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Early Hemodynamic Consequences of Patent Ductus Arteriosus in Preterm Infants with Intrauterine Growth Restriction
Early Hemodynamic Consequences of Patent Ductus Arteriosus in Preterm Infants with Intrauterine Growth Restriction T. RAKZA, MD, E. MAGNENANT, MD, S. KLOSOWSKI, MD, P. TOURNEUX, MD, A. BACHIRI, MD,
AND
L. STORME, MD
Objective To test the hypothesis that significant patent ductus arteriosus (PDA) may occur very early after birth in preterm infants with intrauterine growth restriction (IUGR), we compared the longitudinal changes in left-to-right shunting through DA between eutrophic and preterm infants with IUGR. Study design The preterm infants –26 to 32 weeks gestational age (GA), admitted in our neonatal intensive care unit from February to May 2004 were included. They were separated into an “IUGR of placental origin” group and an “eutrophic” group. Significant PDA was assessed by Doppler echocardiography at 6, 24, and 48 hours of age. Results Thirty-one eutrophic (GA ⴝ 29 ⴞ 1.4 weeks; birth weight [BW] ⴝ 1300 ⴞ 160 g) and 17 infants with IUGR (GA ⴝ 29.3 ⴞ 1.5weeks; BW ⴝ 810 ⴞ 140 g) were studied. Six hours after birth, the rate of significant PDA was higher in the IUGR than in the eutrophic group (10/17 [60%] vs 5/31 [15%]; P < .05). More DA became significant in infants with IUGR (11/17 [65%]) than in eutrophic infants (12/31 [40%]) (P < .05) within the 48 hours after birth. Conclusion Markers of high pulmonary blood flow and systemic vascular steal occur more frequently and earlier after birth in IUGR of placental origin than in eutrophic preterm infants. The management of preterm infants with severe IUGR of placenta origin should include early echocardiographic monitoring to assess for markers of significant PDA. (J Pediatr 2007;151:624-8) ompared with preterm infants with appropriate weight for gestational age (GA), preterm infants with intrauterine growth restriction (IUGR) of placental origin are at high risk for neonatal death and morbidity.1 In particular, excess pulmonary hemorrhage and chronic lung disease have been found in preterm infants with IUGR.2-6 Furthermore, IUGR has been associated with increased severe intraventricular hemorrhage, necrotizing enterocolitis, and renal failure.1,3-7 These complications are usually considered to be caused by uteroplacental insufficiency, fetal hypoxia, and pronounced redistribution of fetal blood flow leading to multiple organs dysfunction.8 However, several lines of evidence suggest that a hemodynamically significant patent ductus arteriosus (PDA) may contribute to an increase of the risk of adverse outcomes in preterm infants with IUGR: (1) a higher incidence of significant PDA was found in small for GA newborn infants9,10; (2) PDA is associated with poor outcome in infants with severe IUGR11; (3) the characteristic hemodynamic features observed in preterm infants with significant PDA including lower mean arterial blood pressure and blood flow velocity in the superior mesenteric artery, and increased cardiac output and heart rate, have been previously reported in small for GA newborn infants9,12; and (4) PDA and IUGR have been associated with similar adverse events such as pulmonary and intraventricular hemorrhage, necrotizing enterocolitis, and renal failure.1-7,13-16 However, to our knowledge, assessment of PDA has not been investigated in the early postnatal period in From Clinique de Médecine Néonatale, preterm infants with IUGR of placental origin. Hôpital Jeanne de Flandre, CHRU de Lille (T.R., E.M., L.S.); Service de Médecine We hypothesized that significant left-to-right shunting through the ductus arteriNéonatale, CHG de Lens (S.K., A.B.); Serosus (DA) may occur very early after birth in preterm infants with IUGR. To test this vice de Réanimation Pédiatrique, CHU d’Amiens (P.T.); and Faculté de Médecine hypothesis, we compared the longitudinal changes in left-to-right shunting through DA Université de Lille II (T.R., E.M., P.T., L.S.), between eutrophic and IUGR preterm newborn infants. France.
C
Ao BW CPAP CRIB DA GA
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Aortic root Birth weight Continuous positive airway pressure Clinical risk index for babies Ductus arteriosus Gestational age
IUGR LA LPA NICU PDA
Intrauterine growth restriction Left atrial Left pulmonary artery Neonatal intensive care unit Patent ductus arteriosus
Submitted for publication Dec 1, 2006; last revision received Jan 22, 2007; accepted Apr 24, 2007. Reprint requests: T. Rakza, MD, Clinique de Medecine Neonatale, Hopital Jeanne de Flandre, CHRU de Lille, Lille cedex 59037, France. E-mail: [email protected] 0022-3476/$ - see front matter Copyright © 2007 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2007.04.058
METHODS We prospectively included all preterm newborn infants from 26 to 32 weeks GA admitted to our neonatal intensive care unit (NICU) from February and May 2004. Exclusion criteria were: cardiac malformations other than PDA, maternofetal infection, need for vasoactive drugs, IUGR of nonplacental origin, and outborn infants. The infants were separated into two groups: (1) a group of infants with IUGR, defined as a diminished growth velocity in the fetus documented by at least two intrauterine echographic growth assessments and a birth weight (BW) ⬍10th percentile (Lubchenko curves); and (2) a group of eutrophic infants, defined as normal growth velocity in the fetus and a BW ⬎10th percentile. The placental origin of the IUGR had been determined during pregnancy by Doppler evaluation of uterine and umbilical arteries. Heart rate, arterial blood pressure (noninvasive measurement), blood gases, and serum lactate concentrations were recorded at 6 hours of age. A clinical risk index for babies (CRIB) score was calculated. Echocardiography was carried out 6 