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Feasibility and safety of intact cord resuscitation in newborn infants with congenital diaphragmatic hernia (CDH)
Accepted Manuscript Title: Feasibility and safety of intact cord resuscitation in newborn infants with congenital diaphragmatic hernia (CDH) Authors: Caroline Lefebvre, Thameur Rakza, Nathalie Weslinck, Pascal Vaast, V´eronique Houfflin-debarge, S´ebastien Mur, Laurent Storme, for the French CDH study group PII: DOI: Reference:
S0300-9572(17)30585-3 http://dx.doi.org/10.1016/j.resuscitation.2017.08.233 RESUS 7292
To appear in:
Resuscitation
Received date: Revised date: Accepted date:
15-5-2017 1-8-2017 23-8-2017
Please cite this article as: Lefebvre Caroline, Rakza Thameur, Weslinck Nathalie, Vaast Pascal, Houfflin-debarge V´eronique, Mur S´ebastien, Storme Laurent.Feasibility and safety of intact cord resuscitation in newborn infants with congenital diaphragmatic hernia (CDH).Resuscitation http://dx.doi.org/10.1016/j.resuscitation.2017.08.233 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Title page information Feasibility and safety of intact cord resuscitation in newborn infants with congenital diaphragmatic hernia (CDH) Caroline LEFEBVRE1,2, Thameur RAKZA1,3,5, Nathalie WESLINCK, Pascal VAAST4, Véronique HOUFFLIN-DEBARGE3,4,5, Sébastien MUR3, Laurent STORME3,5, for the French CDH study group 1 Department
of Neonatology, Jeanne de Flandre Hospital, University Hospital of Lille, F-
59000 France 2 Neonatal Intensive Care Unit, University Hospital of Liège, Belgium 3 French Reference Centre for Congenital Diaphragmatic Hernia, Jeanne de Flandre Hospital, University Hospital of Lille, France 4 Department of Obstetrics, Jeanne de Flandre Hospital, University Hospital of Lille, F-59000 France 5 EA4489, Perinatal Environment and Health, Faculty of Medicine, Lille University, France
The authors report no conflict of interest. Source of financial support for the research: University Hospital of Lille, F-59000 Lille University Lille 2, F-59000 Lille
Corresponding author: Laurent Storme, MD Pôle Femme Mère Nouveau-né, CHRU de Lille 1 rue Eugène Avinée Lille Cedex F-59000 Tel: (0033) 2044 6199 Email: [email protected]
Word count abstract: 250 Word count main text: 3169
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Abstract Background: Starting resuscitation before clamping the umbilical cord at birth may progressively increase pulmonary blood flow while umbilical venous blood flow is still contributing to maintenance of oxygenation and left ventricle preload. Objective: To evaluate the feasibility, safety, and effects of intact cord resuscitation (ICR) on cardiorespiratory adaptation at birth in newborn infants with CDH. Study design: Prospective, observational, single-center pilot study. Methods: Physiologic variables and outcomes were collected prospectively in 40 consecutive newborn infants with an antenatal diagnosis of isolated CDH. Results: Infants were managed with immediate cord clamping (ICC group) from 1/2012 to 5/2014 or the cord was clamped after initiation of resuscitation maneuvers (ICR group) from 6/2014 to 4/2016 (20 in each group). Ante- and postnatal markers of CDH severity were similar between groups. Resuscitation before cord clamping was possible for all infants in the ICR group. No increase in maternal or neonatal adverse events was observed during the period of ICR. The pH was higher and the plasma lactate concentration was significantly lower at one hour after birth in the ICR than in the ICC group (pH=7.17±0.1 vs 7.08±0.2; lactate=3.6±2.3 vs 6.6±4.3mmol/l, p<0.05). Mean blood pressure was significantly higher in the ICR than in the ICC group at H1 (52±7.7 vs 42±7.5mmHg), H6 (47±3.9 vs 40±5.6mmHg) and H12 (44±2.9 vs 39±3.3mmHg) (p<0.05). Conclusion: Commencing resuscitation and initiating ventilation while the infant is still attached to the placenta is feasible in infants with CDH. The procedure may support the cardiorespiratory transition at birth in infants with CDH. Key words: cardiorespiratory transition, congenital diaphragmatic hernia, intact cord resuscitation, newborn infants, delayed cord clamping.
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Main Text Introduction Congenital diaphragmatic hernia (CDH) has an incidence of around 1 per 2200-3500 live births, and accounts for about 8% of all major congenital abnormalities (1,2). This malformation is usually detected by prenatal echography (3). CDH is associated with a failure of cardiorespiratory adaptation at birth, often resulting from persistent pulmonary hypertension of the newborn (PPHN), a life-threatening event that contributes to a mortality rate of around 30% in infants with CDH (4). Management in the resuscitation room at birth remains highly challenging. The 2016 CDH Euroconsortium Consensus (5) recommends that CDH infants should be intubated immediately after birth as a standard of care. Measurements of heart rate and of preductal and postductal saturations are recommended. The goal of resuscitation in the delivery room is to achieve acceptable preductal saturation targets (80-95%) while avoiding high airway pressures. Several randomized controlled trials have documented the safety and benefits of delayed cord clamping (DCC). DCC improves transition at birth in preterm infants, and is associated with decreased need for inotropic support and for blood transfusions and with reduced incidence of necrotizing enterocolitis and intraventricular hemorrhages (6). Benefits of DCC have also been demonstrated in term infants, including higher iron stores up until 6 months (7). No studies have reported adverse effects in the mothers; in particular, no increase in postpartum hemorrhages has been reported (7). Experimental studies in newborn lambs have highlighted that starting ventilation prior to cord clamping markedly improves cardiovascular adaptation at birth by increasing
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pulmonary blood flow before the cord is clamped (8). In the fetus, the umbilical blood flow is largely directed toward the left heart through the foramen ovale, and contributes to the left ventricle preload. Immediate cord clamping at birth is associated with a decrease in the umbilical venous return to the left atrium. Under normal conditions, birth-related stimuli such as spontaneous breathing and increased arterial blood oxygen tension (PaO2) rapidly elevate the pulmonary blood flow; the increase in the pulmonary venous return to the left ventricle compensates for the loss of the umbilical venous return after cord clamping. In CDH infants, lung hypoplasia, increased medial thickness of the pulmonary arteries, and abnormal reactivity of the lung vessels delay the normal increase in pulmonary blood flow at birth. Immediate cord clamping in CDH infants may therefore contribute to failure of the transition at birth. In contrast, starting resuscitation and mechanical ventilation before clamping may progressively increase pulmonary blood flow while the umbilical venous blood flow is still contributing to maintenance of both oxygenation and left ventricle preload. The term “intact cord resuscitation” (ICR) has been used to describe initiation of breathing before clamping the cord in order to promote a more physiological transition (9,10,11). We hypothesized that ICR in CDH infants may promote cardiorespiratory adaptation at birth. To test this hypothesis, we prospectively recorded the physiologic variables and the outcomes in 20 consecutive newborn infants with a prenatal diagnosis of isolated CDH in whom the initial resuscitation maneuvers were performed before the umbilical cord was clamped.
