Influence of infection on patent ductus arteriosus and chronic lung disease in premature infants weighing 1000 grams or less

doi:10.1016/S0022-3476(96)70356-6

The Journal of Pediatrics

Volume 128, Issue 4, April 1996, Pages 470-478

Presented in part at the annual meeting of the Society for Pediatric Research, San Diego, Calif., May 1995.

https://doi.org/10.1016/S0022-3476(96)70356-6 Get rights and content

Abstract

OBJECTIVE: To test the hypotheses that (1) infection increases ductal dilatory prostaglandins and inflammatory mediators that may influence the closure of a patent ductus arteriosus (PDA), increasing the incidence of late episodes of PDA (after 7 days) and the rate of closure failures, and (2) the concurrence of PDA and infection increases the risk of chronic lung disease (CLD). METHODS: One hundred fourteen premature infants (birth weight, 500 to 1000 gm) were prospectively assessed for PDA and infection. Serum levels of 6-ketoprostaglandin F_1α and tumor necrosis factor alpha were measured routinely in all infants and when PDA or infection was present. Multivariate assessment of risk factors for PDA closure failure and for CLD was done by logistic regression, and expressed as an odds ratio and as 95% confidence intervals. RESULTS: Late PDA episodes were more frequent in infants with infection than in those without infection. A temporally related infection (<5 days between both diagnoses) was associated with an increased risk of PDA closure failure (odds ratio, 19.1 [confidence interval, 4 to 90]). In addition to birth weight and the severity of initial respiratory failure, PDA and infection increased the risk of CLD (odds ratio, 11.7 [confidence interval, 1.7 to 81] for PDA; odds ratio, 3.1 [confidence interval, 1 to 11] for infection). Furthermore, when both factors were temporally related, they further increased the risk of CLD (odds ratio, 29.6 [confidence interval, 4.5 to >100]). Infants with infection and those with PDA had higher levels of 6-ketoprostaglandin F_1α than did control subjects. Levels of tumor necrosis factor alpha were also elevated in infants with infection and in those with late PDA. CONCLUSIONS: Infection adversely influences PDA outcome by increasing the risk of late ductal reopening and PDA closure failures. Increased levels of prostaglandins and tumor necrosis factor alpha in infants with infection may explain the poor PDA outcome. The concurrence of PDA and infection potentiates their negative effects on the risk of CLD. (J PEDIATR 1996;128:470-8)

Section snippets

Study patients

We prospectively assessed consecutively born preterm infants with birth weights between 500 and 1000 gm delivered at the University of Miami/Jackson Memorial Medical Center between November 1992 and March 1994. Excluded from the study were patients with congenital anomalies, congenital infections, and intrauterine growth retardation, and infants who died during the first 72 hours after birth. The protocol was approved by the University of Miami Committee for the Protection of Human Subjects,

Patient population

A total of 172 infants with birth weights between 500 and 1000 gm were born during the study period. Of these, 23 infants (13%) died during the first 72 hours and 12 infants met other exclusion criteria. For 23 (17%) of 137 eligible infants, we were unable to obtain consent. Therefore 114 infants were included in the final analysis.

PDA outcome

Of the 114 infants analyzed, symptomatic PDA was diagnosed in 84 infants (74%). Of these 84 infants with symptomatic PDA, 43 (51%) had late PDA episodes (after the

DISCUSSION

This study indicates that systemic infections are associated with an adverse outcome of a PDA in small premature infants, leading to an increased risk of late PDA episodes and medical-treatment closure failures. This, in turn, potentiates the impact of PDA on the risk of CLD damage, as shown by the higher levels of 6-keto PGF_1α observed in infants with infection, which may be one mechanism that explains the poor PDA outcome. The higher TNFα levels observed in infants with late PDA episodes also

Acknowledgements

We thank Dr. Orlando Gomez-Marin for his invaluable assistance in the statistical analysis, Ms. Rosa Nuñez and Ms. Silvia Martinez for their assistance in data collection, and Ms. Lalitha Price and Mr. Miguel Martinez for their help in the radioimmunoassay measurements. We also thank Dr Julienne Prineas for her critical review of this manuscript, and the fellows, attending physicians, and personnel of the divisions of neonatology and pediatric cardiology for their help in the study.

