OBJECTIVES: The objective of this thesis is to explore the effectiveness and safety of common pharmacotherapeutic options used for the management of patent ductus arteriosus (PDA) in preterm infants. METHODS: Following the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) guidance, article 1 develops the protocol to conduct the systematic review and network meta-analysis to answer the research question. Article 2 details the actual methods implemented to conduct the network meta-analysis and presents the results in the form of network plots, league tables, rank heat maps, rankograms and forest plots. RESULTS: Article 1 suggests the need to conduct a Bayesian random-effects network meta-analysis of randomized controlled trials (RCTs) as the analysis would involve multiple treatments with potentially both direct and indirect comparisons. Article 1 also a priori defines potential effect modifiers and statistical strategies to control for the same. In article 2, the results of the meta-analysis show that in 68 RCTs that included 4802 infants, 14 different variations of indomethacin, ibuprofen or acetaminophen were used. Oral high-dose ibuprofen was associated with a significantly higher odds of PDA closure compared with standard-dose intravenous ibuprofen (Odds Ratio [OR], 3.59; 95% Credible Interval [CrI],1.64-8.17) and intravenous indomethacin (OR, 2.35; 95% CrI,1.08-5.31). Oral high-dose ibuprofen ranked the best option for PDA closure (SUCRA [surface under the cumulative ranking curve],0.89 [SD, 0.12]) and to prevent surgical PDA ligation (SUCRA,0.98 [SD, 0.08]). There was no significant difference in the odds of mortality, necrotizing enterocolitis or intra-ventricular hemorrhage with use of placebo or no treatment compared with any of the other treatment modalities. CONCLUSION: This thesis suggests that oral high-dose ibuprofen could be the best treatment option for closure of a hemodynamically significant PDA. Placebo or no treatment for a hemodynamically significant PDA may not increase morbidity and mortality. / Thesis / Master of Science (MSc) / The following thesis explores the effectiveness and safety of commonly used drugs for the treatment of a heart condition in premature infants called the patent ductus arteriosus (PDA). Article 1 outlines the protocol for the systematic review and network meta-analysis designed to evaluate the effectiveness and safety of indomethacin, ibuprofen and acetaminophen for the treatment of PDA in preterm infants. Article 2 provides in detail the results of the network meta-analysis that examined all eligible randomized controlled trials that compared intravenous or oral formulations of indomethacin, ibuprofen or acetaminophen compared against to other or placebo for the treatment of a PDA that may be harmful for a premature infant based on certain clinical and echocardiographic criteria set by the clinicians and researchers. Overall, this body of work suggests that a higher dose of oral ibuprofen is the best treatment for PDA in premature infants.

Background Modern neonatal care has improved the survival rate of extremely preterm infants. These infants are at high risk of malnutrition and growth failure during 3-4 months of hospital care. The objectives of this study was to investigate nutritional intakes during hospitalization and explore associations between nutritional intakes, postnatal growth and retinopathy of prematurity (ROP). Perioperative nutrition in infants undergoing surgery for patent ductus arteriosus (PDA) was also investigated. Methods This is a population-based study of Swedish extremely preterm infants (<27 weeks) born during 2004-2007 (n=602). Detailed data on nutritional supply and anthropometric measurements during hospitalization were retrospectively retrieved from hospital records. Comprehensive data on cohort characteristics, neonatal morbidity and infant mortality were obtained from the Extremely Preterm Infants in Sweden Study (EXPRESS). Results During the first 70 days of life, intakes of energy, protein and several micronutrients, with the exception of iron and some vitamins, were less than estimated requirements, and infants showed severe postnatal growth failure. Energy and protein intake predicted growth in all anthropometric outcomes even when adjusting for severity of illness, and fat intake was positively associated with head growth. Low folate intake was positively correlated with poor weight and length gain while high iron intake, mainly explained by blood transfusions, was negatively associated with poor length gain. Furthermore, a low energy intake was associated with severe ROP (stage 3-5). An increased energy intake of 10 kcal/kg/d was associated with 24% decrease in severe ROP (p=0.01). During the first month, 99% of the infants were exclusively fed human milk. Infants who underwent surgery for PDA (n=140) were malnourished, with energy and macronutrient intakes below minimum estimated requirements before, during and after surgery. Conclusions The severe postnatal growth failure observed in Swedish extremely preterm infants may be prevented by improved intakes of energy, protein, fat and folate and a reduction of the number of blood transfusions. Human milk is the main enteral food source and analyses of human milk macronutrient contents facilitates individualized fortification. Provision of adequate energy intakes during the first four weeks of life may be an effective way to reduce the risk of severe ROP. Perioperative nutrition in infants undergoing PDA surgery needs to be improved. The study results have important implications for nutritional regimens, postnatal growth and health outcome in this new generation of survivors.