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Population and Methods We conducted an observational pilot study in all the newborn infants with a prenatal diagnosis of isolated CDH in the Nord-Pas de Calais region and born at Lille University Hospital from January 1, 2012 to April 30, 2016. Infants with postnatal diagnosis or syndromic CDH were excluded from the study. Infants born from January 1, 2012 to May 31, 2014 were managed conventionally, with immediate cord clamping (“immediate cord clamping” or ICC group); for those born between June 1, 2014 and April 30, 2016, the cord clamping was delayed until after initiation of resuscitation maneuvers (“intact cord resuscitation” or ICR group). The protocol was approved by the local Ethics Committee (reference number: DEC16-57). Approved parental consents were requested after information about the ICR procedure. In the ICC group, the cord was clamped immediately after birth and the infant was transferred to the resuscitation room. The newborn infant was intubated and mechanically ventilated as quickly as possible on the resuscitation table. After cardiorespiratory stabilization (normal heart rate, and steadily increase in preductal SpO2), the infant was transferred to the neonatal intensive care unit (NICU). In the ICR group, the umbilical cord was kept intact during the initial phase of the resuscitation. The infant was placed on a specifically designed compact trolley with a warmed platform, suitable for commencing resuscitation between the mother's legs in case of vaginal birth or near the operating table beside the mother in case of cesarean section. This trolley was fully equipped for resuscitation, including a suction device, gas flowmeter/blender, ventilator, and monitoring system. Its height could be adjusted to position the infant close to the maternal perineum. The infant was intubated and mechanically ventilated on this trolley; special care was taken to prevent stretching, compression, or kinking of the cord. Prior to cord clamping,
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the following parameters were monitored: heart rate, preductal O2 saturation, and maternal blood loss volume. The criteria to cut the cord after intubation were cardiorespiratory stabilization (intubation, adequate ventilation, heart rate > 100/bpm, and steadily increase in preductal SpO2), or spontaneous placental expulsion. The infant was then transferred to the NICU. For both groups, oxytocin was administered to the mother just after cord clamping. The ICR procedure and delegation of roles have been protocolized, and the healthcare team was appropriately trained. In particular, the person’s physical position and the role of each healthcare provider, including midwives, pediatricians, obstetricians, and anesthesiologists, were clearly anticipated. Maternal variables collected included mode of delivery, blood pressure and heart rate, mode of placental expulsion, blood loss volume, and need for intensive care. The observed/expected lung to head ratio assessed by prenatal echography and lung volume assessed by magnetic resonance imaging (MRI) were collected at 24-28 and 32-34 weeks gestational age (GA). Neonatal characteristics recorded included gestational age and birth weight, sex, Apgar score, blood cord gases, temperature at NICU admission, hemoglobin concentration, hematocrit, number of transfusions, and peak serum bilirubin. Variables concerning mechanical ventilation, blood gases, and plasma lactate concentrations were recorded during the first 48 hours after birth. Outcomes including duration of ventilation and O2 supplementation, need for O2 supplementation at discharge, age at weaning from parenteral nutrition, death, and age at discharge home were also recorded. Results are expressed as mean±SD or median and range. A Mann-Whitney test was used to compare variables between the 2 groups. Data were analyzed using repeated-measures analysis of variance when appropriate. Intergroup differences were analyzed with the
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Fisher’s and Bonferroni/Dunn’s significance tests (Stat View for PC; Abacus Concepts, Berkeley, CA). P-values <0.05 were considered significant.
Results Figure 1 shows the disposition of the 59 infants with CDH identified in the Nord Pas de Calais area during the study period. Based on mean numbers of births per year, it is estimated that approximately 220 000 infants were born in this area during this period: the incidence was therefore 1 infant with CDH for 3700 live births. 19 CDH infants were excluded from the study because of syndromic CDH, postnatal diagnosis of CDH, or lack of information regarding the timing of cord clamping. 20 CDH infants were included in each group. Maternal and fetal characteristics were similar between groups (Table 1; Table 2). The usual markers of CDH severity did not differ between groups. In particular, the indexes of fetal lung volume assessed by lung to head ratio and MRI at both 24-28 and 32-34 weeks GA, as well as the number of diaphragmatic agenesia and the need for prosthetic diaphragmatic patches did not differ between the ICC and ICR groups. Maternal blood pressure and heart rate were comparable between groups, as was time before expulsion of the placenta. Manual removal of the placenta was required in 17 cases in the ICC group and 11 cases in the ICR group; the difference was not statistically significant (NS). Median maternal blood loss was 200 ml [50-1750 ml] in the ICC group versus 400 ml [100-2450 ml] in the ICR group, but the difference was not significant. Two severe postpartum hemorrhages (defined as blood loss >1000 ml) occurred in each group. None of these mothers required admission in intensive care unit.
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In the intact cord resuscitation group, the cord was clamped at 7±3.4 minutes after birth. Two cords were clamped because of spontaneous placental delivery at 6 and 7 minutes. For all infants, mechanical ventilation could be initiated before clamping the umbilical cord. Fetal and neonatal characteristics are presented in Table 2. The temperature on admission to NICU was similar in the two groups. At H24, hemoglobin (14.5±1.4 vs 19.4±2.8 g/dl) and hematocrit (42.3±3.8 vs 53.5±7.6%) at H24 were significantly higher in the intact cord resuscitation group (p<0.05). The peak bilirubin concentration was higher in the ICR group, but not significantly so. No polycythemia was observed. Apgar scores were significantly higher in the ICR group than in the ICC group at 1 min (7.7±2.2 vs 4.5±2.1) and at 5 min (9.3±1.1 vs 6±2.8) (Table 3, p<0.05). Although the pH of the umbilical cord blood was similar between groups, the pH was higher at M30 and at H1 in the ICR group than in the ICC group (respectively, 7.12±0.1 vs 7.01±0.2; and 7.17±0.1 vs 7.08±0.2, p<0.05); the plasma lactate concentration was lower at M30 and H1 in the ICR group than in the ICC group (respectively, 3.8±1.7 vs 6.7±3.2; and 3.6±2.3 vs 6.6±4.3 mmol/l, p<0.05). Mean blood pressure was significantly higher in the ICR group than in the ICC group at H1 (52±7.7 vs 42±7.5 mmHg), H6 (47±3.9 vs 40±5.6 mmHg), and H12 (44±2.9 vs 39±3.3 mmHg) (Fig. 2, p<0.05). Inotropic support (mainly Norepinephrine) was used in 12/20 and in 8/20 infants in respectively the ICC and the ICR groups during the first 48 hours after birth (NS). The timing of intubation was similar in both groups (at 2.5±3 min after birth in the ICC group, and at 1.7±0.7min in the ICR group, NS). The parameters of mechanical ventilation did not differ between the two groups (Table 4). No patients were ventilated with bag mask before intubation. Chest compression and adrenalin injection were required at birth in 2 infants,
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both in the ICC group. The pre- and postductal SpO2 were similar in the two groups. Venoarterial extracorporeal membrane oxygenation (ECMO) was required in 2 infants in the ICR group and in 3 infants in the ICC group. Neonatal outcomes are presented in Table 5. Survival at discharge (18/20 vs 19/20), duration of mechanical ventilation (5.2±4.8 vs 5.6±3.2 days), duration of supplemental O2 including continuous positive airway pressure (CPAP) (17±26 vs 18±28 days), and age at discharge home (52±37 vs 77±69 days) were similar between the immediate cord clamping and intact cord resuscitation groups.