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Predictors of a non-response to prophylactic indomethacin for patent ductus arteriosus in preterm infants
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Preterm infants are recommended for prophylactic indomethacin (PIND) to promote closure of patent ductus arteriosus (PDA) and reduce morbidity and mortality. This study investigated the predictive factors of a non-response to PIND for PDA in preterm-birth infants.
Consecutive preterm-birth infants (gestational age: < 28 weeks) who received PIND between 2009 and 2019 were retrospectively enrolled. Seventy-six eligible participants were classified as PIND responders (N = 42) or non-responders (N = 34). Information on potential confounders in maternal obstetric and perinatal data were collected from medical records. Multiple logistic regression analysis was carried out to identify the prognostic factors of a PIND response in preterm-birth infants.
The prevalence of intrauterine infection and multiple births was significantly different between responders and non-responders to PIND (intrauterine infection: 2 [4.8%] vs. 8 [23.5%], P = 0.036; twins: 3 [7.1%] vs. 9 [ 26.5%], P = 0.029, respectively). In multivariate logistic regression analysis after adjustment for multiple births, intrauterine infection was a significant and independent predictive factor of a non-response to PIND (odds ratio [OR] 5.54, 95% confidence interval [CI] 1.05–29.2, P = 0.044). A remarkable association was also noted for multiple births with a non-response to PIND (OR 4.22, 95% CI 0.99–17.8, P = 0.050).
Intrauterine infection and multiple births were identified as potential risk factors of a non-response to PIND for PDA in preterm infants.
Association of patent ductus arteriosus with fetal factors and endotypes of prematurity
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During fetal life, the ductus arteriosus (DA) acquires the mechanisms for its postnatal closure following a thorough developmental program. This program can be interrupted by preterm birth and is also susceptible to alteration during fetal life by numerous physiological and pathological stimuli. In this review, we aim to summarize the evidence on how physiological and pathological factors affect DA development, eventually leading to patent DA (PDA). Specifically, we reviewed the associations of sex, race, and pathophysiological pathways leading to very preterm birth (endotypes) with PDA incidence and pharmacological closure. Summary of evidence suggests that there are no male-female differences in the incidence of PDA among very preterm infants. In contrast, risk of developing PDA appears to be higher in infants exposed to chorioamnionitis or who are small for gestational age. Finally, hypertensive disorders of pregnancy may be associated with a better response to pharmacological treatment of PDA. All of this evidence comes from observational studies and therefore associations do not imply causation. The current trend for many neonatologists is to wait for the natural evolution of preterm PDA. Continued research is needed to identify which fetal and perinatal factors modulate the eventual late closure of PDA in very and extremely preterm infants.
Patent Ductus Arteriosus in the Preterm Infant
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In full-term infants, obliteration of the ductus arteriosus (DA) takes place through a process of vasoconstriction and anatomic remodeling after birth. In contrast, preterm newborn infants frequently fail to close their DA. Factors that play a prominent role in DA regulation involve those that promote constriction of the ductus (e.g., oxygen, endothelin, Ca²⁺ channels, catecholamines, and Rho kinase), those that oppose it (e.g., intraluminal pressure, prostaglandins, nitric oxide, carbon monoxide, potassium channels, and cyclic adenosine monophosphate [AMP] and cyclic guanosine monophosphate [GMP]), and those that regulate ductus smooth muscle hypoxia, neointimal mound formation, and smooth muscle cell death. The relative importance of each of these factors depends on the intrauterine and extrauterine environment, the degree of ductus maturation, and the genetic background and species being studied. The clinical consequences of a patent ductus arteriosus (PDA) are related to the magnitude of the left-to-right shunt through the PDA, the cardiac and vascular responses to the shunt, and the associated changes in blood flow to the lungs, kidneys, intestine, and brain. Controlled clinical trials demonstrate that a moderate-to-large PDA increases the incidence of severe pulmonary hemorrhage and systemic hypotension during the first week as well as the need for higher levels of ventilator support at the end of the first week. However, controversy exists about the consequences of exposure to a persistent moderate-to-large PDA shunt for greater than 1 week. Further investigations will be needed to determine which infants are likely to benefit from early PDA treatment and which infants might best be left untreated while awaiting spontaneous ductus closure.