En dépit du nombre croissant d’études cliniques sur le canal artériel (CA), des failles méthodologiques entretiennent plusieurs incertitudes concernant l’efficacité et la sécurité des traitements chez les bébés nés prématurés. L’objectif de cette recherche était de comparer les concentrations de prostaglandine E2 (PGE2) et les mesures du flux mésentérique par échographie Doppler chez les enfants nés prématurément et ayant un canal artériel traité à l’ibuprofène par voie intraveineuse ou entérale, en utilisant la méthodologie randomisée contrôlée et à double insu. Dans notre étude pilote, 20 nouveau-nés prématurés de moins de 34 semaines ayant un CA symptomatique confirmé par échocardiographie, furent randomisés au traitement à l’ibuprofène par voie intraveineuse ou entérale. La voie d’administration fut maintenue à l’insu de l’équipe traitante, des cardiologues et des investigateurs. Des dosages des prostaglandines plasmatiques ont été mesurés avant le début du traitement ainsi que 3, 24 et 48 h après le début du traitement. Les mesures du flux mésentérique ont été effectuées avant le traitement à l’ibuprofène ainsi que 1 h et 3 h après le traitement. Nous avons démontré à partir de nos observations que les niveaux plasmatiques de prostaglandines E2 diminuent chez les patients ayant répondu au traitement à l’ibuprofène, indépendamment de la voie d’administration. Nous n’avons pas observé de changement dans l’évolution des dosages de PGE2 chez les patients qui n’ont pas répondu au traitement. Les paramètres mesurés par échographie Doppler au niveau de l’artère mésentérique supérieure n’étaient pas affectés par la voie d’administration du traitement à l’ibuprofène, intraveineuse ou entérale. La présente étude suggère ainsi que le traitement du CA par ibuprofène intraveineux ou entéral n’influe pas sur le flux sanguin mesuré par échographie Doppler. La baisse de la prostaglandine E2 coïncide avec la fermeture du CA, et son dosage pourrait jouer un rôle dans la gestion du traitement. Nous avons démontré la faisabilité d’une étude clinique randomisée à double insu dans le traitement du canal artériel; une méthodologie qui devrait désormait être employé dans la recherche clinique sur les traitements de la persistance du CA. / Despite the growing body of research on the patent ductus arteriosus (PDA), issues with clinical research methodology impairs much of our understanding regarding treatment efficacy and safety in the preterm population. The purpose of this study was to determine plasma prostaglandin E2 (PGE2) concentrations in preterm infants with symptomatic persistence of the ductus arteriosus treated with IV and oral ibuprofen, and measure Doppler flow parameters in the superior mesenteric artery, utilizing randomized controlled and double-blind methodology. Twenty patients age < 34 wks with a symptomatic PDA confirmed by echocardiography randomized to oral vs intravenous ibuprofen regimen. Treating physician, cardiologists and study investigators were blinded to treatment allocation. Plasma PGE2 levels were measured prior to ibuprofen treatment and at 3, 24 and 48 h after treatment. Mesenteric Doppler measurements were taken prior to ibuprofen treatment, and 1 h and 3 h after treatment. Our results showed that plasma PGE2 levels decreased over time in patients that exhibited ductal closure after IV or oral ibuprofen treatment; no time-dependent changes in PGE2 were seen in subjects that failed to respond to ibuprofen. Superior mesenteric artery Doppler flow measurements were not affected by ibuprofen treatment (IV or oral), regardless of efficacy on ductal closure and of PGE2 changes. We conclude that treatment with oral or intravenous ibuprofen does not impact on superior mesenteric artery blood flow measured by Doppler ultrasound. Decreases in plasma PGE2 concentrations coincide with ibuprofen efficacy, and may be more cost-effective to monitor than ultrasound. This study also demonstrated the successful use of double blinded randomized controlled research methodology, which should be more strictly applied in future clinical research on PDA treatment.