Discussion CDH is usually associated with impaired cardiorespiratory adaptation at birth. Evidence exists that delayed cord clamping may promote transition at birth in preterm infants (7). In this study, we investigated the feasibility and safety of intact cord resuscitation in newborn infants with isolated CDH. Physiologic variables and outcomes were collected prospectively in 40 successive newborn infants with antenatal diagnosis of isolated CDH. The umbilical cord was clamped immediately in infants born during the first part of the study period, and after initiation of resuscitation maneuvers in infants born during the second part. In this second group, intact cord resuscitation could be performed in all cases, whatever the mode of delivery. No additional maternal or neonatal adverse events were observed when the cord was clamped after starting resuscitation. Compared to the first 20 CDH infants in whom the cord was clamped immediately, Apgar scores at 1 and 5 min, pH at 1 hour after birth and mean blood pressure at H1, H6, and H12 were higher in the group of infants resuscitated while the cord was intact. Plasma lactate concentration was lower at one hour after birth in
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the infants with intact cord resuscitation. Taken together, our results suggest that intact cord resuscitation is feasible and well tolerated by infants with isolated CDH and their mothers, and may improve early cardiorespiratory adaptation at birth. To the best of our knowledge, our study is the first to explore the feasibility of intact cord resuscitation in newborn infants with isolated CDH. The question is important, as the early resuscitation period is quite challenging, with a major risk of hypoxic-ischemic events that may promote persistent pulmonary hypertension. Low Apgar score at 5 min is clearly associated with an increased risk of mortality (12,13,14). Intubation and mechanical ventilation immediately after birth is considered as a standard of care to reduce the risk of persistent pulmonary hypertension. Delayed cord clamping has the potential to promote transition at birth through placental transfusion, improvement in hemodynamics, and sustaining of placental exchange and oxygenation during the critical period of initial resuscitation. However, routine delayed cord clamping may delay resuscitation maneuvers including adequate lung ventilation, which are required immediately at birth for cardiorespiratory adaptation. Starting resuscitation maneuvers while the cord is intact – i.e., intact cord resuscitation – may provide the advantages of both delayed cord clamping and immediate resuscitation. Regarding feasibility, all of the infants in the intact cord resuscitation group could be intubated and mechanically ventilated before cord clamping and placental delivery. When the umbilical cord was short, placing the baby as close as possible to the birth canal and perpendicularly to the mother’s trunk prevented cord traction. Nevertheless, the procedure requires a dedicated written protocol known to the staff and appropriate training of healthcare providers including midwives, obstetricians, pediatricians, and anesthesiologists. It also requires a dedicated resuscitation table small enough and mobile enough to be placed
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rapidly between the mother’s legs at the end of the delivery. Such resuscitation tables are now commercially available (15,16), and the usability and acceptability of these mobile trolleys have been studied (17). Although the difference was not significant, a trend in increased maternal blood loss was observed in the ICR group. Metaanalysis reported no significant differences between early versus late cord clamping groups for severe postpartum hemorrhage, for postpartum hemorrhage of 500 mL or more, or for mean blood loss (6.7). Nevertheless, additional information is required to assess maternal safety of the procedure, as ICR is associated with delayed administration of oxytocin. Current guidelines recommend DCC in newborn infants not requiring resuscitation (18,19,20). However, according to the American Academy of Pediatrics, there is currently insufficient evidence to recommend a particular timing for cord clamping in infants who require resuscitation at birth (21). Our data suggest that initiation of resuscitation while the cord is intact may promote cardiorespiratory transition at birth in infants with CDH. In our study, the timing of cord clamping is explained by the duration of intubation and by the time to ensure adequate ventilation and cardiorespiratory stabilization of the infant after intubation. Apgar scores were higher at 1 and 5 min in infants undergoing intact cord resuscitation than after immediate cord clamping. Apgar score is considered as a reliable marker of postnatal adaptation in newborn infants. Although the pH of umbilical cord blood was similar between groups, pH was higher at one hour after birth in infants with intact cord resuscitation compared to those resuscitated after immediate cord clamping. Lower plasma lactate concentrations at 1 hour in the ICR group further support the hypothesis that starting
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resuscitation while the cord is intact reduces hypoxic insult and promotes transition at birth. Higher hemoglobin concentration may increase oxygen delivery to the tissue, which in turn may explain lower plasma lactate concentration in the ICR group. Maximum bilirubin concentrations were not significantly higher in the ICR group. Despite a resuscitation period in the delivery room, the temperature of the infants at NICU admission was not significantly lower after ICR. Improved cardiorespiratory adaptation can be explained by several mechanisms. Firstly, previous studies have shown that delayed cord clamping promotes blood transfusion from the placenta to the newborn (22). The higher hemoglobin concentrations and hematocrit seen at H24 in the ICR group are consistent with this effect. Higher mean blood pressures in the ICR group at H1, H6, and H12 provide further evidence of hemodynamic benefit with delayed cord clamping. Increased circulating blood volume due to placenta-fetal transfusion contributes to preventing low systemic pressure and cardiac output, and increased hematocrit improves oxygenation at birth. Secondly, in preterm lambs, immediate cord clamping results in a decrease in left ventricle preload, which leads to a decrease in heart rate (8). This phenomenon may explain the observation of momentary bradycardia when the cord is clamped before the first respiratory movements (23). In contrast, starting ventilation before cord clamping improves cardiovascular function by increasing pulmonary blood flow (8). Aerating the lungs increases pulmonary venous return, allowing it to promptly replace umbilical venous return as the primary source of preload, thereby stabilizing the circulation after birth (5). The maintenance of left ventricular preload by sustaining umbilical venous return may play a critical role in newborns with CDH. Our results support this hypothesis, as none of the infants in the ICR group required chest compression and adrenalin administration.
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Finally, a previous study highlighted that in most cases, both arterial and venous flow will continue for several minutes after birth when the cord is intact (24). It is therefore possible that sustained placental exchange may contribute, at least in part, to oxygenation when the cord is not clamped immediately at birth. The study has some limitations. The number of intubation attempts was not collected in this study. However, it is likely that the number of intubation attempts was not greater in the ICR group, as the timing of intubation was similar in both groups. In this pilot observational study, the infants were not randomized to ICR or ICC procedures. We cannot exclude a selection bias in the population of infants that would explain our results. However, the main ante- and postnatal markers of CDH severity were similar between groups, including estimation of lung volume as assessed by LHR and MRI, rates of diaphragmatic agenesia, and need for prosthetic diaphragmatic patches, providing some evidence that the 2 groups were comparable. In addition, the estimation of lung volume as assessed by LHR and MRI was rather favorable during the study and the mortality rate was low in each group. In a future study, inclusion of newborn infants with a more severe form of CDH is required to assess whether ICR may also promote cardiorespiratory adaptation in this high risk population. The outcomes did not differ between the groups; however, the study was clearly underpowered to show a potential long-term benefit of ICR in CDH infants. A randomized trial is required to determine whether ICR might improve outcomes in infants with CDH.
In conclusion, commencing resuscitation and initiating ventilation while the infant is still attached to the placenta is feasible in infants with CDH. Medical resuscitation equipment can be brought close enough to the mother’s perineum (or abdomen, in case of cesarean) to start resuscitation maneuvers without cutting the cord. Better results for Apgar scores,
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mean blood pressure, early blood gases, and lactate concentration indicate that intact cord resuscitation may support the cardiorespiratory transition at birth in infants with CDH.
Source of financial support for the research:
University Hospital of Lille, F-59000 Lille University Lille 2, F-59000 Lille
Conflicts of Interest: The authors report no conflict of interest.
Acknowledgements The authors would like to thank Annette Dubois for editorial assistance in the preparation of the manuscript.
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Hutchon D. Evolution of neonatal resuscitation with intact placental circulation. Clinical Practice 2014;10:28-61.
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Thomas MR, Yoxall CW, Weeks AD and Duley L. Providing newborn resuscitation at the mother's bedside: assessing the safety, usability and acceptability of a mobile trolley. BMC Pediatr 2014;14:135.
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Perlman JM, Wyllie J, Kattwinkel J, et al. Part 11: Neonatal Resuscitation: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Circulation 2010;122:S516-538.
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Committee on Obstetric Practice of the American College of Obstetricians and Gynecologists. Committee Opinion No. 543: Timing of umbilical cord clamping after birth. Obstet Gynecol 2012;120:1522-1526.