hours after birth using a General Electric® VIVID echocardiographic system (GE Vingmed Ultrasound AS N-3190, Hosten, Norway) with a high-frequency 7.5 MHz transducer. An average of three to five consecutive readings for the vessel diameter and flow velocity integrals was used. The angle of insonation was ⬍20 degrees. The following Doppler echocardiographic variables were measured: - LA:Ao ratio: M mode pictures of LA (left atrial) and the Ao (aortic root) were obtained from a parasternal long axis view; - Internal diameter of the DA by both B mode and color Doppler from the high-left parasternal view; - End-diastolic flow velocity of the LPA was measured with pulsed Doppler using a high-left parasternal view; - Left ventricle shortening fraction from a parasternal long axis view; - Superior mesenteric resistance index was also recorded as an estimate of the diastolic steal. Significant left-to-right shunting through the DA was defined by the detection of the following concomitant four echocardiographic criteria12: ductal diameter (B mode and color Doppler) ⱖ1.5 mm, left atrial/aortic root ratio (LA:Ao) ⱖ1.4, pulsatile low blood flow velocity in the DA, and an end-diastolic flow velocity of the LPA ⱖ0.20 m/s. Significant PDA was treated with intervenous ibuprofen (Pedea®, Orphan Europe, loading dose of 10 mg/kg then two maintenance doses of 5 mg/kg at 24-hour intervals). DA was reevaluated by an echocardiogram with color-Doppler-flow at 24 and 48 hours after birth in infants who did not receive ibuprofen, that is, in infants whose DA was considered as nonsignificant at 6 hours of age. An ibuprofen course was then started if substantial PDA was detected. An additional echocardiogram was performed on day 7 after birth in each of the included infants. Mortality, respiratory (duration of mechanical ventilation, duration of nasal continuous positive airway pressure
Table I. General characteristics of the studied population
Gestational age (weeks) BW (g) Birth height (cm) Head circumference (cm) Antenatal corticosteroids RDS CRIB score
Eutrophic (n ⴝ 31)
IUGR (n ⴝ 17)
P
29 ⫾ 1.4 1300 ⫾ 160 39 ⫾ 1 27.2 ⫾ 0.5 27 (87%) 20 (64%) 2.5 ⫾ 0.6
29.3 ⫾ 1.5 810 ⫾ 140 33 ⫾ 1 24.4 ⫾ 0.5 16 (94%) 9 (52%) 4.5 ⫾ 0.7
NS ⬍.01 ⬍.01 ⬍.01 NS NS ⬍.05
Data are expressed as mean ⫾ SD. BW, birth weight; CRIB, clinical risk index for babies; IUGR, intrauterine growth restriction; NS, nonsignificant; RDS, respiratory distress syndrome.
[CPAP], chronic lung disease defined as oxygen dependency at 36 postconceptional weeks), and digestive (necrotizing enterocolitis, date at full-feeding) outcomes were compared between both groups. The parents were informed of the management protocol. As the present protocol was part of the usual management of premature newborn infants in our NICU, no consent from the parents was requested. Statistical analysis: Tests were performed using StatView® for PC (Abacus Concepts; Statview, Cary, NC). Quantitative variables were compared using Student’s nonpaired t test, qualitative variables were compared using 2 tests. Log-rank test was performed to compare the cumulative rate of significant DA between groups. A P ⬍ .05 was considered as statistically significant.
RESULTS Within the study period, 55 preterm infants from 26 to 32 weeks GA were admitted in our NICU. Four were outborn and three required vasoactive drugs for severe sepsis (two eutrophic, one IUGR): they were excluded from the study. Forty-eight infants were eligible for inclusion. There were 31 eutrophic (GA ⫽ 29 ⫾ 1.4 weeks; BW ⫽ 1300 ⫾ 160 g) and 17 growth-restricted newborn infants (GA ⫽ 29.3 ⫾ 1.5 weeks; BW ⫽ 810 ⫾ 140 g). The GA did not differ significantly between groups, but BW, birth height, and head circumference were significantly lower in the IUGR group, as expected (Table I). Exogenous surfactant (Curosurf® 200mg/ kg, SERONO, France) was given to each infant within the first 30 minutes of life, except in two infants with IUGR and three eutrophic infants without respiratory failure. The groups were not statistically different for antenatal corticosteroids and the occurrence of respiratory distress syndrome (Table I). The CRIB score was higher in the IUGR group (Table I). At birth, blood lactate concentration was higher in the IUGR than in the eutrophic group (eutrophic vs IUGR: 4.5 ⫾ 1.9 vs 6.2 ⫾ 2.4 mmol/L, P ⬍ .05). At 6 hours of age, both groups were similar regarding heart rate (eutrophic vs IUGR: 125 ⫾ 13 vs 140 ⫾ 12 beats/min), and systolic (57 ⫾ 9 vs 56 ⫾ 7 mmHg) and mean
Early Hemodynamic Consequences of Patent Ductus Arteriosus in Preterm Infants with Intrauterine Growth Restriction
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Table II. Comparison, at 6 hours of age, of the echocardiographic markers of patent ductus arteriosus between growth-restricted and eutrophic preterm infants
DA diameter (mm) LA:Ao SF (%) ED-LPA (m/s) MRI
Eutrophic (n ⴝ 31)
IUGR (n ⴝ 17)
P
2.1 ⫾ 0.6 1.2 ⫾ 0.06 35 ⫾ 9 0.16 ⫾ 0.03 0.7 ⫾ 0.05
2.7 ⫾ 0.7 1.5 ⫾ 0.08 45 ⫾ 8 0.23 ⫾ 0.02 0.86 ⫾ 0.08
⬍.05 ⬍.01 ⫽.06 ⬍0.05 ⬍.05
Data are expressed as mean ⫾ SD. DA, ductus arteriosus; ED-LPA, end-diastolic blood flow velocity in the left pulmonary artery; IUGR, intrauterine growth restriction; MRI, superior mesenteric resistance index; SF, left ventricle shortening fraction.
Figure. Comparison of cumulative rate of significant patent ductus arteriosus (PDA) at 6, 24, and 48 hours of age, between infants with intrauterine growth restriction (IUGR) and eutrophic preterm infants (expressed as %). Rate of significant ductus arteriosus (DA) within the first 48 hours after birth was higher in the IUGR than in the eutrophic group (Log-rank test, P ⬍ .05). As ibuprofen treatment was started as soon as PDA was found significant, the figure represents also the cumulative rate of ibuprofen treatment in each group (expressed as % of treated infants).