En dépit du nombre croissant d’études cliniques sur le canal artériel (CA), des failles méthodologiques entretiennent plusieurs incertitudes concernant l’efficacité et la sécurité des traitements chez les bébés nés prématurés. L’objectif de cette recherche était de comparer les concentrations de prostaglandine E2 (PGE2) et les mesures du flux mésentérique par échographie Doppler chez les enfants nés prématurément et ayant un canal artériel traité à l’ibuprofène par voie intraveineuse ou entérale, en utilisant la méthodologie randomisée contrôlée et à double insu. Dans notre étude pilote, 20 nouveau-nés prématurés de moins de 34 semaines ayant un CA symptomatique confirmé par échocardiographie, furent randomisés au traitement à l’ibuprofène par voie intraveineuse ou entérale. La voie d’administration fut maintenue à l’insu de l’équipe traitante, des cardiologues et des investigateurs. Des dosages des prostaglandines plasmatiques ont été mesurés avant le début du traitement ainsi que 3, 24 et 48 h après le début du traitement. Les mesures du flux mésentérique ont été effectuées avant le traitement à l’ibuprofène ainsi que 1 h et 3 h après le traitement. Nous avons démontré à partir de nos observations que les niveaux plasmatiques de prostaglandines E2 diminuent chez les patients ayant répondu au traitement à l’ibuprofène, indépendamment de la voie d’administration. Nous n’avons pas observé de changement dans l’évolution des dosages de PGE2 chez les patients qui n’ont pas répondu au traitement. Les paramètres mesurés par échographie Doppler au niveau de l’artère mésentérique supérieure n’étaient pas affectés par la voie d’administration du traitement à l’ibuprofène, intraveineuse ou entérale. La présente étude suggère ainsi que le traitement du CA par ibuprofène intraveineux ou entéral n’influe pas sur le flux sanguin mesuré par échographie Doppler. La baisse de la prostaglandine E2 coïncide avec la fermeture du CA, et son dosage pourrait jouer un rôle dans la gestion du traitement. Nous avons démontré la faisabilité d’une étude clinique randomisée à double insu dans le traitement du canal artériel; une méthodologie qui devrait désormait être employé dans la recherche clinique sur les traitements de la persistance du CA. / Despite the growing body of research on the patent ductus arteriosus (PDA), issues with clinical research methodology impairs much of our understanding regarding treatment efficacy and safety in the preterm population. The purpose of this study was to determine plasma prostaglandin E2 (PGE2) concentrations in preterm infants with symptomatic persistence of the ductus arteriosus treated with IV and oral ibuprofen, and measure Doppler flow parameters in the superior mesenteric artery, utilizing randomized controlled and double-blind methodology. Twenty patients age < 34 wks with a symptomatic PDA confirmed by echocardiography randomized to oral vs intravenous ibuprofen regimen. Treating physician, cardiologists and study investigators were blinded to treatment allocation. Plasma PGE2 levels were measured prior to ibuprofen treatment and at 3, 24 and 48 h after treatment. Mesenteric Doppler measurements were taken prior to ibuprofen treatment, and 1 h and 3 h after treatment. Our results showed that plasma PGE2 levels decreased over time in patients that exhibited ductal closure after IV or oral ibuprofen treatment; no time-dependent changes in PGE2 were seen in subjects that failed to respond to ibuprofen. Superior mesenteric artery Doppler flow measurements were not affected by ibuprofen treatment (IV or oral), regardless of efficacy on ductal closure and of PGE2 changes. We conclude that treatment with oral or intravenous ibuprofen does not impact on superior mesenteric artery blood flow measured by Doppler ultrasound. Decreases in plasma PGE2 concentrations coincide with ibuprofen efficacy, and may be more cost-effective to monitor than ultrasound. This study also demonstrated the successful use of double blinded randomized controlled research methodology, which should be more strictly applied in future clinical research on PDA treatment.