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Yao AC, Moinian M and Lind J. Distribution of blood between infant and placenta after birth. Lancet 1969;2:871-873.
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Dawson JA, Kamlin CO, Wong C, et al. Changes in heart rate in the first minutes after birth. Arch Dis Child Fetal Neonat 2010;95:177-181.
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Legends to figures
Figure 1: Flow chart of the newborn infants with CDH identified in the Nord-Pas de Calais area from January 2012 to May 2016
Assessed for eligibility (n=59)
Enrolled (n = 40)
Excluded (n=19) - Syndromic HDC (n=13) - Postnatal diagnosis (n=4) - Lack of information on the timing of cord clamping (n=2)
Immediate cord clamping (n=20)
Intact cord resuscitation (n=20)
Figure 2: Mean±SD change in blood pressure (mmHg) after birth in immediate cord clamping (ICC) and intact cord resuscitation (ICR) groups. * p<0.05 for comparison between groups.
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60
Blood pressure mmHg
55 50
ICC
45
ICR 40 35 30
H1
H6
H12
H48
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Table 1: Maternal characteristics
Mother's age, years Primiparas, n (%) Caesarean sections, n (%) Systolic blood pressure, mmHg Before birth After birth Diastolic blood pressure, mmHg Before birth After birth Heart rate, beats/min Temperature after birth, °C Time before placental expulsion, min Manual removal of placenta, n Median [range] blood loss, ml Severe postpartum hemorrhage (Blood loss > 1000 ml), n Intensive care, n
Immediate cord clamping (n = 20) 26 ± 5.5 7 (35) 6 (30)
Intact cord resuscitation (n = 20) 29 ± 5.9 10 (50) 5 (25)
P-value
119 ± 14 121 ± 17
123 ± 15 114 ± 8
NS NS
71 ± 9 69 ± 10 82 ± 13 36.9 ± 0.4 9±8 17 200 [50-1750] 2
75 ± 8 66 ± 8 84 ± 11 36.9 ± 0.6 10 ± 3 11 400 [100-2450] 2
NS NS NS NS NS NS NS NS
0
0
NS
NS, not statistically significant (p≥0.05). Expressed as mean±SD unless otherwise specified.
NS NS NS
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Table 2: Fetal and neonatal characteristics of the newborn infants in the immediate cord clamping and intact cord resuscitation groups Immediate Intact P-value cord cord clamping resuscitation (n = 20) (n = 20) Left CDH, n 19 19 NS LHR o/e echography, % 55 ± 20 55 ±20 NS 24-28 weeks GA 54 ± 14 45 ± 12 NS 32-34 weeks GA Volume o/e MRI, % 38 ± 22 33 ± 14 NS 24-28 weeks GA 52 ± 24 40 ± 14 NS 32-34 weeks GA Gestational age, weeks 39 ± 3 38 ± 2 NS Birth weight, g 3060 ± 710 3130 ± 660 NS Sex, male/female 11/9 9/11 NS Temperature at admission to NICU, °C 35.3 ± 1.1 35.7 ± 0.7 NS Hemoglobin H24, g/dl 14.5 ± 1.4 19.4 ± 2.8 <0.05 Hematocrit H24, % 42.3 ±3.8 53.5 ± 7.6 <0.05 Transfusions, n 0.9 ± 1.6 0.8 ± 1.3 NS Maximum serum bilirubin, µmol/l 110 ± 70 140 ± 76 NS CDH, congenital diaphragmatic hernia; NS, not statistically significant (p≥0.05); LHR, Lung to Head ratio; o/e, observed/expected; GA, gestational age; MRI, magnetic resonance imaging; NICU, neonatal intensive care unit; H24, 24 hours after birth. Expressed as mean±SD unless otherwise specified.
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Table 3: Physiological variables of the newborn infants in the immediate cord clamping and intact cord resuscitation groups Immediate cord Intact cord P-value clamping resuscitation (n = 20) (n = 20) Apgar score 4.5 ± 2.1 7.7 ± 2.2 <0.05 1 min 6 ± 2.8 9.3 ± 1.1 <0.05 5 min pH 7.29 ± 0.1 7.25 ± 0.1 NS Cord blood 7.01 ± 0.2 7.12 ± 0.1 <0.05 M30 7.08 ± 0.2 7.17 ± 0.1 <0.05 H1 7.27 ± 0.1 7.23 ± 0.1 NS H6 7.26 ± 0.1 7.24 ± 0.1 NS H12 7.22 ± 0.1 7.23 ± 0.1 NS H48 PCO2, mmHg 93 ± 12 84 ± 16 <0.05 M30 72 ± 24 79 ± 20 NS H1 51 ± 13 58 ± 21 NS H6 53 ± 12 57 ± 16 NS H12 58 ± 8 55 ± 15 NS H48 Lactate, mmol/l 6.7 ± 3.2 3.8 ± 1.7 <0.05 M30 6.6 ± 4.3 3.6 ± 2.3 <0.05 H1 1.6 ± 0.9 2.1 ± 2.4 NS H6 1.3 ± 0.7 2.1 ± 2.4 NS H12 1.3 ± 0.7 1.8 ± 1.5 NS H48 Heart rate, beats/min 142 ± 16 148 ± 18 NS M30 134 ± 13 143 ± 20 NS H1 121 ± 14 123 ± 19 NS H6 120 ± 11 123 ± 17 NS H12 132 ± 15 126 ± 13 NS H48 NS, not statistically significant (p≥0.05); H1, one hour after birth (and so on); PCO 2, partial pressure of carbon dioxide. Expressed as mean±SD.
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Table 4: Timing of intubation and mechanical ventilation parameters of the newborn infants in the immediate cord clamping and the intact cord resuscitation groups Immediate cord Intact cord P-value clamping resuscitation (n = 20) (n = 20) Timing of intubation, min 2.5 ± 3 1.7 ± 0.7 NS Peak inspiratory pressure, cm H20 23 ± 1.3 23 ± 1.5 NS M30 21 ± 2.9 22 ± 2 NS H1 19 ± 3.8 20 ± 4.3 NS H6 18 ± 4.8 19 ± 3.8 NS H12 19 ± 4.2 17 ± 3.8 NS H48 FiO2, % 80 ± 12 84 ± 14 NS M30 50 ± 33 56 ± 31 NS H1 36 ± 23 33 ± 19 NS H6 32 ± 24 34 ± 19 NS H12 26 ± 10 26 ± 7 NS H48 Preductal SpO2, % 82 ± 12 86 ± 9 NS M30 93 ± 8.1 93 ± 6.6 NS H1 95 ± 3.6 90 ± 12.4 NS H6 95 ± 4 92 ± 9.1 NS H12 96 ± 4.6 96 ± 3.3 NS H48 Postductal SpO2, % 76 ± 12 68 ± 9 NS M30 88 ± 9.8 80 ± 13.7 NS H1 87 ± 10.5 80 ± 16.5 NS H6 89 ± 9.5 83 ± 12.3 NS H12 87 ± 13.6 90 ± 8.2 NS H48 NS, not statistically significant (p≥0.05); H1, one hour after birth (and so on); FiO 2, fraction of inspired oxygen; SpO2, peripheral oxygen saturation. Expressed as mean±SD.
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Table 5: Neonatal outcomes
Death, n Duration of mechanical ventilation, days Median [range] CPAP duration, days Duration of O2 supplementation, days Median [range] duration of parenteral nutrition, days Age at discharge home, days
Immediate cord clamping (n = 20) 2 5.2 ± 4.8 5 [2-21] 17 ± 26 21 [6-113]
Intact cord resuscitation (n = 20) 1 5.6 ± 3.2 7 [1-141] 18 ± 28 26 [7-100]
P-value
52 ± 37
77 ± 69
NS
NS NS NS NS NS
NS, not statistically significant (p≥0.05); CPAP, continuous positive airway pressure. Expressed as mean ± SD (except for CPAP and parenteral nutrition duration).
