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Pre-Eclampsia and the Risk of Retinopathy of Prematurity In Original article BMJ Open Ophth: first published as 10.1136/bmjophth-2016-000049 on 19 June 2017. Downloaded from Pre-eclampsia and the risk of retinopathy of prematurity in preterm infants with birth weight <1500 g and/or <31 weeks’ gestation Belal Alshaikh,1 Omar Salman,2 Nancy Soliman,3 Anna Ells,4 Kamran Yusuf1 To cite: Alshaikh B, ABSTRACT Key messages Salman O, Soliman N, et al. Objective To evaluate the relationship between pre- Pre-eclampsia and the risk of eclampsia and development of retinopathy of " Studies on pre-eclampsia and retinopathy of retinopathy of prematurity in prematurity (ROP) in infants with birth weight of prematurity (ROP) show variable results. Some preterm infants with birth are from earlier periods when nutritional weight <1500 g and/or <31 <1500 g and/or gestation <31 weeks. practices, mechanical ventilation, supplemental weeks’ gestation. BMJ Open Methods A retrospective cohort study comprising Ophth 2017;1:e000049. infants born to mothers with pre-eclampsia between oxygen and antenatal corticosteroid use were doi:10.1136/bmjophth-2016- January 2007 and June 2010 at a single tertiary care different from current standard of care. Some 000049 centre. Their ROP outcome was compared with infants studies have included cases of maternal born to the next two normotensive mothers with a hypertension other than pre-eclampsia in their Received 06 October 2016 Æ1 week gestational age difference. Pearson 2 test cohorts, there is marked variation in the Revised 31 January 2017 was used for categorical variables and Mann-Whitney gestational ages and some have substantial Accepted 09 March 2017 U test was used for continuous variables. Multivariable missing data. " regression was used to estimate the OR of ROP with In a well-defined cohort from a recent era, we prenatal pre-eclampsia exposure and adjust for demonstrate pre-eclampsia is not associated confounders. with ROP, either as a protective or as risk Results Of the 97 infants in the pre-eclampsia group, factor. There were no missing data and high 27 (27%) developed ROP and of the 185 infants in the level of antenatal corticosteroid use. Unlike previous studies, chorioamnionitis was defined normotensive group, 50 (27%) developed ROP. On pathologically, and oxygen saturation targets multivariable regression modelling, pre-eclampsia was and mechanical ventilation strategies were not a risk factor for the development of ROP (OR 1.4, consistent during this period. 95% CI 0.46 to 4.1). Gestational age, intrauterine http://bmjophth.bmj.com/ " This is a retrospective cohort study from a growth restriction and blood transfusion were single centre potentially subject to significant risk factors for the development of ROP. confounding. Conclusions In our cohort, pre-eclampsia was not a " Prematurity and intrauterine growth significant risk factor for the development of ROP. restriction, whether in pre-eclamptic or Intrauterine growth restricted infants of pre-eclamptic normotensive pregnancies, are major risk and normotensive mothers were at higher risk of ROP. factors for the development of ROP. 1Department of Pediatrics, on October 2, 2021 by guest. Protected copyright. INTRODUCTION University of Calgary fully understood but involves an intricate Retinopathy of prematurity (ROP), a vaso- Cumming School of interplay between retinal blood vessels, Medicine, Calgary, Canada proliferative disorder of the developing 2 oxygen, angiogenic and growth factors, of University of Toronto at retina, is one of the more severe conse- Scarborough, Toronto, quences of preterm birth and a major cause which vascular endothelial growth factor Canada (VEGF) is the most important.4 ROP is 3 of childhood blindness and visual Department of Obstetrics described in two phases. The first phase and Gynecology, University impairment in the developing and devel- of Calgary Cumming School oped world.1 The disease is more common begins after preterm birth secondary to the of Medicine, Calgary, Canada hyperoxic extrauterine environment and 4 in infants less than 31 weeks’ gestation with Department of infants of lesser gestation at higher risk and involves suppression of VEGF, vaso-obliter- Ophthalmology, University of ation with cessation of retinal blood vessel Calgary Cumming School of severity of ROP. In infants with a birth Medicine, Calgary, Canada weight of <1500 g, the reported incidence growth and endothelial apoptosis. The of ROP ranges from 20% to 50% in second phase is proliferative and involves 1–3 Correspondence to different populations. neovascularisation of retinal vasculature by Dr Kamran Yusuf; kyusuf@ Described first as ‘retrolental fibroplasia’ vasoactive factors such as VEGF, produced ucalgary.ca in 1942, the pathogenesis of ROP is still not secondary to a hypoxic and avascular retina Alshaikh B, et al. BMJ Open Ophth 2017;1:e000049. doi:10.1136/bmjophth-2016-000049 1 Open Access BMJ Open Ophth: first published as 10.1136/bmjophth-2016-000049 on 19 June 2017. Downloaded from of phase 1. The second phase begins around 32 weeks steroids were considered a course if more than