Retinal hemorrhages in preterm infants occur at a rate of around 10% to 12%, roughly half that of term infants.1,2 Most commonly these are benign, self-resolving, and thought to be due to birth trauma; less commonly, they can signify intracranial processes, ongoing trauma (including non-accidental trauma), ocular (eg, retinopathy of prematurity [ROP], Coat's disease, persistent fetal vasculature), or systemic disease (eg, infectious, hematologic or cardiovascular disorder).1 Here we present a preterm infant with unexplained and progressive retinal hemorrhages thought to represent delivery-associated retinopathy and intracranial hemorrhages, which is an underrecognized entity that has been previously described in term infants.3
An 8-day-old male infant born premature at 31 weeks and 6 days and weighing 1,420 grams was referred for dilated fundus exam. He was born via induced vaginal delivery for elevated blood pressure, abdominal pain, proteinuria, and fever in the mother. The delivery was uneventful, and he was placed immediately on continuous positive airway pressure (CPAP), briefly transitioned to positive pressure ventilation for 3 minutes, then continued on CPAP and weaned to room air on Day 3. On Day 3, he was noted to have an elevated direct bilirubin representing cholestatic jaundice; a workup revealed a positive cytomegalovirus (CMV) polymerase chain reaction from peripheral blood thought to be the cause, and he received intravenous ganciclovir (Zirgan; Bausch + Lomb, Rochester, NY) 6 mg/kg twice per day for 14 days followed by oral valganciclovir 16 mg/kg. There were no intracranial calcifications, and the hearing test was normal. A dilated fundus exam was requested on Day 8 (corrected gestational age [CGA]: 33 weeks). The exam revealed zone II immature vasculature without evidence of plus disease or ROP and 360° equatorial large (2 disc diopter) preretinal hemorrhages with more rare intraretinal hemorrhages in both eyes. The right eye had a subretinal hemorrhage inferotemporally. There was no obvious retinitis associated with these hemorrhages, though there was bilateral temporal whitening felt to be consistent with immature retina. The hemorrhages initially improved, but on Day 28 (CGA: 35 weeks, 6 days) he was found to have a new preretinal hemorrhage at the fovea of the right eye and again on Day 30 another hemorrhage along the superotemporal arcade of the right eye despite undetectable CMV viral load at this time (Figures 1A and 1B, respectively).
Worsening retinal hemorrhages in the right eye. (A) Day 28 of life (corrected gestational age [CGA]: 35 weeks, 6 days); bedside fundus photo of the right eye shows new hemorrhages in the posterior pole of the right eye. (B) Day 30 of life (CGA: 36 weeks, 1 day); bedside fundus photos of the right eye shows a new hemorrhage along the superior arcade.
As the exam was not consistent with CMV retinitis, an extensive infectious and coagulopathy workup was initiated with the help of the infectious disease and hematology teams (Table 1). A progressive anemia was noted and felt to be normal anemia of the newborn as well as related to repeated blood draws. The toxoplasmosis immunoglobulin G was positive and felt to represent maternal antibodies. The remainder of the results were normal. The infant was under the care of the neonatal intensive care unit, and there was no ongoing trauma. An exam under anesthesia on Day 34 (CGA: 36 weeks, 5 days) with fluorescein angiography of both eyes revealed improving hemorrhages in both eyes (Figure 2A), normal perfusion of immature vasculature, blockage from preretinal and intraretinal hemorrhages, and no evidence of leakage to suggest vasculitis, retinitis, or neovascularization (Figure 2B). An infant brain ultrasound at this time revealed a new grade 1 germinal matrix hemorrhage and magnetic resonance imaging (MRI)/magnetic resonance venography revealed a small subarachnoid hemorrhage (SAH) within the right superior frontal sulcus with normal cerebral vasculature (Figure 3). A diagnosis of simultaneous subarachnoid hemorrhage and multilaminar vitreoretinal hemorrhages was made.
Laboratory and Radiologic Workup for Premature Infant With Bilateral Retinal Hemorrhages
Examination under anesthesia and fluorescein angiography on Day 34 of life (corrected gestational age: 36 weeks, 5 days). (A) RetCam fundus photos showing preretinal hemorrhages in the posterior pole and a subretinal hemorrhage along the inferotemporal arcade (right eye, left panel, dotted circle and arrow) and a partially dehemoglobized preretinal hemorrhage along the inferotemporal arcade (left eye, right panel). There is an unusual reflection on RetCam imaging of the left macula that represents artifact and not hemorrhage as is corroborated by fluorescein angiogram. (B) Fluorescein angiography shows no evidence of vasculitis or neovascularization.
Susceptibility-weighted magnetic resonance imaging showing subarachnoid hemorrhage. Small dark linear foci in the superior frontal sulcus indicate subarachnoid hemorrhage (arrows).
