male‐to‐female ratio was 4.2). 10 In our study, we did not find that sex affected outcomes statistically, although there were more boys with ASD. Perhaps, this is a result of a small sample size or that the male sex does not have the same impact in extremely preterm with respect to ASD. In the light of this report, our finding that approximately 20% of extremely premature children will develop ASD is of great importance and must be addressed in subsequent follow‐up care of extremely preterm children. Our results are in accordance with the literature. 4 , 5 , 6 , 8
Our study does not establish a causal relationship between ASD and ROP. However, several possible explanations may exist for the association. The retina is an extension of the central nervous system, 13 , 14 , 15 and although ROP was initially considered a vascular disease, ROP is now recognised as a neuroretinal disease triggered by astrocytes in a hypoxic retina. 25 , 26 Astrocytes and neuroinflammatory response are also hypothesised to play a major role in the development of ASD. 27 , 28 Thus, we speculate that astrocyte involvement in both ROP and ASD may be a potential connecting factor.
In our cohort, we saw a clear association between the number of days with oxygen support and ASD. Pre‐ and perinatal hypoxia has been associated with ASD. 21 It is suggested that hypoxia promotes the increase in reactive oxygen species and a reduction in antioxidant capacity, which has been detected in the brains of ASD patients. This can directly enhance neuroinflammation and cytokine release. We hypothesise that days of oxygen support may reflect increasing vessel loss and hypoxia. Fluctuating and high oxygen levels and prolonged oxygen support are well‐known risk factors with a high impact on ROP development. 12 , 22 Interestingly, when evaluating days of oxygen support, it was only a risk factor for those children with no or mild ROP, suggesting that the presence of more severe ROP overshadowed the days of oxygen support as a risk factor for ASD.
Another indication of a plausible connection between ASD and ROP is that both diseases are associated with reduced brain volumes. The third trimester, when severe ROP disease may occur, is an especially vulnerable period for fetal brain development. Altered brain volumes, particularly in the cerebellum and white matter, are associated with ROP. 29 In ASD, various brain alterations have been reported in the cerebellum, hippocampus and cerebral cortex. 7 Reduced brain development can be detected long before the onset of ASD in extremely preterm children. 3 , 9 Another way to estimate neural structure is to measure the retinal layers with optical coherence tomography. In patients with ASD, symptoms are associated with thinner macular and ocular nuclear layers in the retina. 30
The inflammatory component in both diseases may also be a plausible explanation for the association between ROP and ASD. Elevated inflammatory markers are well‐recognised biomarkers for ROP development, and in ASD, peripheral and local neuroinflammatory processes in the brain have been recognised. 31 , 32
In our study, we observed that more children who received ROP treatment developed ASD; however, this was not statistically significant, possibly due to a small sample size. All the children without brain injuries or documented genetic disorders had received laser treatment if needed. In recent years, ROP treatment with intravitreal anti‐VEGF has become more commonly used than laser treatment. The two strategies have similar effects on retinal pathological neovascularisation as they aim to reduce excessive VEGF in the retina. Laser obtains this effect through general destruction of the retinal layers, while anti‐VEGF injection directly affects VEGF concentrations. 15 ROP treatment is typically initiated several weeks postnatally (equivalent to the late third trimester), and the potential impact on the developing brain must be acknowledged, regardless of the treatment method. There have been concerns about the systemic effects of anti‐VEGF and indication of abnormal brain development and later neurodevelopmental impairment. 6 To our knowledge, no studies have addressed the impact of laser versus anti‐VEGF treatment for ROP in extremely preterm children in relation to ASD outcomes.
4.1. Limitations
This study's limitations include a relatively small population size and, as with all retrospective studies, the difficulty of demonstrating causation.
4.2. Strengths
The strengths of this study included scrutinising all patient records and an extensive follow‐up according to national guidelines, providing early and reliable diagnoses.
5. CONCLUSION
In this cohort, we evaluated extremely preterm children without brain injuries or documented genetic disorders, and we report a clear association with a history of prior moderate‐to‐severe ROP and later ASD diagnosis. Both diseases are considered to have a multifactorial background, and we speculate that ROP and ASD share similar pathophysiological features. The high prevalence of ASD in extremely preterm children underlines the necessity of guidelines for neurodevelopmental follow‐up and assessment, particularly in children with a previous history of moderate‐to‐severe ROP.
AUTHOR CONTRIBUTIONS
Pia Lundgren: Conceptualization; investigation; funding acquisition; writing – original draft; methodology; validation; visualization; writing – review and editing; formal analysis; project administration; supervision; software. Hanna B. K. Olsson: Validation; supervision; writing – review and editing; writing – original draft; investigation. Aldina Pivodic: Writing – original draft; writing – review and editing; formal analysis; supervision; methodology; conceptualization; investigation. Lena Jacobson: Writing – original draft; writing – review and editing; supervision; methodology. Liv Vallin: Writing – original draft; conceptualization; supervision; writing – review and editing; validation. Lois E. Smith: Writing – original draft; writing – review and editing; conceptualization; funding acquisition; supervision. Karin Sävman: Funding acquisition; writing – original draft; writing – review and editing; validation; supervision. Ann Hellström: Writing – original draft; funding acquisition; investigation; conceptualization; methodology; validation; writing – review and editing; supervision; project administration.
FUNDING INFORMATION
This study was supported by grants provided by the Gothenburg Medical Society, Frimurare Barnhusdirektionen, De Blindas Vänner, Carmen och Bertil Regnérs Stiftelse, Ögonfonden, Cronqvists stiftelse, Swedish Research Council (2015‐00810, 2016‐01131, and 2022‐01562), the Swedish state under the agreement between the Swedish government and the county councils—the ALF‐agreement (ALFGBG‐71971, ALFGBG‐812951, ALFGBG‐971188), The Wallenberg Clinical Scholars (KAW 2018.0310), the SciLifeLab & Wallenberg Data Driven Life Science Program (KAW 2020.0239), Dr. Reinhard Marcuses fond, Magnus Bergvalls stiftelse (2021‐04347), The Operational Healthcare Committee, Region Västra Götaland VGFOUREG‐982302, NIH EY017017, EY030904‐01, Boston Children's Hospital Intellectual and Developmental Disabilities Research Center (1U54HD090255), Massachusetts Lions Eye Foundation and The Royal Society of Arts and Sciences in Gothenburg.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflicts of interest.
Supporting information
Appendix S1. Supporting Information.
Lundgren P, Olsson HBK, Pivodic A, Jacobson L, Vallin L, Smith LE, et al. Increased risk of autism in extremely preterm children with a history of retinopathy of prematurity. Acta Paediatr. 2025;114:1161–1168. 10.1111/apa.17539
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Appendix S1. Supporting Information.