The fate of ductus arteriosus in infants at 23-27 weeks of gestation: from spontaneous closure to ibuprofen resistance

BACKGROUND: Some extremely preterm infants experience spontaneous closure of the ductus arteriosus. On the other side, a high percentage (22-30%) of preterm infants born at the lower gestational age fail to respond to a single course of ibuprofen. AIM: To assess if there are clinical characteristics effective as predictive factors for spontaneous closure of the ductus arteriosus, development of patent ductus arteriosus (PDA) and ibuprofen-resistant PDA. METHODS: A cohort of inborn infants less than 28 weeks of gestation were prospectively studied. We distinguished infants who had spontaneous closure of ductus arteriosus, who developed PDA and who developed ibuprofen-resistant PDA. RESULTS: We studied 34 infants. Eight infants (24%) had spontaneous closure of PDA, 17 infants (50%) had a closure of PDA following the first ibuprofen course, while 9 infants (26%) failed to respond to the first ibuprofen course. Infants born at 23-25 weeks of gestation were found to have lower likelihood of PDA spontaneous closure, and higher risk of developing PDA refractory to ibuprofen therapy. Sepsis was found to increase significantly the risk of ibuprofen failure in closing PDA. CONCLUSION: An important percentage of extremely preterm infants exhibited spontaneous closure of PDA. Among clinical characteristics lowest gestational ages predict PDA and ibuprofen-resistant PDA, while sepsis predicts only ibuprofen-resistant PDA.     

The fate of ductus arteriosus in infants at 23–27 weeks of gestation: from spontaneous closure to ibuprofen resistance

Background: Some extremely preterm infants experience spontaneous closure of the ductus arteriosus. On the other side, a high percentage (22–30%) of preterm infants born at the lower gestational age fail to respond to a single course of ibuprofen.
Aim: To assess if there are clinical characteristics effective as predictive factors for spontaneous closure of the ductus arteriosus, development of patent ductus arteriosus (PDA) and ibuprofen-resistant PDA.
Methods: A cohort of inborn infants less than 28 weeks of gestation were prospectively studied. We distinguished infants who had spontaneous closure of ductus arteriosus, who developed PDA and who developed ibuprofen-resistant PDA.
Results: We studied 34 infants. Eight infants (24%) had spontaneous closure of PDA, 17 infants (50%) had a closure of PDA following the first ibuprofen course, while 9 infants (26%) failed to respond to the first ibuprofen course. Infants born at 23–25 weeks of gestation were found to have lower likelihood of PDA spontaneous closure, and higher risk of developing PDA refractory to ibuprofen therapy. Sepsis was found to increase significantly the risk of ibuprofen failure in closing PDA.
Conclusion: An important percentage of extremely preterm infants exhibited spontaneous closure of PDA. Among clinical characteristics lowest gestational ages predict PDA and ibuprofen-resistant PDA, while sepsis predicts only ibuprofen-resistant PDA.     

Serum levels of magnesium at birth related to complications of immaturity

Magnesium is a natural calcium channel blocker inhibiting vasoconstriction in numerous vascular beds. Magnesium sulphate given prior to birth to pre-eclamptic mothers and mothers in preterm labour has in retrospect been found to be associated with a decreased incidence of both intraventricular haemorrhage and cerebral palsy. Little is known about the effect of normal variations of serum magnesium in the very preterm baby, where morbidity is closely related to rapid vascular changes. We have analysed the absolute levels and normal variations of magnesium concentration in cord blood and during the first 3 weeks after birth for 69 infants born before 32 gestational weeks of age. The results show an inverse relation between serum magnesium at birth and gestational age. Higher levels of serum magnesium at birth within normal variations were associated with a delayed closure of the ductus arteriosus, and mild but not severe peri- and intraventricular haemorrhage.     

Closure of the ductus arteriosus and development of pulmonary branch stenosis in babies of less than 32 weeks gestation

AIMS: To define how often transient pulmonary branch stenosis (PBS) develops after closure of a patent ductus arteriosus (PDA) in babies born at less than 32 weeks gestation; to describe the natural history of PBS and the relation between PBS and a cardiac murmur. METHODS: Fifty three preterm infants born at a gestational age less than 32 weeks and who had PDA diagnosed on echocardiography were recruited. An echocardiogram was performed on alternate days until the ductus arteriosus closed. If PBS was diagnosed, the baby was followed up until PBS resolved. RESULTS: In 59%, PBS developed in one or both branches after closure of the PDA. In 21%, both pulmonary branches were affected. In 79%, the left pulmonary artery alone was involved but the right side was never affected alone. PBS had resolved in 74% by the time the infants reached 40 weeks, in 95% at a corrected age of 6 weeks, and in 100% at a corrected age of 3 months. There is a better correlation between a cardiac murmur and PBS than between a murmur and PDA. CONCLUSIONS: PBS in preterm infants is usually not present at birth but develops after closure of a PDA. PBS resolves by a corrected age of 3 months. The presence of a murmur after closure of a PDA is usually related to PBS and not to reopening of the ductus arteriosus.     