arterial blood pressure (44 ⫾ 6 vs 40 ⫾ 5 mmHg). However, diastolic arterial blood pressure was lower in the IUGR group than in the eutrophic group (eutrophic vs IUGR: 37 ⫾ 4 vs 28 ⫾ 3 mmHg; P ⬍ .05). Values of pH (eutrophic vs IUGR: 7.35 ⫾ 0.06 vs 7.32 ⫾ 0.07), and PaCO2 (45 ⫾ 6 vs 48 ⫾ 5 mmHg) were not different between groups. Oxygen requirement was similar in both groups (eutrophic vs IUGR: 24 ⫾ 4 vs 23 ⫾ 3%). Blood lactate concentration was higher in the IUGR group at 6 hours of age than in the eutrophic group (eutrophic vs IUGR: 2.6 ⫾ 0.6 vs 4.7 ⫾ 0.7 mmol/L, P ⬍ .01). The DA closed spontaneously at 6 hours of age in one eutrophic infant and did not occur in the infants with IUGR. Six hours after birth, the rate of significant left-to-right shunting through DA was higher in the IUGR than in the eutrophic group (eutrophic vs IUGR: 5/31 (15%) vs 10/17 (60%); P ⬍ .05) (Figure). The DA was larger in the IUGR than in the eutrophic group (eutrophic [after the exclusion of the infant with closed DA] vs IUGR: 2.1 ⫾ 0.6 vs 2.7 ⫾ 0.7 mm; P ⬍ .05) (Table II). A more striking difference was found when the DA diameter was expressed as millimeters per kilogram (eutrophic vs IUGR: 1.9 ⫾ 0.9 vs 3.5 ⫾ 1 mm/kg; P ⬍ .001). Mean LA:Ao was higher in the IUGR group than in the eutrophic group (eutrophic vs IUGR: 1.2 ⫾ 0.06 vs 1.5 ⫾ 0.08, P ⬍ .05) (Table II). Left ventricle shortening fraction did not differ significantly between groups (eutrophic vs IUGR: 35 ⫾ 9% vs 45 ⫾ 8%, P ⫽ .06) (Table II). Mean end-diastolic blood flow velocity in the LPA was higher in the IUGR than in the eutrophic group (eutrophic vs IUGR: 0.16 ⫾ 0.03 vs 0.23 ⫾ 0.02 m/s, P ⬍ .05) (Table II). A higher mesenteric resistance index was found in the IUGR 626
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compared with the eutrophic group (eutrophic vs IUGR: 0.7 ⫾ 0.05 vs 0.86 ⫾ 0.08, P ⬍ .05) (Table II). Between 6 and 24 hours of age, five additional infants in the eutrophic group and one in the IUGR group exhibited a significant PDA. Between 24 and 48 hours of age, two additional infants in the eutrophic group had a significant PDA. Within the same period of time, no additional significant PDA was found in the IUGR group. The rate of significant DA was higher in the IUGR than in the eutrophic group (P ⬍ .05) (Figure). As ibuprofen treatment was started as soon as a PDA was found significant, the Figure depicts the timing of treatment. Ibuprofen treatment was used in 12 of 31 eutrophic infants at a mean postnatal age of 20 ⫾ 15 hours and in 11 of 17 IUGR infants at a mean postnatal age of 8 ⫾ 5 hours (P ⬍ .05). Fluid management was similar in both groups. The total amount of fluid was 79 ⫾ 8 and 72 ⫾ 12 mL/kg during the first day and 88 ⫾ 7 and 84 ⫾ 10 mL/kg between 24 and 48 hours after birth in respectively the eutrophic and IUGR group. On day 7 after birth, five infants from the Eutrophic group still had a significant PDA, whereas the DA was closed in all infants with IUGR. Despite a second course of ibuprofen, surgical ligation of the DA was required in these five eutrophic infants. None of the infants with IUGR required surgery for PDA. There was no statistical difference between the groups regarding the duration of mechanical ventilation, the duration of nasal CPAP and O2 therapy, chronic lung disease, the occurrence of necrotizing enterocolitis, postnatal age at full oral feeding, or death (Table III). Causes of death were necrotizing enterocolitis (two infants with IUGR), intracranial hemorrhage grade IV (one eutrophic infant), and severe sepsis (one infant with IUGR).
DISCUSSION In this prospective study, we compared the longitudinal changes in left-to-right shunting through the DA between eutrophic and preterm newborn infants with IUGR. Echocardiograms with color Doppler flow were performed at 6 hours of age to assess hemodynamic significance of the PDA The Journal of Pediatrics • December 2007
Table III. Short-term outcome of the studied population
Pulmonary hemorrhage Mechanical ventilation (hours) CPAP (days) O2 supplementation (days) CLD NEC Postnatal age at full-feeding (days) Death
Eutrophic (n ⴝ 31)
IUGR (n ⴝ 17)
P
0 75 ⫾ 24 8⫾2 21 ⫾ 6 6 (19%) 4 (13%) 21 ⫾ 3 1
0 49 ⫾ 20 10 ⫾ 4 30 ⫾ 9 4 (23%) 2 (12%) 25 ⫾ 3 3
NS NS NS NS NS NS NS NS
Data are expressed as mean ⫾ SD. CLD, chronic lung disease; CPAP, continuous positive airway pressure; IUGR, intrauterine growth restriction; NEC, necrotizing enterocolitis; NS, nonsignificant.