S0300-9572(17)30585-3 http://dx.doi.org/10.1016/j.resuscitation.2017.08.233 RESUS 7292
To appear in:
Resuscitation
Received date: Revised date: Accepted date:
15-5-2017 1-8-2017 23-8-2017
Please cite this article as: Lefebvre Caroline, Rakza Thameur, Weslinck Nathalie, Vaast Pascal, Houfflin-debarge V´eronique, Mur S´ebastien, Storme Laurent.Feasibility and safety of intact cord resuscitation in newborn infants with congenital diaphragmatic hernia (CDH).Resuscitation http://dx.doi.org/10.1016/j.resuscitation.2017.08.233 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Title page information Feasibility and safety of intact cord resuscitation in newborn infants with congenital diaphragmatic hernia (CDH) Caroline LEFEBVRE1,2, Thameur RAKZA1,3,5, Nathalie WESLINCK, Pascal VAAST4, Véronique HOUFFLIN-DEBARGE3,4,5, Sébastien MUR3, Laurent STORME3,5, for the French CDH study group 1 Department
of Neonatology, Jeanne de Flandre Hospital, University Hospital of Lille, F-
59000 France 2 Neonatal Intensive Care Unit, University Hospital of Liège, Belgium 3 French Reference Centre for Congenital Diaphragmatic Hernia, Jeanne de Flandre Hospital, University Hospital of Lille, France 4 Department of Obstetrics, Jeanne de Flandre Hospital, University Hospital of Lille, F-59000 France 5 EA4489, Perinatal Environment and Health, Faculty of Medicine, Lille University, France
The authors report no conflict of interest. Source of financial support for the research: University Hospital of Lille, F-59000 Lille University Lille 2, F-59000 Lille
Corresponding author: Laurent Storme, MD Pôle Femme Mère Nouveau-né, CHRU de Lille 1 rue Eugène Avinée Lille Cedex F-59000 Tel: (0033) 2044 6199 Email: [email protected]
Word count abstract: 250 Word count main text: 3169
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Abstract Background: Starting resuscitation before clamping the umbilical cord at birth may progressively increase pulmonary blood flow while umbilical venous blood flow is still contributing to maintenance of oxygenation and left ventricle preload. Objective: To evaluate the feasibility, safety, and effects of intact cord resuscitation (ICR) on cardiorespiratory adaptation at birth in newborn infants with CDH. Study design: Prospective, observational, single-center pilot study. Methods: Physiologic variables and outcomes were collected prospectively in 40 consecutive newborn infants with an antenatal diagnosis of isolated CDH. Results: Infants were managed with immediate cord clamping (ICC group) from 1/2012 to 5/2014 or the cord was clamped after initiation of resuscitation maneuvers (ICR group) from 6/2014 to 4/2016 (20 in each group). Ante- and postnatal markers of CDH severity were similar between groups. Resuscitation before cord clamping was possible for all infants in the ICR group. No increase in maternal or neonatal adverse events was observed during the period of ICR. The pH was higher and the plasma lactate concentration was significantly lower at one hour after birth in the ICR than in the ICC group (pH=7.17±0.1 vs 7.08±0.2; lactate=3.6±2.3 vs 6.6±4.3mmol/l, p<0.05). Mean blood pressure was significantly higher in the ICR than in the ICC group at H1 (52±7.7 vs 42±7.5mmHg), H6 (47±3.9 vs 40±5.6mmHg) and H12 (44±2.9 vs 39±3.3mmHg) (p<0.05). Conclusion: Commencing resuscitation and initiating ventilation while the infant is still attached to the placenta is feasible in infants with CDH. The procedure may support the cardiorespiratory transition at birth in infants with CDH. Key words: cardiorespiratory transition, congenital diaphragmatic hernia, intact cord resuscitation, newborn infants, delayed cord clamping.
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Main Text Introduction Congenital diaphragmatic hernia (CDH) has an incidence of around 1 per 2200-3500 live births, and accounts for about 8% of all major congenital abnormalities (1,2). This malformation is usually detected by prenatal echography (3). CDH is associated with a failure of cardiorespiratory adaptation at birth, often resulting from persistent pulmonary hypertension of the newborn (PPHN), a life-threatening event that contributes to a mortality rate of around 30% in infants with CDH (4). Management in the resuscitation room at birth remains highly challenging. The 2016 CDH Euroconsortium Consensus (5) recommends that CDH infants should be intubated immediately after birth as a standard of care. Measurements of heart rate and of preductal and postductal saturations are recommended. The goal of resuscitation in the delivery room is to achieve acceptable preductal saturation targets (80-95%) while avoiding high airway pressures. Several randomized controlled trials have documented the safety and benefits of delayed cord clamping (DCC). DCC improves transition at birth in preterm infants, and is associated with decreased need for inotropic support and for blood transfusions and with reduced incidence of necrotizing enterocolitis and intraventricular hemorrhages (6). Benefits of DCC have also been demonstrated in term infants, including higher iron stores up until 6 months (7). No studies have reported adverse effects in the mothers; in particular, no increase in postpartum hemorrhages has been reported (7). Experimental studies in newborn lambs have highlighted that starting ventilation prior to cord clamping markedly improves cardiovascular adaptation at birth by increasing
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pulmonary blood flow before the cord is clamped (8). In the fetus, the umbilical blood flow is largely directed toward the left heart through the foramen ovale, and contributes to the left ventricle preload. Immediate cord clamping at birth is associated with a decrease in the umbilical venous return to the left atrium. Under normal conditions, birth-related stimuli such as spontaneous breathing and increased arterial blood oxygen tension (PaO2) rapidly elevate the pulmonary blood flow; the increase in the pulmonary venous return to the left ventricle compensates for the loss of the umbilical venous return after cord clamping. In CDH infants, lung hypoplasia, increased medial thickness of the pulmonary arteries, and abnormal reactivity of the lung vessels delay the normal increase in pulmonary blood flow at birth. Immediate cord clamping in CDH infants may therefore contribute to failure of the transition at birth. In contrast, starting resuscitation and mechanical ventilation before clamping may progressively increase pulmonary blood flow while the umbilical venous blood flow is still contributing to maintenance of both oxygenation and left ventricle preload. The term “intact cord resuscitation” (ICR) has been used to describe initiation of breathing before clamping the cord in order to promote a more physiological transition (9,10,11). We hypothesized that ICR in CDH infants may promote cardiorespiratory adaptation at birth. To test this hypothesis, we prospectively recorded the physiologic variables and the outcomes in 20 consecutive newborn infants with a prenatal diagnosis of isolated CDH in whom the initial resuscitation maneuvers were performed before the umbilical cord was clamped.
