Journal of Perinatology (2015) 35, 590–594 © 2015 Nature America, Inc. All rights reserved 0743-8346/15 www.nature.com/jp
ORIGINAL ARTICLE
One-time umbilical cord milking after cord cutting has same effectiveness as multiple-time umbilical cord milking in infants born at o 29 weeks of gestation: a retrospective study S Hosono1, H Mugishima1, S Takahashi1, S Takahashi1, N Masaoka2,3, T Yamamoto3 and M Tamura4 OBJECTIVE: To compare two strategies to potentiate the effects of placental transfusion in infants born at o29 weeks of gestation. STUDY DESIGN: Twenty infants who received one-time umbilical cord milking after umbilical cord cutting were compared with 20 infants from a previous study group who received multiple-time umbilical cord milking. The primary outcome measurements were the probability of not needing a red blood cell (RBC) transfusion during the hospital stay and the total number of RBC transfusions within 21 days after birth. RESULT: There was no significant difference in the probability of not needing a transfusion during the hospital stay (P = 0.75) and the mean number of RBC transfusions given within the first 21 days of life (1.1 ± 1.8 for the one-time umbilical cord-milking group vs 0.7 ± 1.2 for the multiple-time umbilical cord-milking group, P = 0.48). CONCLUSION: One-time umbilical cord milking after umbilical cord cutting had similar beneficial effects to multiple-time umbilical cord milking before umbilical cord cutting in very premature infants. Journal of Perinatology (2015) 35, 590–594; doi:10.1038/jp.2015.15; published online 12 March 2015
INTRODUCTION The most recent evidence has shown benefits of delayed cord clamping (DCC) in premature infants.1 However, the survey of the members of the American College of Obstetricians and Gynecologists revealed that obstetricians often preferred immediate cord clamping due to the fear of delaying resuscitation.2 In Japan, as in the United States, DCC is not the usual practice in both term infants and preterm infants, and umbilical cord milking in premature infants has become an alternative procedure in place of DCC. We first described that umbilical cord milking reduced the need for red blood cell (RBC) transfusions and improved neonatal adaptation in premature infants.3,4 Nine studies on umbilical cord milking5–13 have been published in the years following the initial report. However, there is no welldesigned, standardized protocol for umbilical cord milking. Our original procedure for umbilical cord milking, performed by the obstetrician, was to place the infant at or below the level of the placenta and to milk vigorously ~ 20 cm of the umbilical cord toward the umbilicus two to three times before clamping the umbilical cord. The milking speed was ~ 20 cm per 2 s.3 After January 2007, we changed the umbilical cord-milking procedure from multiple-time umbilical cord milking before umbilical cord cutting by the obstetrician to one-time umbilical cord milking after umbilical cord cutting by the neonatologist. This procedure was adopted because we found that a 30-cm length of umbilical cord contained 17.7 ± 5.5 (8.9 to 29.0) ml per birth weight (kg) of whole blood in preterm infants14 and that this transfused volume might be adequate for placental transfusion. Another reason for this change in procedure was that obstetricians were occupied
with surgery, they often felt it was a hindrance to perform multiple-time umbilical cord milking. Therefore, we introduced the technique of one-time umbilical cord milking by the neonatologist after cutting the umbilical cord as an alternative to management by obstetrician. In 2013 Upadhyay et al.7 first reported one-time umbilical cord milking in term and near term infants. There might be theoretically a large difference in the placental transfusion volume between the procedure of one-time umbilical cord milking, which involved milking the umbilical cord once after umbilical cord cutting, and other procedures that involved milking the umbilical cord two to four times before umbilical cord cutting. If umbilical cord milking after umbilical cord cutting is performed, the maximum blood volume of the placental transfusion is the residual blood volume in the remaining segment of the umbilical cord. In contrast, it is unclear that placental transfusion volume might depend on the number of umbilical cord milking because there was no data whether enough umbilical vessels refilling from placenta occur after umbilical cord milking. The recent study by Boere et al.15 revealed no flow or reversed flow in a vein during expiration, and unidirectional or bidirectional flow in arteries during DCC by using ultrasound machine. Blood flow in the cord vessels is very complex and depends on the many factors. The aims of this study were to test the equivalence or noninferiority of one-time umbilical cord milking after cutting the umbilical cord long by the obstetrician compared with multipletime umbilical cord milking before umbilical cord cutting by the neonatologist and to obtain preliminary data prior to conducting a multicenter prospective randomized trial in Japan.