by using previously validated measures. The DA was reevaluated at 24 and 48 hours in infants with a nonsignificant PDA at 6 hours of age. We found that the rate of clinically significant PDA in the first 48 hours of life was higher in infants with IUGR than in eutrophic preterm infants. Furthermore, PDA became significant earlier in infants with IUGR than in eutrophic infants. Previous reports mentioned a higher incidence of PDA in small for GA newborn infants. PDA was more prevalent on day 1, 2, 3, and 5 in a cohort of 41 small for GA preterm infants than in 40 appropriate for GA preterm infants.9 Furthermore, IUGR has been recognized as a risk factor for PDA.10 However, the degree of left-to-right shunting through the DA had not been evaluated in these studies. Our study provides new information as we found that more PDAs were hemodynamically significant in infants with IUGR than in eutrophic preterm infants. Furthermore, our data show that echocardiographic markers of high left-to-right ductal flow can be recorded during the first hours of life in preterm infants with IUGR. IUGR in preterm infants is associated with increased risks of neonatal death and morbidity such as pulmonary hemorrhage, chronic lung disease, severe intraventricular hemorrhage, necrotizing enterocolitis, and renal failure.1-7 Similar adverse events exist in preterm infants with significant left-to-right shunting through the DA.13-17 Although PDA has been previously associated with poor outcomes in infants with severe IUGR,11 no study evaluated the role of PDA in the IUGR-associated morbidity. We found that the DA was larger in infants with IUGR than in eutrophic preterm infants, as soon as 6 hours after birth. The DA diameter was twice greater when it is expressed as millimeters per kilogram. It seems logical to take into account the body weight, as a 2-mm DA may not have the same hemodynamic consequence in an 800-g or a 1300-g preterm newborn. Markers of high pulmonary blood flow—increase in LA:Ao ratio and in telediastolic blood flow velocity in the LPA—were found more frequently in infants with IUGR than in eutrophic preterm infants. The elevation of pulmonary blood flow may cause stress failure of the thin-walled pulmonary capillaries.13 Pul-
monary hemorrhage in preterm infants has been associated with high pulmonary blood flow.13 We speculate that a higher proportion of clinically significant PDA may explain why the incidence of pulmonary hemorrhage is increased in the IUGR population.2 Furthermore, our data suggest that PDA results in earlier and greater systemic vascular steal in infants with IUGR than in eutrophic preterm infants. In particular, the diastolic blood flow velocity of the superior mesenteric artery was lower in the preterm infants with IUGR. In the same way, diastolic blood pressure was found lower in the IUGR group, although concerns exist about the accuracy of diastolic blood pressure measurement obtained with a non-invasive blood pressure monitor. An increased lactate serum concentration in preterm infants with IUGR may indicate an unbalance between O2 delivery and O2 consumption. By decreasing systemic blood flow and O2 delivery, a large PDA may contribute to the elevation of lactate concentration. Alternatively, increased lactate concentration in the infants with IUGR may result from perinatal lactate accumulation, caused by placental insufficiency as suggested by the elevated lactate concentration at birth in this group. The role of significant PDA in the etiology of intraventricular hemorrhage, renal dysfunction, and necrotizing enterocolitis has been suggested.15-20 Moreover, increased shunting through the PDA observed within the first 24 hours of life has been associated with intraventicular hemorrhage in preterm infants.21 We speculate that significant PDA may contribute, at least in part, to an increase in the risks of adverse neonatal outcomes among preterm infants with IUGR. The mechanisms explaining the earlier and greater hemodynamic effects of PDA in infants with IUGR remain uncertain. The clinical significance of the DA is dependent on the degree of left-to-right shunting through the ductus. Ductal flow is directly proportional to DA diameter. Compared with eutrophic preterm infants, a histological examination of DA from infants with IUGR highlighted major anomalies of both intima and media of the vessel wall.22 These changes may play a role in keeping the lumen of the DA open in preterm infants with IUGR. However, the DA was responsive to the inhibition of cyclooxygenase as significant PDA was closed in all infants with IUGR by ibuprofen treatment. This positive response to treatment may be a result of an early use of ibuprofen in the preterm infants with IUGR. Clinical and experimental investigations showed that prostaglandin inhibitors administered early after birth are more effective in constricting the DA than later treatment.23 In addition to a larger DA diameter, higher pulmonary blood flow observed in the preterm infants with IUGR may also result from lower pulmonary vascular resistance. Pulmonary vascular resistance is dependant on blood gases and on the degree of the respiratory failure. In our study, arterial pH, PaO2 and PaCO2, and oxygen need were similar in IUGR and eutrophic preterm infants. Alternatively, chronic hypoxia in utero may contribute to a faster decrease in pulmonary vascular resistance in growth-restricted babies, through the production of vasodilator stress-related factors. We previously showed that cat-
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echolamines, especially norepinephrine, increase pulmonary blood flow in fetal lambs through the activation of ␣2-adrenoceptor and NO release.24,25 Moreover, the pulmonary vasodilator effect of norepinephrine can be enhanced by glucocorticoids,26 production of which is increased in IUGR of placental origin.27 Neonatologists should be aware that PDA may become hemodynamically significant from the first hours of life in preterm infants with IUGR. The management of preterm infants with severe IUGR of placental origin should include early echocardiographic monitoring to assess for markers of significant PDA.
REFERENCES 1. Bernstein IM, Horbar JD, Badger GJ, Ohlsson A, Golan A. Morbidity and mortality among very low birth weight neonates with intra-uterine growth restriction. The Vermont Oxford Network. Am J Obstet Gynecol 2000;182:1998-206. 2. Braun KR, Davidson KM, Henry M, Nielsen HC. Severe pulmonary hemorrhage in the premature newborn infant: analysis of presurfactant and surfactant eras. Biol Neonate 1999;75:18-30. 3. Regev RH, Lusky A, Dolfin T, Litmanovitz I, Arnon S, Reichman B. Israel Neonatal Network. Excess mortality and morbidity among small-for-gestational-age premature infants: a population-based study. J Pediatr 2003;143:186-91. 4. Lal MK, Manktelow BN, Draper ES, Field DJ. Chronic lung disease of prematurity and intrauterine growth retardation: a population-based study. Pediatrics. 2003;111:483-7. 5. Garite TJ, Clark R, Thorp JA. Intrauterine growth restriction increases morbidity and mortality among premature neonates. Am J Obstet Gynecol 2004;191:481-7. 6. Aucott SW, Donohue PK, Northington FJ. Increased morbidity in severe early intrauterine growth restriction. J Perinatol 2004;24:435-40. 7. Keijzer-Veen MG, Schrevel M, Finken MJ, Dekker FW, Nauta J, Hille ET, et al. Microalbuminuria and lower glomerular filtration rate at young adult age in subjects born very premature and after intrauterine growth retardation. J Am Soc Nephrol 2005;16:2762-8. 8. Fang S. Management of preterm infants with intrauterine growth restriction. Early Hum Dev 2005;81:889-900. 9. Robel-Tillig E, Knupfer M, Vogtmann C. Cardiac adaptation in small for gestational age neonates after prenatal hemodynamic disturbances. Early Hum Dev 2003;72:123-9. 10. Cotton RB, Lindstrom DP, Stahlman MT. Early prediction of symptomatic patent ductus arteriosus from perinatal risk factors: a discriminant analysis model. Acta Paediatr Scand 1981;70:723-7.