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Population and Methods We conducted an observational pilot study in all the newborn infants with a prenatal diagnosis of isolated CDH in the Nord-Pas de Calais region and born at Lille University Hospital from January 1, 2012 to April 30, 2016. Infants with postnatal diagnosis or syndromic CDH were excluded from the study. Infants born from January 1, 2012 to May 31, 2014 were managed conventionally, with immediate cord clamping (“immediate cord clamping” or ICC group); for those born between June 1, 2014 and April 30, 2016, the cord clamping was delayed until after initiation of resuscitation maneuvers (“intact cord resuscitation” or ICR group). The protocol was approved by the local Ethics Committee (reference number: DEC16-57). Approved parental consents were requested after information about the ICR procedure. In the ICC group, the cord was clamped immediately after birth and the infant was transferred to the resuscitation room. The newborn infant was intubated and mechanically ventilated as quickly as possible on the resuscitation table. After cardiorespiratory stabilization (normal heart rate, and steadily increase in preductal SpO2), the infant was transferred to the neonatal intensive care unit (NICU). In the ICR group, the umbilical cord was kept intact during the initial phase of the resuscitation. The infant was placed on a specifically designed compact trolley with a warmed platform, suitable for commencing resuscitation between the mother's legs in case of vaginal birth or near the operating table beside the mother in case of cesarean section. This trolley was fully equipped for resuscitation, including a suction device, gas flowmeter/blender, ventilator, and monitoring system. Its height could be adjusted to position the infant close to the maternal perineum. The infant was intubated and mechanically ventilated on this trolley; special care was taken to prevent stretching, compression, or kinking of the cord. Prior to cord clamping,
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the following parameters were monitored: heart rate, preductal O2 saturation, and maternal blood loss volume. The criteria to cut the cord after intubation were cardiorespiratory stabilization (intubation, adequate ventilation, heart rate > 100/bpm, and steadily increase in preductal SpO2), or spontaneous placental expulsion. The infant was then transferred to the NICU. For both groups, oxytocin was administered to the mother just after cord clamping. The ICR procedure and delegation of roles have been protocolized, and the healthcare team was appropriately trained. In particular, the person’s physical position and the role of each healthcare provider, including midwives, pediatricians, obstetricians, and anesthesiologists, were clearly anticipated. Maternal variables collected included mode of delivery, blood pressure and heart rate, mode of placental expulsion, blood loss volume, and need for intensive care. The observed/expected lung to head ratio assessed by prenatal echography and lung volume assessed by magnetic resonance imaging (MRI) were collected at 24-28 and 32-34 weeks gestational age (GA). Neonatal characteristics recorded included gestational age and birth weight, sex, Apgar score, blood cord gases, temperature at NICU admission, hemoglobin concentration, hematocrit, number of transfusions, and peak serum bilirubin. Variables concerning mechanical ventilation, blood gases, and plasma lactate concentrations were recorded during the first 48 hours after birth. Outcomes including duration of ventilation and O2 supplementation, need for O2 supplementation at discharge, age at weaning from parenteral nutrition, death, and age at discharge home were also recorded. Results are expressed as mean±SD or median and range. A Mann-Whitney test was used to compare variables between the 2 groups. Data were analyzed using repeated-measures analysis of variance when appropriate. Intergroup differences were analyzed with the
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Fisher’s and Bonferroni/Dunn’s significance tests (Stat View for PC; Abacus Concepts, Berkeley, CA). P-values <0.05 were considered significant.
Results Figure 1 shows the disposition of the 59 infants with CDH identified in the Nord Pas de Calais area during the study period. Based on mean numbers of births per year, it is estimated that approximately 220 000 infants were born in this area during this period: the incidence was therefore 1 infant with CDH for 3700 live births. 19 CDH infants were excluded from the study because of syndromic CDH, postnatal diagnosis of CDH, or lack of information regarding the timing of cord clamping. 20 CDH infants were included in each group. Maternal and fetal characteristics were similar between groups (Table 1; Table 2). The usual markers of CDH severity did not differ between groups. In particular, the indexes of fetal lung volume assessed by lung to head ratio and MRI at both 24-28 and 32-34 weeks GA, as well as the number of diaphragmatic agenesia and the need for prosthetic diaphragmatic patches did not differ between the ICC and ICR groups. Maternal blood pressure and heart rate were comparable between groups, as was time before expulsion of the placenta. Manual removal of the placenta was required in 17 cases in the ICC group and 11 cases in the ICR group; the difference was not statistically significant (NS). Median maternal blood loss was 200 ml [50-1750 ml] in the ICC group versus 400 ml [100-2450 ml] in the ICR group, but the difference was not significant. Two severe postpartum hemorrhages (defined as blood loss >1000 ml) occurred in each group. None of these mothers required admission in intensive care unit.
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In the intact cord resuscitation group, the cord was clamped at 7±3.4 minutes after birth. Two cords were clamped because of spontaneous placental delivery at 6 and 7 minutes. For all infants, mechanical ventilation could be initiated before clamping the umbilical cord. Fetal and neonatal characteristics are presented in Table 2. The temperature on admission to NICU was similar in the two groups. At H24, hemoglobin (14.5±1.4 vs 19.4±2.8 g/dl) and hematocrit (42.3±3.8 vs 53.5±7.6%) at H24 were significantly higher in the intact cord resuscitation group (p<0.05). The peak bilirubin concentration was higher in the ICR group, but not significantly so. No polycythemia was observed. Apgar scores were significantly higher in the ICR group than in the ICC group at 1 min (7.7±2.2 vs 4.5±2.1) and at 5 min (9.3±1.1 vs 6±2.8) (Table 3, p<0.05). Although the pH of the umbilical cord blood was similar between groups, the pH was higher at M30 and at H1 in the ICR group than in the ICC group (respectively, 7.12±0.1 vs 7.01±0.2; and 7.17±0.1 vs 7.08±0.2, p<0.05); the plasma lactate concentration was lower at M30 and H1 in the ICR group than in the ICC group (respectively, 3.8±1.7 vs 6.7±3.2; and 3.6±2.3 vs 6.6±4.3 mmol/l, p<0.05). Mean blood pressure was significantly higher in the ICR group than in the ICC group at H1 (52±7.7 vs 42±7.5 mmHg), H6 (47±3.9 vs 40±5.6 mmHg), and H12 (44±2.9 vs 39±3.3 mmHg) (Fig. 2, p<0.05). Inotropic support (mainly Norepinephrine) was used in 12/20 and in 8/20 infants in respectively the ICC and the ICR groups during the first 48 hours after birth (NS). The timing of intubation was similar in both groups (at 2.5±3 min after birth in the ICC group, and at 1.7±0.7min in the ICR group, NS). The parameters of mechanical ventilation did not differ between the two groups (Table 4). No patients were ventilated with bag mask before intubation. Chest compression and adrenalin injection were required at birth in 2 infants,
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both in the ICC group. The pre- and postductal SpO2 were similar in the two groups. Venoarterial extracorporeal membrane oxygenation (ECMO) was required in 2 infants in the ICR group and in 3 infants in the ICC group. Neonatal outcomes are presented in Table 5. Survival at discharge (18/20 vs 19/20), duration of mechanical ventilation (5.2±4.8 vs 5.6±3.2 days), duration of supplemental O2 including continuous positive airway pressure (CPAP) (17±26 vs 18±28 days), and age at discharge home (52±37 vs 77±69 days) were similar between the immediate cord clamping and intact cord resuscitation groups.