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Differential determinants of patent ductus arteriosus closure for prematurity of varying birth body weight: A Retrospective Cohort Study
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Patent ductus arteriosus (PDA) remains a critical issue in prematurity care. To predict the PDA closure early, we aimed to clarify the association of PDA closure with the initial postnatal 24-hour clinical characteristics and maternal and gestational histories of preterm neonates.
A retrospective cohort study was conducted in a pediatric-neonatal-intensive-care-unit from 2008 to 2013. Data relating to birth histories, maternal histories, and clinical data from the first 24 h of life were analyzed according to three types of PDA closure—non-treated, medically-responsive, and surgically-ligated PDA and birth body weights (BBWs). Univariate analysis was performed using non-parametric analysis and Chi-square test or Fisher's exact test. Multivariate analysis was performed using multinomial logistic regression to determine the independent risk factors for the PDA closure.
This study involved 682 preterm infants with median gestational age of 31 (interquartile, IQR: 28–34) weeks and BBW of 1360 (IQR: 1085–1861) g. Inclusively, 16.7% of (P)DAs underwent medical and/or surgical treatment. For very low birth body weight (VLBW) neonates, surfactant use not only predicted the requirement of PDA treatment, but together with dopamine use and the larger amount of first 24-hour intravenous fluid (IVF) per kilogram of BBW, it also predicted the possibility of surgical ligation. Meanwhile, the cut-off values of the IVF amount (87 and 89.5 ml/kg/day, respectively) might predict the PDA treatment necessity and surgical ligation. For neonates with BBW ≥1500 g, placenta previa and lower BBW and systolic blood pressure (SBP) predicted the risk of treatment for PDA and its treatment response.
Neonatal care for PDA in prematurity should be meticulously personalized. Surfactant use, dopamine administration and the first 24-hour IVF management may be critical for PDA closure in VLBW neonates. Antepartum history of placenta previa, BBW and SBP control may be important for BBW≥1500 g.
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Caffeine is currently one of the most commonly used medications for preterm neonates in neonatal intensive care units. Caffeine was initially used in the preterm infant population to treat apnea of prematurity, but new evidence is additionally showing a reduction of bronchopulmonary dysplasia associated with its use. This chapter highlights the recent evidence about use of caffeine in premature infants for the prevention of bronchopulmonary dysplasia. Finally, we will explore the impact of caffeine on neurodevelopmental outcomes, the controversies regarding caffeine use that remain unanswered, and potential future directions for research.

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^☆: From the Department of Pediatrics, Divisions of Neonatology and Pediatric Cardiology, University of Miami School of Medicine, Miami, Florida

^☆☆: ^aPresently at the Catholic University of Chile, Santiago.

^★: Reprint requests: Eduardo Bancalari, MD, Department of Pediatrics (R131), Division of Neonatology, PO Box 016960, Miami, FL 33101.

^★★: 0022-3476/96/$5.00 + 0 9/20/71604

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Influence of infection on patent ductus arteriosus and chronic lung disease in premature infants weighing 1000 grams or less☆,☆☆,★,★★

Abstract

Section snippets

Study patients

Patient population

PDA outcome

DISCUSSION

Acknowledgements

J Pediatr

Lancet

J Pediatr

Prostaglandins Leukotrienes and Medicine

J Pediatr

Immunopharmacology

Evaluation of the preterm infant for patent ductus arteriosus

Pediatrics

Incidence of patent ductus arteriosus in premature infants less than 2000 g

Rev Chil Pediatr

Very low birth weight outcome of National Institute of Child Health and Human Development Neonatal Network

Pediatrics

The role of prostaglandins in sepsis

Scand J Infect Dis

The response of the ductus arteriosus to prostaglandins

Can J Physiol Pharmacol