postmenstrual age but can have a wide range of onset.2 12 hours had elapsed after the first dose. 4 Prematurity continues to be the single most impor- tant risk factor for ROP, but given its developmental Neonatal data nature, efforts have recently focused on identifying Screening for ROP in Calgary is based on published antenatal risk factors for ROP. recommendations and includes infants <1500 g and/or Pre-eclampsia is characterised by new-onset maternal gestation <31 weeks as well as infants with birth weight hypertension and proteinuria at or after 20 weeks of of >1500 g and gestation >30 weeks who have a gestation. Although the aetiology of pre-eclampsia severe and complicated clinical course. All infants have remains unknown, evidence suggests that a hypoxic their first examination at 28 days of life and then at 1– and dysfunctional placenta produces excess antiangio- 2 weeks interval depending on the findings of the genic factors, soluble fms-like tyrosine kinase 1 and initial examination. All funduscopic examinations were soluble endoglin, resulting in decreased maternal performed by two paediatric ophthalmologists. levels of angiogenic factors, VEGF and placental The severity of ROP was based on the International growth factor. This imbalance between angiogenic and Classification of ROP.8 No ROP was designated as antiangiogenic factors is responsible for maternal stage 0, stage 1 was a line of demarcation, stage 2 a endothelial damage and manifestations of pre- ridge, stage 3 intravitreous neovascularisation, stage 4 5 eclampsia. How this antiangiogenic intrauterine partial retinal detachment and stage 5 total retinal milieu in pre-eclampsia affects retinal vasculature detachment. Severe ROP was defined as >stage 2. Plus development is not well understood. Given that angio- disease, an indication of severity of ROP, was defined genic factors such as VEGF are involved in the as venous dilation and arteriolar tortuosity of the pathogenesis of ROP, and pre-eclampsia is associated posterior retinal vessels sometimes including vascular with lower levels of VEGF, we hypothesised that engorgement of the iris, poor papillary dilation and preterm infant less than 31 weeks’ gestation and\or vitreous haze. with a birth weight of <1500 g born to mothers with GA was assessed in the following order of preference: pre-eclampsia would be at a lower risk of developing date of embryo transfer for in vitro fertilisation, first ROP when compared with infants born to normoten- trimester fetal ultrasound, second trimester fetal ultra- sive mothers. sound, date of the last menstrual period and postnatal assessment using the modified Ballard score. METHODS Intraventricular haemorrhage (IVH) was graded on Papile’s criteria.9 The diagnosis of necrotising entero- The Neonatal Intensive Care Unit (NICU) in Calgary colitis (NEC) was based on modified Bell’s criteria.9 maintains a prospectively collected electronic database Neonatal sepsis was the presence of single organism of all infants admitted to the NICU. Infants less than 31 weeks gestational age (GA) and/or with a birth from either blood or cerebrospinal fluid culture. Respi- http://bmjophth.bmj.com/ ratory distress syndrome (RDS) was diagnosed based weight of <1500 g born to mothers with pre-eclampsia on the presence of signs of respiratory distress, a between January 2007 and June 2010 were included in typical chest X-ray and/or need for surfactant. Patent the study. Their outcome was compared with infants ductus arteriosus (PDA) was diagnosed based on clin- born to the next two normotensive mothers with ical signs and echocardiography. Bronchopulmonary a Æ1 week GA difference. In case of missing data, the dysplasia (BPD) was defined as the need for supple- infant’s medical record charts were reviewed. The mental oxygen or any form of ventilation including Conjoint Health Research Ethics Board of the Univer- sity of Calgary approved the study. continuous positive airways pressure at 36 weeks post- on October 2, 2021 by guest. Protected copyright. menstrual age.9 Intrauterine growth restriction (IUGR) was defined as birth weight less than the 10th percen- Maternal data tile based on the growth charts of Kramer et al.10 Pre-eclampsia was defined as systolic blood pressure Exclusion criteria included infants born with any 140 mm Hg or a diastolic level of (Korotkoff congenital malformations or chromosomal anomalies, 5) 90 mm Hg on two or more occasions at least 4– mothers with chronic hypertension, maternal renal, 6 hours (but not more than 7 days) apart after 20 cardiovascular or autoimmune disease, substance weeks’ gestation in a woman with previously normal abuse, TORCH infections and infants who died before blood pressure. Proteinuria was defined as 0.3 g their first eye examination. protein in a 24-hour urine sample. When a 24-hour As the distribution of the relevant variables was not urine sample was not feasible, 0.3 g/L protein or 1+ normal, we chose conservative non-parametric anal- on a dipstick test strip on two random urine samples ysis for continuous variables, using the Mann- taken at least 4–6 hours apart was used as criteria for Whitney U test.
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