Discussion CDH is usually associated with impaired cardiorespiratory adaptation at birth. Evidence exists that delayed cord clamping may promote transition at birth in preterm infants (7). In this study, we investigated the feasibility and safety of intact cord resuscitation in newborn infants with isolated CDH. Physiologic variables and outcomes were collected prospectively in 40 successive newborn infants with antenatal diagnosis of isolated CDH. The umbilical cord was clamped immediately in infants born during the first part of the study period, and after initiation of resuscitation maneuvers in infants born during the second part. In this second group, intact cord resuscitation could be performed in all cases, whatever the mode of delivery. No additional maternal or neonatal adverse events were observed when the cord was clamped after starting resuscitation. Compared to the first 20 CDH infants in whom the cord was clamped immediately, Apgar scores at 1 and 5 min, pH at 1 hour after birth and mean blood pressure at H1, H6, and H12 were higher in the group of infants resuscitated while the cord was intact. Plasma lactate concentration was lower at one hour after birth in
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the infants with intact cord resuscitation. Taken together, our results suggest that intact cord resuscitation is feasible and well tolerated by infants with isolated CDH and their mothers, and may improve early cardiorespiratory adaptation at birth. To the best of our knowledge, our study is the first to explore the feasibility of intact cord resuscitation in newborn infants with isolated CDH. The question is important, as the early resuscitation period is quite challenging, with a major risk of hypoxic-ischemic events that may promote persistent pulmonary hypertension. Low Apgar score at 5 min is clearly associated with an increased risk of mortality (12,13,14). Intubation and mechanical ventilation immediately after birth is considered as a standard of care to reduce the risk of persistent pulmonary hypertension. Delayed cord clamping has the potential to promote transition at birth through placental transfusion, improvement in hemodynamics, and sustaining of placental exchange and oxygenation during the critical period of initial resuscitation. However, routine delayed cord clamping may delay resuscitation maneuvers including adequate lung ventilation, which are required immediately at birth for cardiorespiratory adaptation. Starting resuscitation maneuvers while the cord is intact – i.e., intact cord resuscitation – may provide the advantages of both delayed cord clamping and immediate resuscitation. Regarding feasibility, all of the infants in the intact cord resuscitation group could be intubated and mechanically ventilated before cord clamping and placental delivery. When the umbilical cord was short, placing the baby as close as possible to the birth canal and perpendicularly to the mother’s trunk prevented cord traction. Nevertheless, the procedure requires a dedicated written protocol known to the staff and appropriate training of healthcare providers including midwives, obstetricians, pediatricians, and anesthesiologists. It also requires a dedicated resuscitation table small enough and mobile enough to be placed
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rapidly between the mother’s legs at the end of the delivery. Such resuscitation tables are now commercially available (15,16), and the usability and acceptability of these mobile trolleys have been studied (17). Although the difference was not significant, a trend in increased maternal blood loss was observed in the ICR group. Metaanalysis reported no significant differences between early versus late cord clamping groups for severe postpartum hemorrhage, for postpartum hemorrhage of 500 mL or more, or for mean blood loss (6.7). Nevertheless, additional information is required to assess maternal safety of the procedure, as ICR is associated with delayed administration of oxytocin. Current guidelines recommend DCC in newborn infants not requiring resuscitation (18,19,20). However, according to the American Academy of Pediatrics, there is currently insufficient evidence to recommend a particular timing for cord clamping in infants who require resuscitation at birth (21). Our data suggest that initiation of resuscitation while the cord is intact may promote cardiorespiratory transition at birth in infants with CDH. In our study, the timing of cord clamping is explained by the duration of intubation and by the time to ensure adequate ventilation and cardiorespiratory stabilization of the infant after intubation. Apgar scores were higher at 1 and 5 min in infants undergoing intact cord resuscitation than after immediate cord clamping. Apgar score is considered as a reliable marker of postnatal adaptation in newborn infants. Although the pH of umbilical cord blood was similar between groups, pH was higher at one hour after birth in infants with intact cord resuscitation compared to those resuscitated after immediate cord clamping. Lower plasma lactate concentrations at 1 hour in the ICR group further support the hypothesis that starting
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resuscitation while the cord is intact reduces hypoxic insult and promotes transition at birth. Higher hemoglobin concentration may increase oxygen delivery to the tissue, which in turn may explain lower plasma lactate concentration in the ICR group. Maximum bilirubin concentrations were not significantly higher in the ICR group. Despite a resuscitation period in the delivery room, the temperature of the infants at NICU admission was not significantly lower after ICR. Improved cardiorespiratory adaptation can be explained by several mechanisms. Firstly, previous studies have shown that delayed cord clamping promotes blood transfusion from the placenta to the newborn (22). The higher hemoglobin concentrations and hematocrit seen at H24 in the ICR group are consistent with this effect. Higher mean blood pressures in the ICR group at H1, H6, and H12 provide further evidence of hemodynamic benefit with delayed cord clamping. Increased circulating blood volume due to placenta-fetal transfusion contributes to preventing low systemic pressure and cardiac output, and increased hematocrit improves oxygenation at birth. Secondly, in preterm lambs, immediate cord clamping results in a decrease in left ventricle preload, which leads to a decrease in heart rate (8). This phenomenon may explain the observation of momentary bradycardia when the cord is clamped before the first respiratory movements (23). In contrast, starting ventilation before cord clamping improves cardiovascular function by increasing pulmonary blood flow (8). Aerating the lungs increases pulmonary venous return, allowing it to promptly replace umbilical venous return as the primary source of preload, thereby stabilizing the circulation after birth (5). The maintenance of left ventricular preload by sustaining umbilical venous return may play a critical role in newborns with CDH. Our results support this hypothesis, as none of the infants in the ICR group required chest compression and adrenalin administration.
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Finally, a previous study highlighted that in most cases, both arterial and venous flow will continue for several minutes after birth when the cord is intact (24). It is therefore possible that sustained placental exchange may contribute, at least in part, to oxygenation when the cord is not clamped immediately at birth. The study has some limitations. The number of intubation attempts was not collected in this study. However, it is likely that the number of intubation attempts was not greater in the ICR group, as the timing of intubation was similar in both groups. In this pilot observational study, the infants were not randomized to ICR or ICC procedures. We cannot exclude a selection bias in the population of infants that would explain our results. However, the main ante- and postnatal markers of CDH severity were similar between groups, including estimation of lung volume as assessed by LHR and MRI, rates of diaphragmatic agenesia, and need for prosthetic diaphragmatic patches, providing some evidence that the 2 groups were comparable. In addition, the estimation of lung volume as assessed by LHR and MRI was rather favorable during the study and the mortality rate was low in each group. In a future study, inclusion of newborn infants with a more severe form of CDH is required to assess whether ICR may also promote cardiorespiratory adaptation in this high risk population. The outcomes did not differ between the groups; however, the study was clearly underpowered to show a potential long-term benefit of ICR in CDH infants. A randomized trial is required to determine whether ICR might improve outcomes in infants with CDH.
In conclusion, commencing resuscitation and initiating ventilation while the infant is still attached to the placenta is feasible in infants with CDH. Medical resuscitation equipment can be brought close enough to the mother’s perineum (or abdomen, in case of cesarean) to start resuscitation maneuvers without cutting the cord. Better results for Apgar scores,
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mean blood pressure, early blood gases, and lactate concentration indicate that intact cord resuscitation may support the cardiorespiratory transition at birth in infants with CDH.
Source of financial support for the research:
University Hospital of Lille, F-59000 Lille University Lille 2, F-59000 Lille
Conflicts of Interest: The authors report no conflict of interest.
Acknowledgements The authors would like to thank Annette Dubois for editorial assistance in the preparation of the manuscript.
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Hutchon D. Evolution of neonatal resuscitation with intact placental circulation. Clinical Practice 2014;10:28-61.
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Thomas MR, Yoxall CW, Weeks AD and Duley L. Providing newborn resuscitation at the mother's bedside: assessing the safety, usability and acceptability of a mobile trolley. BMC Pediatr 2014;14:135.
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Perlman JM, Wyllie J, Kattwinkel J, et al. Part 11: Neonatal Resuscitation: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Circulation 2010;122:S516-538.
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Committee on Obstetric Practice of the American College of Obstetricians and Gynecologists. Committee Opinion No. 543: Timing of umbilical cord clamping after birth. Obstet Gynecol 2012;120:1522-1526.
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Yao AC, Moinian M and Lind J. Distribution of blood between infant and placenta after birth. Lancet 1969;2:871-873.
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Dawson JA, Kamlin CO, Wong C, et al. Changes in heart rate in the first minutes after birth. Arch Dis Child Fetal Neonat 2010;95:177-181.