Ductal closure with paracetamol: a surprising new approach to patent ductus arteriosus treatment

Standard pharmacologic closure of the patent ductus arteriosus currently involves the administration of 1 of 2 cyclooxygenase inhibitors: either indomethacin or ibuprofen. However, both of these drugs can be associated with potentially significant adverse effects. We present here the cases of 5 preterm infants (gestational age: 26-32 weeks; postnatal age: 3-35 days) with large, hemodynamically significant patent ductus arteriosus who had either failed or had contraindications to ibuprofen therapy. Each of these infants was treated with off-label oral paracetamol (15 mg/kg per dose every 6 hours). Ductal closure was achieved within 48 hours in all the treated infants. No toxicity was observed.     

极低出生体重儿动脉导管未闭转归的影响因素分析

目的分析极低出生体重儿动脉导管未闭(PDA)转归的影响因素。方法以2012年1月至2014年12月收治的194例极低出生体重儿为研究对象,根据心脏超声检查及治疗转归情况分为无PDA组,PDA自然关闭组、药物关闭组、手术关闭组,分析其临床及超声心动图特征。结果 PDA自然关闭率58.7%。自然关闭组的出生胎龄、出生体重、小于胎龄儿比例均大于药物和手术关闭组,药物及手术关闭组的新生儿呼吸窘迫综合征发生率及肺表面活性物质(PS)应用比例高于自然关闭组(P0.05)。不同时间段自然关闭组的动脉导管直径均明显小于药物和手术关闭组(P0.05)。多因素logistic回归分析示出生胎龄、PS应用及48 h动脉导管直径与PDA转归显著相关。自然关闭组PDA分流类型均以关闭型为主,而药物及手术关闭组在48 h以肺高压型及进展型为主,在4 d、7 d时均以进展型为主。结论极低出生体重儿PDA自然关闭率较高,出生胎龄越小以及应用PS的患儿自然关闭率越低;动脉导管直径越大且分流类型为进展型或脉冲型的PDA不易自然关闭。     

Cerebral and Abdominal Arterial Hemodynamics in Preterm Infants with Patent Ductus Arteriosus

Using Doppler echocardiography we evaluated the effect of ductal shunt flow on the cerebral and abdominal arterial blood flow in 25 preterm infants. Eligible for inclusion in this study were healthy preterm newborn infants. They were divided into two groups based on their gestational age: group A, 33-36 weeks (15 infants) and group B, 28–32 weeks (10 infants). Two-dimensional Doppler echocardiograms were obtained in each infant during the first 8 hours of life and repeated every 6–12 hours until no ductal shunt flow could be detected. Flow in the ductus arteriosus, the basilar artery and the coeliac artery were examined. Closure of the ductus arteriosus occurred significantly later(p< 0.05) in group B than in group A. Pulsatility indices of flow in the basilar and coeliac arteries were high when the ductus was patent, decreasing to a fixed level with closure. This study suggests that a shunt of the patent ductus arteriosus (PDA) adversely influences the cerebral and abdominal blood flow in preterm infants.     

Incidence and clinical features of patent ductus arteriosus in low-birthweight infants: a prospective analysis of 150 consecutively born infants.

The incidence of persistent patency of the ductus arteriosus beyond the third day of life was prospectively determined in 100 preterm infants with birthweights of 2,000 gm or less and 50 infants with birthweights of 2,001 to 2,500 gm. The overall incidence was 21% and was inversely related to increasing gestational age and birthweight. The data suggest that immaturity is the major determinant of the persistent patency of the ductus arteriosus. Spontaneous delayed closure of the ductus occurred in 79% of patients that survived the immediate neonatal period. There was a high degree of association between the presence of a patent ductus arteriosus (PDA) and respiratory distress syndrome (RDS). Eight infants with severe RDS and PDA developed heart failure and four required surgical ligation of the ductus. None of the infants with birthweights greater than 2,000 gm who had PDA developed heart failure or required surgical ligation of the ductus arteriosus.     