The prevalence of neonatal intracranial hemorrhage (ICH) is high in premature infants, and estimates range from 25% to 40% in those born at less than 32 weeks gestation.4–6 Most commonly these hemorrhages are intra- or periventricular, whereas SAH is less common.7 SAH is often asymptomatic and is thought to be due to compression during vaginal delivery causing intraventricular hemorrhage that tracks into the subarachnoid space. Less commonly, SAH is due to vascular and coagulopathic abnormalities.8
Benign retinal hemorrhages in premature infants are not uncommon (around 10% incidence), but typically the hemorrhages are small and resolve within the first 2 weeks of life.2 In this case, the progressive and profound nature of the hemorrhages prompted further workup. The concurrence of retinal hemorrhage and ICH in preterm infants has been described by others in a small case series, but all of these cases represented minor hemorrhages that resolved within 10 days. Furthermore, the ICH was intraventricular, which is much more common than SAH.2 Moshfeghi et al. described a term infant with SAH and bilateral multilaminar hemorrhages and discussed whether an appropriate description is “delivery-associated retinopathy and intracranial hemorrhages.”3
We considered that this case may represent a rare form of Terson syndrome. Terson syndrome refers to retinal or vitreous hemorrhage with ICH. The syndrome was first described by the German ophthalmologist Litten in 1881 as vitreous hemorrhage occurring with subarachnoid hemorrhage.9 Terson later (and independently) expanded the definition to include any intracranial hemorrhage accompanied by vitreous hemorrhage.10 Now, we know that the retinal hemorrhages are often multilaminar and can include subretinal, intraretinal, preretinal, and vitreous hemorrhage.11 The mechanism of Terson syndrome is felt to be transmission of intracranial pressure to the optic nerve sheaths and thereby the retinal vasculature. In the case we describe here, the MRI had no evidence of elevated intracranial pressure and there were no bulging fontanelles; therefore, the term coined by Moshfeghi is more appropriate. Hypothetically the mechanism involves compression-decompression changes that happen during vaginal delivery, but the mechanism of ongoing hemorrhages is not clear.
In summary, we described a case of simultaneous SAH with diffuse and progressive preretinal hemorrhages in a preterm male with extensive workup that ruled out other etiologies. Though he incidentally tested positive for CMV, the hemorrhages were not consistent with retinitis and they worsened despite viral control. Delivery-associated retinopathy and intracranial hemorrhages is likely an underrecognized mechanism of retinal hemorrhage in the premature infant. The recommended management is conservative with serial exams to ensure resolution of the hemorrhages, and vitrectomy should be reserved for cases where there is a high concern for amblyopia or retinal traction.
- Ju R-H, Ke X-Y, Zhang J-Q, Fu M. Outcomes of 957 preterm neonatal fundus examinations in a Guangzhou NICU through 2008 to 2011. Int J Ophthalmol. 2012;5(4):469–472. doi:10.3980/j.issn.2222-3959.2012.04.12 [CrossRef] PMID:22937507
- Anteby II, Anteby EY, Chen B, Hamvas A, McAlister W, Tychsen L. Retinal and intraventricular cerebral hemorrhages in the preterm infant born at or before 30 weeks' gestation. J AAPOS. 2001;5(2):90–94. doi:10.1067/mpa.2001.113841 [CrossRef] PMID:11304816
- Moshfeghi DM. Terson Syndrome in a Healthy Term Infant: Delivery-Associated Retinopathy and Intracranial Hemorrhage. Ophthalmic Surg Lasers Imaging Retina. 2018;49(10):e154–e156. doi:10.3928/23258160-20181002-20 [CrossRef] PMID:30395678
- Huang Y-F, Chen W-C, Tseng J-J, Ho ES-C, Chou M-M. Fetal intracranial hemorrhage (fetal stroke): report of four antenatally diagnosed cases and review of the literature. Taiwan J Obstet Gynecol. 2006;45(2):135–141. doi:10.1016/S1028-4559(09)60211-4 [CrossRef] PMID:
- Osborn DA, Evans N, Kluckow M. Hemodynamic and antecedent risk factors of early and late periventricular/intraventricular hemorrhage in premature infants. Pediatrics. 2003;112(1 Pt 1):33–39. doi:10.1542/peds.112.1.33 [CrossRef] PMID:12837865
- Tan AP, Svrckova P, Cowan F, Chong WK, Mankad K. Intracranial hemorrhage in neonates: A review of etiologies, patterns and predicted clinical outcomes. Eur J Paediatr Neurol. 2018;22(4):690–717. doi:10.1016/j.ejpn.2018.04.008 [CrossRef] PMID:29731328
- Ballabh P. Intraventricular hemorrhage in premature infants: mechanism of disease. Pediatr Res. 2010;67(1):1–8. doi:10.1203/PDR.0b013e3181c1b176 [CrossRef] PMID:
- Chamnanvanakij S, Perlman JM. Extensive late-onset primary subarachnoid hemorrhage in a preterm infant. Pediatr Neurol. 1999;21(4):735–738. doi:10.1016/S0887-8994(99)00067-3 [CrossRef] PMID:10580887
- Litten M. Ueber einige vom allgemein-klinischen Standpunkt aus interessante Augenveränderungen. Berl Klin Wochenschr. 1881;18:23–27.
- Terson A. syndrome du corps vitré et de l'hémorrhagie intracrânienne spontane. Ann Oculist. 163:666–673.
- Czorlich P, Skevas C, Knospe V, et al. Terson syndrome in subarachnoid hemorrhage, intracerebral hemorrhage, and traumatic brain injury. Neurosurg Rev. 2015;38(1):129–136. doi:10.1007/s10143-014-0564-4 [CrossRef] PMID:
Laboratory and Radiologic Workup for Premature Infant With Bilateral Retinal Hemorrhages
|Day 8||Day 30||Day 45|
|Total bilirubin / direct bilirubin||3.5 / 2.2|
|Toxoplasmosis IgG/IgM||Positive / Negative|
| Factor XIII||Normal|
| Thrombin time||Normal|
| Reptilase time||Trace elevation|
| Von Willenbrand Panel||Normal|
| Reticulocytes||Trace elevation|
| Manual blood smear||Normal|