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11. Lee MJ, Conner EL, Charafeddine L, Woods JR Jr, Priore GD. A critical birth weight and other determinants of survival for infants with severe intrauterine growth restriction. Ann N Y Acad Sci 2001;943:326-39. 12. El Hajjar M, Vaksmann G, Rakza T, Kongolo G, Storme L. Severity of the ductal shunt: a comparison of different markers. Arch Dis Child Fetal Neonatal Ed 2005;90:F419-F422. 13. Kluckow M, Evans N. Ductal shunting, high pulmonary blood flow, and pulmonary hemorrhage. J Pediatr 2000;137:68-72. 14. Garland J, Buck R, Weinberg M. Pulmonary hemorrhage risk in infants with a clinically diagnosed patent ductus arteriosus: a retrospective cohort study. Pediatrics 1994;94:719-23. 15. Evans N, Moorcraft J. Effect of patency of the ductus arteriosus on blood pressure in very preterm infants. Arch Dis Child 1992;67:1169-73. 16. Shimada S, Kasai T, Konishi M, Fujiwara T. Effects of patent ductus arteriosus on left ventricular output and organ blood flows in preterm infants with respiratory distress syndrome treated with surfactant. J Pediatr 1994;125:270-7. 17. Marshall DD, Kotelchuck M, Young TE, Bose CL, Kruyer L, O’Shea TM. Risk factors for chronic lung disease in the surfactant era: a North Carolina population-based study of very low birth weight infants. Pediatrics 1999;104:1345-50. 18. Evans N, Kluckow M. Early determinants of right and left ventricular output in ventilated preterm infants. Arch Dis Child Fetal Neonatal Ed 1996;74:F88-F94. 19. Bomelburg T, Jorch G. Abnormal blood flow patterns in renal arteries of small preterm infants with patent ductus arteriosus detected by Doppler ultrasonography. Eur J Pediatr 1989;148:660-4. 20. Phillipos EZ, Robertson MA, Byrne PJ. Serial assessment of ductus arteriosus hemodynamics in hyaline membrane disease. Pediatrics 1996;98:1149-53. 21. Evans N, Kluckow M. Early ductal shunting and intraventricular haemorrhage in ventilated preterm infants. Arch Dis Child Fetal Neonatal Ed 1996;75:F183-F186. 22. Ibara S, Tokunaga M, Ikenoue T, Murata Y, Hirano T, Asano H, et al. Histologic observation of the ductus arteriosus in premature infants with intrauterine growth retardation. J Perinatol 1994;14:411-6. 23. Shah SS, Ohlsson A. Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants. Cochrane Database Syst Rev 2006;25: CD004213. 24. Jaillard S, Houfflin-Debarge V, Riou Y, Rakza T, Klosowski S, Lequien P, et al. Effects of catecholamines on the pulmonary circulation in the ovine fetus. Am J Physiol Regul Integr Comp Physiol 2001;281:R607-R614. 25. Magnenant E, Jaillard S, Deruelle P, Houfflin-Debarge V, Riou Y, Klosowski S, et al. Role of the alpha2-adrenoceptors on the pulmonary circulation in the ovine fetus. Pediatr Res 2003;54:44-51. 26. Deruelle P, Houfflin-Debarge V, Magnenant E, Jaillard S, Riou Y, Puech F, et al. Effects of antenatal glucocorticoids on pulmonary vascular reactivity in the ovine fetus. Am J Obstet Gynecol 2003;189:208-15. 27. Goland RS, Jozak S, Warren WB, Conwell IM, Stark RI, Tropper PJ. Elevated levels of umbilical cord plasma corticotropin-releasing hormone in growth-retarded fetuses. J Clin Endocrinol Metab 1993;77:1174-9.
The Journal of Pediatrics • December 2007
AND
L. STORME, MD
Objective To test the hypothesis that significant patent ductus arteriosus (PDA) may occur very early after birth in preterm infants with intrauterine growth restriction (IUGR), we compared the longitudinal changes in left-to-right shunting through DA between eutrophic and preterm infants with IUGR. Study design The preterm infants –26 to 32 weeks gestational age (GA), admitted in our neonatal intensive care unit from February to May 2004 were included. They were separated into an “IUGR of placental origin” group and an “eutrophic” group. Significant PDA was assessed by Doppler echocardiography at 6, 24, and 48 hours of age. Results Thirty-one eutrophic (GA ⴝ 29 ⴞ 1.4 weeks; birth weight [BW] ⴝ 1300 ⴞ 160 g) and 17 infants with IUGR (GA ⴝ 29.3 ⴞ 1.5weeks; BW ⴝ 810 ⴞ 140 g) were studied. Six hours after birth, the rate of significant PDA was higher in the IUGR than in the eutrophic group (10/17 [60%] vs 5/31 [15%]; P < .05). More DA became significant in infants with IUGR (11/17 [65%]) than in eutrophic infants (12/31 [40%]) (P < .05) within the 48 hours after birth. Conclusion Markers of high pulmonary blood flow and systemic vascular steal occur more frequently and earlier after birth in IUGR of placental origin than in eutrophic preterm infants. The management of preterm infants with severe IUGR of placenta origin should include early echocardiographic monitoring to assess for markers of significant PDA. (J Pediatr 2007;151:624-8) ompared with preterm infants with appropriate weight for gestational age (GA), preterm infants with intrauterine growth restriction (IUGR) of placental origin are at high risk for neonatal death and morbidity.1 In particular, excess pulmonary hemorrhage and chronic lung disease have been found in preterm infants with IUGR.2-6 Furthermore, IUGR has been associated with increased severe intraventricular hemorrhage, necrotizing enterocolitis, and renal failure.1,3-7 These complications are usually considered to be caused by uteroplacental insufficiency, fetal hypoxia, and pronounced redistribution of fetal blood flow leading to multiple organs dysfunction.8 However, several lines of evidence suggest that a hemodynamically significant patent ductus arteriosus (PDA) may contribute to an increase of the risk of adverse outcomes in preterm infants with IUGR: (1) a higher incidence of significant PDA was found in small for GA newborn infants9,10; (2) PDA is associated with poor outcome in infants with severe IUGR11; (3) the characteristic hemodynamic features observed in preterm infants with significant PDA including lower mean arterial blood pressure and blood flow velocity in the superior mesenteric artery, and increased cardiac output and heart rate, have been previously reported in small for GA newborn infants9,12; and (4) PDA and IUGR have been associated with similar adverse events such as pulmonary and intraventricular hemorrhage, necrotizing enterocolitis, and renal failure.1-7,13-16 However, to our knowledge, assessment of PDA has not been investigated in the early postnatal period in From Clinique de Médecine Néonatale, preterm infants with IUGR of placental origin. Hôpital Jeanne de Flandre, CHRU de Lille (T.R., E.M., L.S.); Service de Médecine We hypothesized that significant left-to-right shunting through the ductus arteriNéonatale, CHG de Lens (S.K., A.B.); Serosus (DA) may occur very early after birth in preterm infants with IUGR. To test this vice de Réanimation Pédiatrique, CHU d’Amiens (P.T.); and Faculté de Médecine hypothesis, we compared the longitudinal changes in left-to-right shunting through DA Université de Lille II (T.R., E.M., P.T., L.S.), between eutrophic and IUGR preterm newborn infants. France.