1 Division of Neonatology, Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan; 2Department of Obstetrics and Gynecology, Tokyo Women’s Medical University Yachiyo Medical Center, Chiba, Japan; 3Department of Obstetrics and Gynecology, Nihon University School of Medicine, Tokyo, Japan and 4Division of Neonatal Medicine, Center for Maternal, Fetal and Neonatal Medicine, Saitama Medical University Kawagoe Medical Center, Saitama, Japan. Correspondence: Dr S Hosono, Division of Neonatology, Department of Pediatrics and Child Health, Nihon University School of Medicine, 30-1 Oyaguchi Itabashi, Tokyo 173-8610, Japan. E-mail: [email protected] Received 22 October 2014; revised 3 February 2015; accepted 4 February 2015; published online 12 March 2015
One-time umbilical cord milking S Hosono et al
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This study was a retrospective study comparing two treatment arms. We evaluated 40 very low birth weight infants born between 24 and 28 weeks of gestation who were admitted to the level III neonatal intensive care unit (NICU) at Nihon University Itabashi Hospital in Tokyo, Japan. Twenty infants, admitted between 2007 and 2008, who received one-time umbilical cord milking, were compared with 20 infants from a previous study group who received multiple-time umbilical cord milking.3 For all cases of intervention with one-time umbilical cord milking after delivery, infants were placed at or below the level of the placenta, and within 30 s of birth, the umbilical cord was clamped and cut at 30 cm of length from the umbilical stump before moving the infant to the radiant warmer. Next, a neonatologist raised the cut end of the umbilical cord, released umbilical cord torsion, milked the umbilical cord once from the cut end toward the infant at a speed of 10 cm s − 1, and clamped the cord at 1 to 2 cm from the umbilical stump. In contrast, for multiple-time umbilical cord milking, the infant was placed at or below the level of the placenta, and ~ 20 cm of the umbilical cord was vigorously milked toward the umbilicus two to three times before clamping of the cord by the obstetrician. The milking speed was ~ 10 cm per 1 s as same speed as one-time umbilical cord milking. The primary outcome measurements were the probability of not needing an RBC transfusion during the hospital stay and the total number of RBC transfusions within 21 days after birth. The secondary outcome variables were hemoglobin level and morbidity. Diagnosis and treatment strategies including RBC transfusion criteria were described in a previous study,3 and there was no change in the RBC transfusion criteria during the care of two study cohorts. Prenatal, delivery and infant data were collected from medical charts. This study was approved by the hospital investigation committee (RK-140314-4).
Statistical analysis Normally distributed continuous outcome variables were compared using the Student's unpaired t-test, and non-parametric continuous variables were analyzed using the Mann–Whitney U-test. Categorical variables were compared using the chi-square test. Fisher’s exact test was used for contingency tables showing expected cell counts o5. Kaplan–Meier analysis and the log-rank test were used to evaluate the transfusion-free duration. In patients who did not require RBC transfusion, the time from birth to hospital discharge was used as the transfusion-free duration. The data are expressed as the mean ± s.d. All of the analyses were conducted with two-tailed tests. P-values o0.05 were considered significant. The statistical analysis was performed using SPSS (Statistical Package for the Social Science) software, version 20 (Chicago, IL, USA).
RESULTS Table 1 lists the infants’ characteristics and clinical data on admission, which were not significantly different between the
Table 1.
two groups. One infant in the one-time umbilical cord-milking group died on day 45 due to intestinal perforation, and two infants in the multiple-time umbilical cord-milking group died, one at 15 days due to sepsis and one at 35 days due to intestinal perforation. Therefore, there was no significant difference in mortality between the two groups (P = 0.67). Each of these three infants received at least one RBC transfusion within 21 days after birth. There was no significant difference in the probability of being free from transfusion during the hospital stay between the two groups by the log-rank test (P = 0.60; Figure 1). Table 2 shows the clinical characteristics of the infants. The initial mean hemoglobin values were 16.9 ± 2.7 g l − 1 for the one-time umbilical cordmilking group and 16.5 ± 1.4 g l − 1 for the multiple-time umbilical cord-milking group (P = 0.46). There was no significant difference in the mean number of transfusions within the first 21 days of life (one-time umbilical cord-milking group 1.1 ± 0.8; multiple-time umbilical cord-milking group 0.7 ± 1.2; P = 0.79) or during the hospital stay (one-time umbilical cord-milking group 1.8 ± 2.8; multiple-time umbilical cord-milking group 1.7 ± 3.0; P = 0.91). Mean peak bilirubin and the duration of phototherapy were comparable between the two groups. Table 3 shows the cardiopulmonary status of the infant. No differences in systolic or diastolic blood pressure were observed between the two groups. Table 4 provides the information about major morbidities during the hospital stay. The morbidities during the hospital stay were similar between the two groups. One infant in the one-time umbilical cord-milking group whose weight was appropriate for dates, born to a mother with a non-complicated pregnancy, had non-symptomatic polycythemia with a hemoglobin value of 23.1 g dl − 1 on day 0.