Abstract The ductus arteriosus connects the pulmonary artery and the descending aorta in the foetus. In normal neonatal transition, the ductus closes soon after birth. If the duct remains significantly open after birth, it may complicate the recovery of a very preterm infant. Present treatments of patent ductus arteriosus (PDA) are either medical (ibuprofen or indomethacin) or surgical (ligation). However, these treatments can have serious side effects, especially in the most immature infants. This doctoral thesis studied the potential role of intravenous paracetamol for PDA treatment in very preterm infants born before 32 weeks of gestation. Consequences of the PDA treatments in an epidemiological birth cohort were also studied. In retrospective Study I stated that treatments of PDA decreased after the introduction of IV paracetamol for early pain management in preterm infants. Study II showed in a randomised clinical trial for the first time that paracetamol has a biological effect on the ductus arteriosus in preterm infants soon after birth. The ductus closed significantly earlier in the paracetamol group than in the placebo group. The epidemiological cohort Study III showed evidence that both medical and surgical treatment of PDA associated with severe bronchopulmonary dysplasia in infants born very preterm. Additionally, surgical PDA ligation was associated with increased risk of necrotising enterocolitis and intraventricular haemorrhage. Study IV showed that treatment of PDA was not associated with increased mortality, even in the most immature preterm infants born before 28 weeks of gestation. / Tiivistelmä Valtimotiehyt on sikiöaikana avoimena oleva suoni, joka yhdistää keuhkovaltimon laskevaan aorttaan ja ohjaa vähähappisen veren istukkaan. Yhdessä soikean aukon kanssa suoni takaa sikiön verenkierron normaalin toiminnan ennen keuhkojen avautumista. Mikäli valtimotiehyt jää syntymän jälkeen pitkittyneesti auki, muuttaa se keskosen verenkiertoa siten, että osa aortan verenkiertoa ohjautuu keuhkoverenkiertoon vaikeuttaen pienen keskosen toipumista. Nykyhoitoina käytetään joko lääkkeellistä (ibuprofeeni tai indometasiini) tai kirurgista sulkua. Lääkkeellinen hoito ei ole kovin tehokas kaikista epäkypsimmillä keskosilla ja hoitoihin liittyy vakaviakin sivuvaikutuksia. Väitöskirjassa tutkittiin parasetamolilääkityksen vaikutusta hyvin pienen keskosen avoimen valtimotiehyen sulkeutumiseen. Epidemiologisessa osiossa tutkittiin nykyhoitojen sivuvaikutuksia hyvin pienillä keskosilla. Osatyössä I todettiin, että avoimen valtimotiehyen hoidon tarve väheni merkittävästi sen jälkeen kun parasetamoli oli otettu käyttöön kivun hoidossa vastasyntyneiden teholla. Osatyö II oli satunnaistettu ja sokkoutettu hoitotutkimus, jossa todettiin alkuperäishavaintona, että parasetamolilla on biologinen vaikutus keskosen avoimeen valtimotiehyeen. Parasetamolia saaneilla keskosilla valtimotiehyt sulkeutui aikaisemmin kuin verrokeilla. Hoidolla ei todettu merkittäviä sivuvaikutuksia. Osatöissä III ja IV tutkittiin kaikkien vuosina 2005−2013 Suomessa syntyneiden hyvin pienten keskosten avoimen valtimotiehyen hoitoja. Lääkehoidolla (ibuprofeeni ja indometasiini) ja kirurgisella hoidolla todettiin olevan yhteys keskosen kroonisen keuhkotaudin (BPD) vaikeimpaan muotoon. Kirurgisella hoidolla oli yhteys keskosen vaikeaan suolitulehdukseen ja vaikeaan aivoverenvuotoon. Kuolleisuuden riskin ei kuitenkaan todettu lisääntyneen valtimotiehyen hoitoihin liittyen.