C
Ao BW CPAP CRIB DA GA
624
Aortic root Birth weight Continuous positive airway pressure Clinical risk index for babies Ductus arteriosus Gestational age
IUGR LA LPA NICU PDA
Intrauterine growth restriction Left atrial Left pulmonary artery Neonatal intensive care unit Patent ductus arteriosus
Submitted for publication Dec 1, 2006; last revision received Jan 22, 2007; accepted Apr 24, 2007. Reprint requests: T. Rakza, MD, Clinique de Medecine Neonatale, Hopital Jeanne de Flandre, CHRU de Lille, Lille cedex 59037, France. E-mail: [email protected] 0022-3476/$ - see front matter Copyright © 2007 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2007.04.058
METHODS We prospectively included all preterm newborn infants from 26 to 32 weeks GA admitted to our neonatal intensive care unit (NICU) from February and May 2004. Exclusion criteria were: cardiac malformations other than PDA, maternofetal infection, need for vasoactive drugs, IUGR of nonplacental origin, and outborn infants. The infants were separated into two groups: (1) a group of infants with IUGR, defined as a diminished growth velocity in the fetus documented by at least two intrauterine echographic growth assessments and a birth weight (BW) ⬍10th percentile (Lubchenko curves); and (2) a group of eutrophic infants, defined as normal growth velocity in the fetus and a BW ⬎10th percentile. The placental origin of the IUGR had been determined during pregnancy by Doppler evaluation of uterine and umbilical arteries. Heart rate, arterial blood pressure (noninvasive measurement), blood gases, and serum lactate concentrations were recorded at 6 hours of age. A clinical risk index for babies (CRIB) score was calculated. Echocardiography was carried out 6 hours after birth using a General Electric® VIVID echocardiographic system (GE Vingmed Ultrasound AS N-3190, Hosten, Norway) with a high-frequency 7.5 MHz transducer. An average of three to five consecutive readings for the vessel diameter and flow velocity integrals was used. The angle of insonation was ⬍20 degrees. The following Doppler echocardiographic variables were measured: - LA:Ao ratio: M mode pictures of LA (left atrial) and the Ao (aortic root) were obtained from a parasternal long axis view; - Internal diameter of the DA by both B mode and color Doppler from the high-left parasternal view; - End-diastolic flow velocity of the LPA was measured with pulsed Doppler using a high-left parasternal view; - Left ventricle shortening fraction from a parasternal long axis view; - Superior mesenteric resistance index was also recorded as an estimate of the diastolic steal. Significant left-to-right shunting through the DA was defined by the detection of the following concomitant four echocardiographic criteria12: ductal diameter (B mode and color Doppler) ⱖ1.5 mm, left atrial/aortic root ratio (LA:Ao) ⱖ1.4, pulsatile low blood flow velocity in the DA, and an end-diastolic flow velocity of the LPA ⱖ0.20 m/s. Significant PDA was treated with intervenous ibuprofen (Pedea®, Orphan Europe, loading dose of 10 mg/kg then two maintenance doses of 5 mg/kg at 24-hour intervals). DA was reevaluated by an echocardiogram with color-Doppler-flow at 24 and 48 hours after birth in infants who did not receive ibuprofen, that is, in infants whose DA was considered as nonsignificant at 6 hours of age. An ibuprofen course was then started if substantial PDA was detected. An additional echocardiogram was performed on day 7 after birth in each of the included infants. Mortality, respiratory (duration of mechanical ventilation, duration of nasal continuous positive airway pressure
Table I. General characteristics of the studied population
Gestational age (weeks) BW (g) Birth height (cm) Head circumference (cm) Antenatal corticosteroids RDS CRIB score
Eutrophic (n ⴝ 31)
IUGR (n ⴝ 17)
P
29 ⫾ 1.4 1300 ⫾ 160 39 ⫾ 1 27.2 ⫾ 0.5 27 (87%) 20 (64%) 2.5 ⫾ 0.6
29.3 ⫾ 1.5 810 ⫾ 140 33 ⫾ 1 24.4 ⫾ 0.5 16 (94%) 9 (52%) 4.5 ⫾ 0.7
NS ⬍.01 ⬍.01 ⬍.01 NS NS ⬍.05
Data are expressed as mean ⫾ SD. BW, birth weight; CRIB, clinical risk index for babies; IUGR, intrauterine growth restriction; NS, nonsignificant; RDS, respiratory distress syndrome.
[CPAP], chronic lung disease defined as oxygen dependency at 36 postconceptional weeks), and digestive (necrotizing enterocolitis, date at full-feeding) outcomes were compared between both groups. The parents were informed of the management protocol. As the present protocol was part of the usual management of premature newborn infants in our NICU, no consent from the parents was requested. Statistical analysis: Tests were performed using StatView® for PC (Abacus Concepts; Statview, Cary, NC). Quantitative variables were compared using Student’s nonpaired t test, qualitative variables were compared using 2 tests. Log-rank test was performed to compare the cumulative rate of significant DA between groups. A P ⬍ .05 was considered as statistically significant.