Indomethacin responsiveness of patent ductus arteriosus and renal abnormalities in preterm infants treated with indomethacin

OBJECTIVES: We evaluated the factors related to indomethacin responsiveness of the patent ductus arteriosus (PDA) and subsequent renal and electrolyte abnormalities in a large number of low birth weight infants. METHODS: The ductus was evaluated by Doppler echocardiogram or clinical signs after the last administration of indomethacin for 2538 low birth weight infants, through the use of postmarketing surveillance data. RESULTS: Multivariate logistic regression analyses demonstrated that clinical closure of PDA was significantly associated with pregnancy-induced hypertension and respiratory distress syndrome. In contrast, a 1-point increase of cardiovascular dysfunction score or a 1-day increase in postnatal age at the first indomethacin treatment decreased the responsiveness of the ductus to indomethacin. Clinical ductal reopening was significantly less likely to occur for each week of increased gestational age. Ductal reopening was more likely for each day of postnatal life at the first administration of indomethacin. Infants with preexisting renal and electrolyte abnormalities and infants whose mothers had received indomethacin tocolysis or who had chorioamnionitis were at increased risk of development of renal impairment. CONCLUSIONS: Both antenatal and postnatal factors predict good or poor response to indomethacin therapy for PDA.     

Patent ductus arteriosus: how important to which babies?

An overview is presented of 21 randomised controlled trials of either surgical closure of the ductus arteriosus or indomethacin therapy in preterm infants. All trials included backup treatment if the ductus arteriosus persisted. Overall, there is no significant effect on mortality or chronic lung disease. In trials treating at a presymptomatic stage, there is a trend to reduce the incidence of chronic lung disease. Early treatment with indomethacin reduces the incidence of periventricular haemorrhage. An ultrasound study of 110 very low birth weight infants showed ductus arteriosus size at 3 days to be related to factors reflecting the infants' condition (ventilation indices, blood product administration), but not to birth weight or gestational age. Infants with a moderate to large ductus arteriosus at 3 days had a significantly lower blood pressure from 12 h of age onwards than those with a closed or small ductuses.     

Postnatal closure of ductus venosus in preterm infants < or = 32 weeks. An ultrasonographic study

AIM: To assess ultrasonographically the flow pattern and the time of postnatal closure of ductus venosus in preterm infants < or = 32 weeks. METHODS: Thirty-three preterm infants < or = 32 weeks were studied within the first 1 to 5 days of life and followed every second day with ultrasound until no flow was detected either through the ductus venosus or the ductus arteriosus. RESULTS: The ductus venosus was closed in only 9% by day 3, in 40% by day 8 and 88% by day 18. All were closed by day 37. This is significantly later than in healthy term neonates. Closure of the ductus venosus was not significantly correlated with closure of ductus arteriosus. CONCLUSION: The ductus venosus shows a delayed closure in preterm infants, with no significant correlation to the closure of the ductus arteriosus or the condition of the infant. We speculate that immaturity of the ductus venosus and possibly increased levels of dilating prostaglandins leads to a delayed obliteration of the vessel. An open ductus venosus represents a portocaval shunt and may have metabolical and pharmacological consequences.     

Effect of persistent patent ductus arteriosus on mortality and morbidity in very low-birthweight infants

Aim: Because New Caledonia is geographically isolated from the nearest cardiac surgical centre, surgical closure of ductus arteriosus is not performed in very low‐birthweight (VLBW) infants who have a persistent patent ductus in spite of having undergone treatment with ibuprofen. This study aimed at investigating the possible effect of persistent patent ductus in VLBW infants. Methods: The study included 177 VLBW infants born at 25–31 weeks of gestation from January 2006 to May 2011. Mortality and major morbidities were compared between infants with a persistent patent ductus (n = 33) and those without it (n = 104). Statistical associations between potential neonatal risk factors and significant morbidities were identified using multivariate regression analyses. Results: Rates of mortality and major morbidities, including the rate of bronchopulmonary dysplasia, necrotizing enterocolitis, intraventricular haemorrhage grades I–II and III–IV, periventricular leucomalacia, late‐onset infections and failure of hearing screening, were insignificantly higher in VLBW infants with a persistent patent ductus than in those without it. Conclusion: This study adds further evidence that persistent patent ductus arteriosus has no significant effect on mortality and morbidity in VLBW infants born at ≥25 weeks’ gestational age.     