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Legends to figures
Figure 1: Flow chart of the newborn infants with CDH identified in the Nord-Pas de Calais area from January 2012 to May 2016
Assessed for eligibility (n=59)
Enrolled (n = 40)
Excluded (n=19) - Syndromic HDC (n=13) - Postnatal diagnosis (n=4) - Lack of information on the timing of cord clamping (n=2)
Immediate cord clamping (n=20)
Intact cord resuscitation (n=20)
Figure 2: Mean±SD change in blood pressure (mmHg) after birth in immediate cord clamping (ICC) and intact cord resuscitation (ICR) groups. * p<0.05 for comparison between groups.
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60
Blood pressure mmHg
55 50
ICC
45
ICR 40 35 30
H1
H6
H12
H48
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Table 1: Maternal characteristics
Mother's age, years Primiparas, n (%) Caesarean sections, n (%) Systolic blood pressure, mmHg Before birth After birth Diastolic blood pressure, mmHg Before birth After birth Heart rate, beats/min Temperature after birth, °C Time before placental expulsion, min Manual removal of placenta, n Median [range] blood loss, ml Severe postpartum hemorrhage (Blood loss > 1000 ml), n Intensive care, n
Immediate cord clamping (n = 20) 26 ± 5.5 7 (35) 6 (30)
Intact cord resuscitation (n = 20) 29 ± 5.9 10 (50) 5 (25)
P-value
119 ± 14 121 ± 17
123 ± 15 114 ± 8
NS NS
71 ± 9 69 ± 10 82 ± 13 36.9 ± 0.4 9±8 17 200 [50-1750] 2
75 ± 8 66 ± 8 84 ± 11 36.9 ± 0.6 10 ± 3 11 400 [100-2450] 2
NS NS NS NS NS NS NS NS
0
0
NS
NS, not statistically significant (p≥0.05). Expressed as mean±SD unless otherwise specified.
NS NS NS
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Table 2: Fetal and neonatal characteristics of the newborn infants in the immediate cord clamping and intact cord resuscitation groups Immediate Intact P-value cord cord clamping resuscitation (n = 20) (n = 20) Left CDH, n 19 19 NS LHR o/e echography, % 55 ± 20 55 ±20 NS 24-28 weeks GA 54 ± 14 45 ± 12 NS 32-34 weeks GA Volume o/e MRI, % 38 ± 22 33 ± 14 NS 24-28 weeks GA 52 ± 24 40 ± 14 NS 32-34 weeks GA Gestational age, weeks 39 ± 3 38 ± 2 NS Birth weight, g 3060 ± 710 3130 ± 660 NS Sex, male/female 11/9 9/11 NS Temperature at admission to NICU, °C 35.3 ± 1.1 35.7 ± 0.7 NS Hemoglobin H24, g/dl 14.5 ± 1.4 19.4 ± 2.8 <0.05 Hematocrit H24, % 42.3 ±3.8 53.5 ± 7.6 <0.05 Transfusions, n 0.9 ± 1.6 0.8 ± 1.3 NS Maximum serum bilirubin, µmol/l 110 ± 70 140 ± 76 NS CDH, congenital diaphragmatic hernia; NS, not statistically significant (p≥0.05); LHR, Lung to Head ratio; o/e, observed/expected; GA, gestational age; MRI, magnetic resonance imaging; NICU, neonatal intensive care unit; H24, 24 hours after birth. Expressed as mean±SD unless otherwise specified.
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Table 3: Physiological variables of the newborn infants in the immediate cord clamping and intact cord resuscitation groups Immediate cord Intact cord P-value clamping resuscitation (n = 20) (n = 20) Apgar score 4.5 ± 2.1 7.7 ± 2.2 <0.05 1 min 6 ± 2.8 9.3 ± 1.1 <0.05 5 min pH 7.29 ± 0.1 7.25 ± 0.1 NS Cord blood 7.01 ± 0.2 7.12 ± 0.1 <0.05 M30 7.08 ± 0.2 7.17 ± 0.1 <0.05 H1 7.27 ± 0.1 7.23 ± 0.1 NS H6 7.26 ± 0.1 7.24 ± 0.1 NS H12 7.22 ± 0.1 7.23 ± 0.1 NS H48 PCO2, mmHg 93 ± 12 84 ± 16 <0.05 M30 72 ± 24 79 ± 20 NS H1 51 ± 13 58 ± 21 NS H6 53 ± 12 57 ± 16 NS H12 58 ± 8 55 ± 15 NS H48 Lactate, mmol/l 6.7 ± 3.2 3.8 ± 1.7 <0.05 M30 6.6 ± 4.3 3.6 ± 2.3 <0.05 H1 1.6 ± 0.9 2.1 ± 2.4 NS H6 1.3 ± 0.7 2.1 ± 2.4 NS H12 1.3 ± 0.7 1.8 ± 1.5 NS H48 Heart rate, beats/min 142 ± 16 148 ± 18 NS M30 134 ± 13 143 ± 20 NS H1 121 ± 14 123 ± 19 NS H6 120 ± 11 123 ± 17 NS H12 132 ± 15 126 ± 13 NS H48 NS, not statistically significant (p≥0.05); H1, one hour after birth (and so on); PCO 2, partial pressure of carbon dioxide. Expressed as mean±SD.
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Table 4: Timing of intubation and mechanical ventilation parameters of the newborn infants in the immediate cord clamping and the intact cord resuscitation groups Immediate cord Intact cord P-value clamping resuscitation (n = 20) (n = 20) Timing of intubation, min 2.5 ± 3 1.7 ± 0.7 NS Peak inspiratory pressure, cm H20 23 ± 1.3 23 ± 1.5 NS M30 21 ± 2.9 22 ± 2 NS H1 19 ± 3.8 20 ± 4.3 NS H6 18 ± 4.8 19 ± 3.8 NS H12 19 ± 4.2 17 ± 3.8 NS H48 FiO2, % 80 ± 12 84 ± 14 NS M30 50 ± 33 56 ± 31 NS H1 36 ± 23 33 ± 19 NS H6 32 ± 24 34 ± 19 NS H12 26 ± 10 26 ± 7 NS H48 Preductal SpO2, % 82 ± 12 86 ± 9 NS M30 93 ± 8.1 93 ± 6.6 NS H1 95 ± 3.6 90 ± 12.4 NS H6 95 ± 4 92 ± 9.1 NS H12 96 ± 4.6 96 ± 3.3 NS H48 Postductal SpO2, % 76 ± 12 68 ± 9 NS M30 88 ± 9.8 80 ± 13.7 NS H1 87 ± 10.5 80 ± 16.5 NS H6 89 ± 9.5 83 ± 12.3 NS H12 87 ± 13.6 90 ± 8.2 NS H48 NS, not statistically significant (p≥0.05); H1, one hour after birth (and so on); FiO 2, fraction of inspired oxygen; SpO2, peripheral oxygen saturation. Expressed as mean±SD.
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Table 5: Neonatal outcomes
Death, n Duration of mechanical ventilation, days Median [range] CPAP duration, days Duration of O2 supplementation, days Median [range] duration of parenteral nutrition, days Age at discharge home, days
Immediate cord clamping (n = 20) 2 5.2 ± 4.8 5 [2-21] 17 ± 26 21 [6-113]
Intact cord resuscitation (n = 20) 1 5.6 ± 3.2 7 [1-141] 18 ± 28 26 [7-100]
P-value
52 ± 37
77 ± 69
NS
NS NS NS NS NS
NS, not statistically significant (p≥0.05); CPAP, continuous positive airway pressure. Expressed as mean ± SD (except for CPAP and parenteral nutrition duration).