RESULTS Within the study period, 55 preterm infants from 26 to 32 weeks GA were admitted in our NICU. Four were outborn and three required vasoactive drugs for severe sepsis (two eutrophic, one IUGR): they were excluded from the study. Forty-eight infants were eligible for inclusion. There were 31 eutrophic (GA ⫽ 29 ⫾ 1.4 weeks; BW ⫽ 1300 ⫾ 160 g) and 17 growth-restricted newborn infants (GA ⫽ 29.3 ⫾ 1.5 weeks; BW ⫽ 810 ⫾ 140 g). The GA did not differ significantly between groups, but BW, birth height, and head circumference were significantly lower in the IUGR group, as expected (Table I). Exogenous surfactant (Curosurf® 200mg/ kg, SERONO, France) was given to each infant within the first 30 minutes of life, except in two infants with IUGR and three eutrophic infants without respiratory failure. The groups were not statistically different for antenatal corticosteroids and the occurrence of respiratory distress syndrome (Table I). The CRIB score was higher in the IUGR group (Table I). At birth, blood lactate concentration was higher in the IUGR than in the eutrophic group (eutrophic vs IUGR: 4.5 ⫾ 1.9 vs 6.2 ⫾ 2.4 mmol/L, P ⬍ .05). At 6 hours of age, both groups were similar regarding heart rate (eutrophic vs IUGR: 125 ⫾ 13 vs 140 ⫾ 12 beats/min), and systolic (57 ⫾ 9 vs 56 ⫾ 7 mmHg) and mean
Early Hemodynamic Consequences of Patent Ductus Arteriosus in Preterm Infants with Intrauterine Growth Restriction
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Table II. Comparison, at 6 hours of age, of the echocardiographic markers of patent ductus arteriosus between growth-restricted and eutrophic preterm infants
DA diameter (mm) LA:Ao SF (%) ED-LPA (m/s) MRI
Eutrophic (n ⴝ 31)
IUGR (n ⴝ 17)
P
2.1 ⫾ 0.6 1.2 ⫾ 0.06 35 ⫾ 9 0.16 ⫾ 0.03 0.7 ⫾ 0.05
2.7 ⫾ 0.7 1.5 ⫾ 0.08 45 ⫾ 8 0.23 ⫾ 0.02 0.86 ⫾ 0.08
⬍.05 ⬍.01 ⫽.06 ⬍0.05 ⬍.05
Data are expressed as mean ⫾ SD. DA, ductus arteriosus; ED-LPA, end-diastolic blood flow velocity in the left pulmonary artery; IUGR, intrauterine growth restriction; MRI, superior mesenteric resistance index; SF, left ventricle shortening fraction.
Figure. Comparison of cumulative rate of significant patent ductus arteriosus (PDA) at 6, 24, and 48 hours of age, between infants with intrauterine growth restriction (IUGR) and eutrophic preterm infants (expressed as %). Rate of significant ductus arteriosus (DA) within the first 48 hours after birth was higher in the IUGR than in the eutrophic group (Log-rank test, P ⬍ .05). As ibuprofen treatment was started as soon as PDA was found significant, the figure represents also the cumulative rate of ibuprofen treatment in each group (expressed as % of treated infants).
arterial blood pressure (44 ⫾ 6 vs 40 ⫾ 5 mmHg). However, diastolic arterial blood pressure was lower in the IUGR group than in the eutrophic group (eutrophic vs IUGR: 37 ⫾ 4 vs 28 ⫾ 3 mmHg; P ⬍ .05). Values of pH (eutrophic vs IUGR: 7.35 ⫾ 0.06 vs 7.32 ⫾ 0.07), and PaCO2 (45 ⫾ 6 vs 48 ⫾ 5 mmHg) were not different between groups. Oxygen requirement was similar in both groups (eutrophic vs IUGR: 24 ⫾ 4 vs 23 ⫾ 3%). Blood lactate concentration was higher in the IUGR group at 6 hours of age than in the eutrophic group (eutrophic vs IUGR: 2.6 ⫾ 0.6 vs 4.7 ⫾ 0.7 mmol/L, P ⬍ .01). The DA closed spontaneously at 6 hours of age in one eutrophic infant and did not occur in the infants with IUGR. Six hours after birth, the rate of significant left-to-right shunting through DA was higher in the IUGR than in the eutrophic group (eutrophic vs IUGR: 5/31 (15%) vs 10/17 (60%); P ⬍ .05) (Figure). The DA was larger in the IUGR than in the eutrophic group (eutrophic [after the exclusion of the infant with closed DA] vs IUGR: 2.1 ⫾ 0.6 vs 2.7 ⫾ 0.7 mm; P ⬍ .05) (Table II). A more striking difference was found when the DA diameter was expressed as millimeters per kilogram (eutrophic vs IUGR: 1.9 ⫾ 0.9 vs 3.5 ⫾ 1 mm/kg; P ⬍ .001). Mean LA:Ao was higher in the IUGR group than in the eutrophic group (eutrophic vs IUGR: 1.2 ⫾ 0.06 vs 1.5 ⫾ 0.08, P ⬍ .05) (Table II). Left ventricle shortening fraction did not differ significantly between groups (eutrophic vs IUGR: 35 ⫾ 9% vs 45 ⫾ 8%, P ⫽ .06) (Table II). Mean end-diastolic blood flow velocity in the LPA was higher in the IUGR than in the eutrophic group (eutrophic vs IUGR: 0.16 ⫾ 0.03 vs 0.23 ⫾ 0.02 m/s, P ⬍ .05) (Table II). A higher mesenteric resistance index was found in the IUGR 626
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compared with the eutrophic group (eutrophic vs IUGR: 0.7 ⫾ 0.05 vs 0.86 ⫾ 0.08, P ⬍ .05) (Table II). Between 6 and 24 hours of age, five additional infants in the eutrophic group and one in the IUGR group exhibited a significant PDA. Between 24 and 48 hours of age, two additional infants in the eutrophic group had a significant PDA. Within the same period of time, no additional significant PDA was found in the IUGR group. The rate of significant DA was higher in the IUGR than in the eutrophic group (P ⬍ .05) (Figure). As ibuprofen treatment was started as soon as a PDA was found significant, the Figure depicts the timing of treatment. Ibuprofen treatment was used in 12 of 31 eutrophic infants at a mean postnatal age of 20 ⫾ 15 hours and in 11 of 17 IUGR infants at a mean postnatal age of 8 ⫾ 5 hours (P ⬍ .05). Fluid management was similar in both groups. The total amount of fluid was 79 ⫾ 8 and 72 ⫾ 12 mL/kg during the first day and 88 ⫾ 7 and 84 ⫾ 10 mL/kg between 24 and 48 hours after birth in respectively the eutrophic and IUGR group. On day 7 after birth, five infants from the Eutrophic group still had a significant PDA, whereas the DA was closed in all infants with IUGR. Despite a second course of ibuprofen, surgical ligation of the DA was required in these five eutrophic infants. None of the infants with IUGR required surgery for PDA. There was no statistical difference between the groups regarding the duration of mechanical ventilation, the duration of nasal CPAP and O2 therapy, chronic lung disease, the occurrence of necrotizing enterocolitis, postnatal age at full oral feeding, or death (Table III). Causes of death were necrotizing enterocolitis (two infants with IUGR), intracranial hemorrhage grade IV (one eutrophic infant), and severe sepsis (one infant with IUGR).
