JAMA Ophthalmology Journal Club Slides: Maternal Preeclampsia and Risk of Retinopathy of Prematurity Shulman JP, Weng C, Wilkes J, Greene T, Hartnett ME. Association of maternal preeclampsia with infant risk of premature birth and retinopathy of prematurity. JAMA Ophthalmol. Published online August 10, 2017. doi:10.1001/jamaophthalmol.2017.2697

Introduction Importance: Previous literature reports conflicting associations between preeclampsia and retinopathy of prematurity (ROP). This study clarifies the discrepancies in previous literature and sheds light on the relationship between preeclampsia and ROP. Objective: To evaluate the association of maternal preeclampsia and risk of ROP among infants in an unrestricted birth cohort and a restricted subcohort of preterm, very low birth weight infants (P-VLBW).

Methods Study Design, Setting, and Participants: A retrospective review of 290 992 live births within the Intermountain Healthcare System in Utah from January 1, 2001, through December 31, 2010, was performed. Maternal age, maternal race/ethnicity, indicator variable for multiple gestations, infant’s sex, and maternal alcohol, substance, and tobacco use during pregnancy were controlled as variables. Main Outcomes and Measures Two parallel sets of analyses were performed on the cohort: first, the relationship between maternal preeclampsia and ROP was analyzed in the full cohort; second, the analysis was repeated in the P-VLBW cohort of infants younger than 31 weeks’ gestation and weighing less than 1500 g.

Methods Limitations: Reliance on International Classification of Diseases, Ninth Revision, codes for the diagnoses of preeclampsia and ROP. Infants in only 1 region of the country were analyzed. Because of the retrospective nature of the analysis, further categorization of ROP by stage or zone was not possible; however, patients with diagnosis codes for later treatment or surgery for ROP were categorized as severe, which has been used in other large retrospective studies on ROP.

Baseline Characteristics Methods Baseline Characteristics

Results To address the effect of infant death on the analyses, the percentage of infants who died in both groups prior to the first ROP screening examination was determined, and the composite outcomes of ROP or death were analyzed.

Results Association of All ROP With Preeclampsia and Covariates in the Full Cohort and P-VLBW Subcohort

Results Association of ROP-Related Outcomes With Preeclampsia in the Full Cohort and in the P-VLBW Subcohort

Results The analysis in the unrestricted cohort represents the total effect of preeclampsia on ROP, which we believe is more clinically relevant. The analysis in the P-VLBW cohort represents the direct effect of preeclampsia on ROP, which is subject to a substantially greater risk of bias from uncontrolled confounding than the analysis of direct effect.

Results Directed Acyclic Graphs (DAGs) Corresponding to the Estimation of the Total and Direct Effects of Preeclampsia on Retinopathy of Prematurity (ROP)

Results Maternal preeclampsia increased the risk of ROP in the unrestricted cohort (adjusted odds ratio [aOR], 2.46; 95% CI, 2.17-2.79; P < .001) but appeared protective against ROP in the P-VLBW subcohort (aOR, 0.79; 95% CI, 0.68-0.92; P = .003). A similar relationship was found between preeclampsia and infant death (aOR, 1.66; 95% CI, 1.16-2.38; P = .006 in the unrestricted cohort and aOR, 0.19; 95% CI, 0.11-0.32; P < .001 in the subcohort). This result may represent a true adverse total and protective direct effect or be the result of bias due to uncontrolled confounding. Including death before the first ROP examination did not alter the results of the analysis.

Comment The study results are strongly suggestive of an adverse total effect of preeclampsia on ROP, informing clinical prognostication and the implications of treatment. The protective direct effect of preeclampsia on ROP may be true physiologically or represent collider bias or another form of uncontrolled confounding.

Conflict of Interest Disclosures Contact Information If you have questions, please contact the corresponding author: M. Elizabeth Hartnett, John A. Moran Eye Center, University of Utah, 65 Mario Capecchi Dr, Salt Lake City, UT 84132 (me.hartnett@hsc.utah.edu). Funding/Support This study was supported by award UL1TR001067 from the National Center for Advancing Translational Sciences of the National Institutes of Health. Conflict of Interest Disclosures All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Hartnett receives support from grants EY015130 and R01EY017011 from the National Eye Institute as well as consulting fees from SanBio. No other disclosures are reported.