Outcomes following PDA surgery in extremely preterm born subjects. Focusing on left vocal cord paralysis and associated short- and long-tem outcomes

Background: Extremely preterm born (EPB) infants are at risk of a range of complications, among them a patent ductus arteriosus (PDA). If a conservative approach does not reduce the cardiopulmonary compromise imposed by the PDA, pharmacological or surgical closure is required. The rate of PDA surgery has declined over the last decade, in part due to reports of postoperative complications such as left vocal cord paralysis. The incidence and prevalence of LVCP and outcomes associated with left vocal cord paralysis (LVCP) after neonatal PDA surgery has not been sufficiently described. \n\nAim: The aims of this thesis were to investigate incidence and prevalence of LVCP after surgical PDA closure in EPB subjects, and to study associations between PDA surgery with or without LVCP versus outcomes in the neonatal period and later, focusing on respiratory and voice related symptoms, exercise capacity and lung function. \n\nMethods: In Study #I, we conducted a systematical review and meta-analysis to investigate previous reports of LVCP incidence after PDA surgery and associated outcomes using the Newcastle-Ottawa Scale for quality assessment of individual studies. Study #II and #III were both based on a national prospective cohort study, enrolling all infants born at gestational age (GA) <28 weeks or with birthweight (BW) <1000 grams during 1999–2000. In Study #II, we compared parental reports on voice and exercise related respiratory symptoms in three groups of EPB schoolchildren who either underwent neonatal PDA surgery, received other management for PDA or did not have PDA. In Study #III, EPB young adults with a history of neonatal PDA surgery, EPB controls, and term-born controls underwent spirometry, maximal treadmill exercise testing and answered questionnaires including questions about voice and exercise related respiratory symptoms. The PDA surgery-group also underwent laryngoscopy examination at rest and during the exercise test, allowing the scoring of exercise induced laryngeal obstruction.\n\nResults: The systematic review showed an overall incidence of LVCP following surgical closure of PDA was 9%, with a wide dispersion (0–67%). The incidence was highest in a subanalysis of studies where all subjects underwent laryngoscopy examinations after PDA surgery (overall: 32%, range 11–67%), and heterogeneity decreased with stratification based on study design. LVCP was associated with dysphonia, stridor, and adverse neonatal outcomes, such as chronic lung disease and feeding difficulties. In Study #II, surgical closure of a PDA was associated with an increased crude odds ratio of parental reports regarding voice and exercise related respiratory symptoms compared to other methods of managing PDA. However, days on mechanical ventilation was identified as a potential confounder in multivariate analyses. Study #III revealed a 53% prevalence of LVCP in the PDA surgery group. LVCP was associated with increased laryngeal obstruction during physical exertion and subjective reports of voice symptoms, but not with lung function (zFEV1), exercise capacity (peakVO2) or subjective reports of exercise related respiratory symptoms. PDA surgery was associated with impaired lung function, also after adjusting for BPD. Exercise capacity was not associated with LVCP nor PDA surgery, but all EPB groups performed poorer compared to term-born subjects, even after adjusting for gender. However, low levels of physical activity among those born EP may have impacted the results.\n\nConclusion and implications: We found that reported incidence of LVCP after PDA surgery in EPB subjects varied across studies and study designs, and that the prevalence of LVCP in our national cohort was high compared to the pooled incidence from the systematic review. Despite associations between LVCP and adverse neonatal outcomes, exercise induced laryngeal obstruction and frequent reports of voice and exercise related respiratory symptoms, LVCP was not associated with poor lung function or exercise capacity. PDA surgery was associated with increased rates of voice- and exercise related respiratory symptoms, but not with exercise capacity. However, the average lung function in the PDA surgery group was below the 5th percentile, and these individuals might represent a group in need of extra pulmonary follow-up in the future. To ensure correct diagnosis and follow-up of patients with LVCP, laryngoscopy examination should be performed routinely after PDA surgery in EPB neonates. Further, EPB adults with a history of PDA surgery who complain of voice problems or respiratory symptoms should undergo laryngoscopy examination to look for LVCP. Despite a nationwide recruitment, relatively low sample size may have contributed to some of the results being inconclusive. To further enlighten our research questions on incidence, prevalence, and outcomes of LVCP after PDA surgery in the EPB population, an international longitudinal multicentre study is warranted to enable recruitment of a sample with power to detect any true between-group differences.

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