DISCUSSION In this prospective study, we compared the longitudinal changes in left-to-right shunting through the DA between eutrophic and preterm newborn infants with IUGR. Echocardiograms with color Doppler flow were performed at 6 hours of age to assess hemodynamic significance of the PDA The Journal of Pediatrics • December 2007
Table III. Short-term outcome of the studied population
Pulmonary hemorrhage Mechanical ventilation (hours) CPAP (days) O2 supplementation (days) CLD NEC Postnatal age at full-feeding (days) Death
Eutrophic (n ⴝ 31)
IUGR (n ⴝ 17)
P
0 75 ⫾ 24 8⫾2 21 ⫾ 6 6 (19%) 4 (13%) 21 ⫾ 3 1
0 49 ⫾ 20 10 ⫾ 4 30 ⫾ 9 4 (23%) 2 (12%) 25 ⫾ 3 3
NS NS NS NS NS NS NS NS
Data are expressed as mean ⫾ SD. CLD, chronic lung disease; CPAP, continuous positive airway pressure; IUGR, intrauterine growth restriction; NEC, necrotizing enterocolitis; NS, nonsignificant.
by using previously validated measures. The DA was reevaluated at 24 and 48 hours in infants with a nonsignificant PDA at 6 hours of age. We found that the rate of clinically significant PDA in the first 48 hours of life was higher in infants with IUGR than in eutrophic preterm infants. Furthermore, PDA became significant earlier in infants with IUGR than in eutrophic infants. Previous reports mentioned a higher incidence of PDA in small for GA newborn infants. PDA was more prevalent on day 1, 2, 3, and 5 in a cohort of 41 small for GA preterm infants than in 40 appropriate for GA preterm infants.9 Furthermore, IUGR has been recognized as a risk factor for PDA.10 However, the degree of left-to-right shunting through the DA had not been evaluated in these studies. Our study provides new information as we found that more PDAs were hemodynamically significant in infants with IUGR than in eutrophic preterm infants. Furthermore, our data show that echocardiographic markers of high left-to-right ductal flow can be recorded during the first hours of life in preterm infants with IUGR. IUGR in preterm infants is associated with increased risks of neonatal death and morbidity such as pulmonary hemorrhage, chronic lung disease, severe intraventricular hemorrhage, necrotizing enterocolitis, and renal failure.1-7 Similar adverse events exist in preterm infants with significant left-to-right shunting through the DA.13-17 Although PDA has been previously associated with poor outcomes in infants with severe IUGR,11 no study evaluated the role of PDA in the IUGR-associated morbidity. We found that the DA was larger in infants with IUGR than in eutrophic preterm infants, as soon as 6 hours after birth. The DA diameter was twice greater when it is expressed as millimeters per kilogram. It seems logical to take into account the body weight, as a 2-mm DA may not have the same hemodynamic consequence in an 800-g or a 1300-g preterm newborn. Markers of high pulmonary blood flow—increase in LA:Ao ratio and in telediastolic blood flow velocity in the LPA—were found more frequently in infants with IUGR than in eutrophic preterm infants. The elevation of pulmonary blood flow may cause stress failure of the thin-walled pulmonary capillaries.13 Pul-
monary hemorrhage in preterm infants has been associated with high pulmonary blood flow.13 We speculate that a higher proportion of clinically significant PDA may explain why the incidence of pulmonary hemorrhage is increased in the IUGR population.2 Furthermore, our data suggest that PDA results in earlier and greater systemic vascular steal in infants with IUGR than in eutrophic preterm infants. In particular, the diastolic blood flow velocity of the superior mesenteric artery was lower in the preterm infants with IUGR. In the same way, diastolic blood pressure was found lower in the IUGR group, although concerns exist about the accuracy of diastolic blood pressure measurement obtained with a non-invasive blood pressure monitor. An increased lactate serum concentration in preterm infants with IUGR may indicate an unbalance between O2 delivery and O2 consumption. By decreasing systemic blood flow and O2 delivery, a large PDA may contribute to the elevation of lactate concentration. Alternatively, increased lactate concentration in the infants with IUGR may result from perinatal lactate accumulation, caused by placental insufficiency as suggested by the elevated lactate concentration at birth in this group. The role of significant PDA in the etiology of intraventricular hemorrhage, renal dysfunction, and necrotizing enterocolitis has been suggested.15-20 Moreover, increased shunting through the PDA observed within the first 24 hours of life has been associated with intraventicular hemorrhage in preterm infants.21 We speculate that significant PDA may contribute, at least in part, to an increase in the risks of adverse neonatal outcomes among preterm infants with IUGR. The mechanisms explaining the earlier and greater hemodynamic effects of PDA in infants with IUGR remain uncertain. The clinical significance of the DA is dependent on the degree of left-to-right shunting through the ductus. Ductal flow is directly proportional to DA diameter. Compared with eutrophic preterm infants, a histological examination of DA from infants with IUGR highlighted major anomalies of both intima and media of the vessel wall.22 These changes may play a role in keeping the lumen of the DA open in preterm infants with IUGR. However, the DA was responsive to the inhibition of cyclooxygenase as significant PDA was closed in all infants with IUGR by ibuprofen treatment. This positive response to treatment may be a result of an early use of ibuprofen in the preterm infants with IUGR. Clinical and experimental investigations showed that prostaglandin inhibitors administered early after birth are more effective in constricting the DA than later treatment.23 In addition to a larger DA diameter, higher pulmonary blood flow observed in the preterm infants with IUGR may also result from lower pulmonary vascular resistance. Pulmonary vascular resistance is dependant on blood gases and on the degree of the respiratory failure. In our study, arterial pH, PaO2 and PaCO2, and oxygen need were similar in IUGR and eutrophic preterm infants. Alternatively, chronic hypoxia in utero may contribute to a faster decrease in pulmonary vascular resistance in growth-restricted babies, through the production of vasodilator stress-related factors. We previously showed that cat-
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echolamines, especially norepinephrine, increase pulmonary blood flow in fetal lambs through the activation of ␣2-adrenoceptor and NO release.24,25 Moreover, the pulmonary vasodilator effect of norepinephrine can be enhanced by glucocorticoids,26 production of which is increased in IUGR of placental origin.27 Neonatologists should be aware that PDA may become hemodynamically significant from the first hours of life in preterm infants with IUGR. The management of preterm infants with severe IUGR of placental origin should include early echocardiographic monitoring to assess for markers of significant PDA.
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The Journal of Pediatrics • December 2007