Closure of the ductus arteriosus and mechanics of breathing in preterm infants after surfactant replacement therapy

Treatment of premature infants with exogenous surfactant is thought to increase the incidence of the patent ductus arteriosus (PDA) due to improved mechanics of breathing and the resultant reduced pulmonary vascular resistance. As part of a prospective, blinded, controlled study of human amniotic fluid-derived surfactant, we assessed the time of closure of the PDA, defined by Doppler echocardiographic studies, performed at 6-h intervals, and the mechanics of breathing at 6, 18, and 30 h of age in 61 infants (gestational age, 25-29 wk, and birth wt, 450-1580 g). All infants had respiratory distress syndrome as confirmed by immature surfactant phospholipid profiles determined on either amniotic fluid and/or tracheal aspirate analysis, and chest radiograph, and all had a PDA at 6 h of age. Surfactant treatment was associated with more frequent clinically determined need for treatment of the PDA, but did not prolong the patency of the ductus in infants with spontaneous closure or in those requiring treatment with indomethacin. Infants with spontaneous closure of the PDA had significantly higher dynamic lung compliances and lower oxygen requirements and were treated with lower mean airway pressures than those requiring PDA treatment, although their arterial blood gas status was the same. The dynamic lung compliance of infants with right to left ductal shunting was significantly lower than those with left to right shunting at 6 and 18 h but was not different thereafter. This study suggests that the maturity of the ductus arteriosus, reflected by its tendency to close spontaneously, parallels the maturity of the lungs, reflected by their mechanical stability, and that ductal closing is not significantly altered by surfactant therapy.     

Severe pulmonary hypertension with therapeutic L-lysine ibuprofen in 2 preterm neonates

Persistently patent ductus arteriosus (PDA), affecting approximately one-third of all very low birth weight infants, can lead to significant morbidity and mortality. Recently, ibuprofen has been recommended over indomethacin to close PDAs because of a reduction in risk of necrotizing enterocolitis. Pulmonary hypertension is a rare but potentially fatal complication of ibuprofen administration in preterm infants. We report 2 infants who developed this complication after receiving therapeutic L-lysine ibuprofen preparation for the PDA closure. The first infant, 1 of twins weighing 640 g, was born at 24 weeks' gestation. The second infant, born at 26 weeks' gestation, was small for gestational age, weighing 439 g. In both cases, ibuprofen was initiated after echocardiographic confirmation of a moderate-sized to large PDA and an otherwise normal intracardiac anatomy. Both infants had echocardiographic evidence of increased pulmonary vascular resistance but shunting across the PDA was left to right. The infants deteriorated within 48 to 72 hours, and repeat echocardiograms revealed evidence of severe pulmonary hypertension. Both infants died of refractory hypotension and hypoxemia. When considering the use of ibuprofen therapy for PDA closure, clinicians should keep in mind the potential serious complication of pulmonary hypertension, even if a shunt across the PDA is left to right.     

Indomethacin and cerebral blood flow in premature infants treated for patent ductus arteriosus

Central blood flow (CBF) was estimated by an intravenous 133-xenon technique in six preterm infants before and after administration of indomethacin for closure of patent ductus arteriosus. CBF fell in all infants (range 12%–40%), the mean fall was 24% (P<0.005). Though none of the infants showed signs of impaired cerebral function during or following the injections, the results do not indicate whether or not the use of indomethacin is a potential hazard.Abbreviations PDA patent ductus arteriosus - CBF cerebral blood flow - PaCO₂ arterial carbon dioxide tension - MAP mean arterial blood pressure     

Bidirectional flow through the ductus arteriosus in normal newborns: Evaluation by Doppler color flow imaging

Summary To determine the duration of bidirectional flow through the ductus arteriosus and to confirm the time of functional closure of the ductus arteriosus, 25 normal full-term newborns were studied serially using Doppler color flow imaging beginning at 2–7 h after birth and continuing until no ductal flow was detected (defined as functional closure). At the first examination, blood flow was bidirectional in 19 of 25 infants and continuously left-to-right in the remaining six. Subsequent studies revealed that bidirectional ductal flow changed to continuous left-to-right flow in 17 of 19 infants, whereas two of 19 abolished the flow completely at the second examination. Three of the 19 infants still had bidirectional flow through the ductus arteriosus at 12, 18.5, and 24 h after birth. The percentage of newborns who had bidirectional flow through the ductus arteriosus decreased roughly as a negative exponential function of age. The earliest functional closure of the ductus arteriosus was at 8 h after birth: by 24 hours 44% and by 48 h, 88% were functionally closed. By 72 h of age, the ductus arteriosus was functionally closed in all 25 infants. This study shows that bidirectional flow through the ductus arteriosus changes to continuous left-to-right flow before the functional closure, but can persist up to 24 h after birth.     

Cross sectional echocardiography in determining persistent patency of the ductus arteriosus in preterm infants.

Thirty preterm infants (gestational age 26 to 30 weeks) were investigated by cross sectional echocardiography using a 5 or 7.5 MHz transducer positioned in the suprasternal notch or the left subclavicular position to enable visualisation of the aortic arch, main pulmonary artery, left pulmonary artery, and ductus arteriosus. Each infant was investigated on at least one occasion during both the first and second weeks of life and when possible between the ages of 26 and 31 days. There was prolonged patency of the ductus arteriosus during the first two weeks of life in all infants, and complete closure of the ductus arteriosus occurred only in four patients, all of whom had reached a postconceptional age of 32 to 34 weeks. Eighteen infants received intravenous indomethacin between the age of 5 and 10 days. In these patients ductal narrowing did not occur until a maximum postconceptional age of 29 weeks.     

Renal function in sick,very low-birth-weight infants

Renal immaturity is pronounced in very low-birth-weight infants with a gestational age ≤ 30 weeks. We attempted to elucidate if conditions requiring mechanical ventilation, including patent ductus arteriosus, might further compromise renal function due to decreased renal perfusion. Forty infants studied between 4 and 28 days of age were divided into four groups: Control with no patent ductus or mechanical ventilation (n= 8); PDA + MV, with both patent ductus and mechanical ventilation (n=17); PDA, with patent ductus (n= 6); MV, with mechanical ventilation (n= 9). The groups PDA + MV and MV had significantly lower creatinine clearances and significantly higher fractional sodium excretions than controls. Mean arterial pressure was significantly lower in all groups compared to controls and correlated significantly with creatinine clearance (r = 0.47, p < 0.02). In conclusion, low renal function in these infants is further compromised by a patent ductus arteriosus and/or the use of mechanical ventilation.     

EARLY CLOSURE OF PATENT DUCTUS ARTERIOSUS WITH INDOMETHACIN IN PRETERM INFANTS WITH IDIOPATHIC RESPIRATORY DISTRESS SYNDROME

ABSTRACT. Thirty-seven preterm infants with idiopathic respiratory distress syndrome were prospectively studied for the effect of the early closure of patent ductus arteriosus with indomethacin on the course of idiopathic respiratory distress syndrome. Serial retrograde aortograms were performed in all infants in order to visualize the ductus arteriosus, apart from three patients, who died early and were evaluated aortographically only once. The ductus was initially open in 27 infants and closed in 10 infants. The infants with open ductus arteriosus were randomly divided into two groups. The first group consisted of 13 infants, in whom the ductus was closed with indomethacin at a median age of 18 hours. The other 14 infants served as controls. Total time on assisted ventilation and duration of exposure to additional oxygen were significantly shorter in medicated infants than in controls. Oxygenation of infants with an initially closed ductus was better from birth and duration of their ventilatory assistance and oxygen exposure were shorter than in infants with initial ductal shunting. The data suggest that the early closure of the patent ductus arteriosus with indomethacin in distressed preterm infants has a favourable effect on the course of idiopathic respiratory distress syndrome.     

Mid-arm circumference/head circumference ratios for identification of symptomatic LGA, AGA, and SGA newborn infants

Mid-arm circumference/head circumference ratios (MAC/HC) and birth weights obtained in 73 neonates were studied to compare which of these growth measurements could more accurately predict risk of metabolic complications resulting from either acceleration or retardation of fetal growth. The MAC/HC ratio was more sensitive than birth weight in distinguishing symptomatic large for gestational age (LGA) infants who were born to diabetic mothers from other LGA infants who were asymptomatic, and symptomatic from asymptomatic small for gestational age infants. In addition, the MAC/HC ratio identified symptomatic appropriate for gestational age (AGA) infants born to diabetic mothers and AGA infants with signs and symptoms of growth retardation. The MAC/HC is more useful than birth weight in assessing newborn infants at risk for the metabolic complications associated with fetal growth disorders.