Probability of being free from transfusion
METHODS
1.0 0.8
Multiple-time milking
0.6 0.4
One-time milking
Log-rank test p=0.60
0.2 0 0
50 Day after birth
100
Figure 1. There was no significant difference in the probability of being free from transfusion between the two groups by the log-rank test (P = 0.60).
Baseline characteristics
Characteristics Gestational age (weeks) Birth weight (g) Male Antenatal steroids PROM Chorioamnionitis Small for gestational age 1-min Apgar 5-min Apgar Cesarean delivery Death
One-time milking (n = 20)
Multiple-time milking (n = 20)
95% CI
P-value
27.0 ± 1.6 24–28 852 ± 234 453–1404 7 (35) 5 (25) 6 (30) 9 (45) 5 (25) 5 7 18 (90) 1 (5)
27.0 ± 1.5 24–28 836 ± 223 494–1198 10 (50) 7 (35) 6 (30) 10 (50) 6 (30) 6 8 14 (70) 2 (10)
− 0.85 to 1.15
0.77
− 164 to 131
0.83
0.34 0.27 0.39 0.47 0.31
0.36 0.73 1.00 0.76 1.00 0.11 0.11 0.24 1.00
to to to to to
1.44 1.82 2.55 1.71 2.24
0.31 to 2.24 0.07 to 3.66
Abbreviations: CI, confidence interval; PROM, premature rupture of membranes. Data are expressed as mean ± s.d. except Apgar score. Apgar scores are expressed as median. Percentages, given in parentheses, are calculated as a proportion of the total number.
© 2015 Nature America, Inc.
Journal of Perinatology (2015), 590 – 594
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592 Table 2.
Clinical characteristics
Hemoglobin value at birth (g dl − 1; range) Phlebotomy loss per birth weight (ml kg − 1) First day of EPO (day) Hemoglobin value at the start of EPO (g dl − 1) No RBC transfusion ⩽ 21 days No RBC transfusion during hospital stay Number of blood transfusions ⩽ 21 days Total number of blood transfusions Maximum serum bilirubin (mg dl Duration of phototherapy (day)
−1
)
One-time milking (n = 20)
Multiple-time milking (n = 20)
16.9 ± 2.7 (11.7–23.1) 18.3 ± 1.5 19.9 ± 1.4 12.4 ± 2.7 12 (60) 11 (55) 1.1 ± 1.8 0–4 1.8 ± 2.8 0–9 8.5 ± 2.2 7.7 ± 2.0
16.5 ± 1.4 (13.7–19.6) 16.7 ± 4.8 19.3 ± 4.9 12.0 ± 2.0 13 (65) 13 (65) 0.7 ± 1.2 0–4 1.7 ± 3.0 0–9 8.2 ± 2.6 8.2 ± 2.6
95% CI − 1.93 − 5.40 − 4.28 − 1.51 0.59 0.52 − 1.34
to to to to to to to
P-value
0.90 2.19 3.11 0.74 1.47 1.39 0.64
0.46 0.40 0.75 0.50 1.00 0.75 0.48
− 1.95 to 1.75
0.91
− 1.83 to 1.25 − 1.04 to 1.94
0.71 0.54
Abbreviations: CI, confidence interval; EPO, erythropoietin; RBC, red blood cell. Data are expressed as mean ± s.d. Percentages, given in parentheses, are calculated as a proportion of the total number.
Table 3.
Cardiopulmonary status
Systolic blood pressure at admission (mmHg) Diastolic blood pressure at admission (mmHg) Hypotension at admission Blood transfusion for hypotension Volume expander DOA+DOB ⩽ 5 μg kg − 1 min − 1 DOA+DOB 45 μg kg − 1 min − 1 Duration of mechanical ventilation (days) Duration of O2 (days) Duration of O2 ⩾ 30% (days)
One-time milking (n = 20)
Multiple-time milking (n = 20)
95% CI
P-value
42 ± 10 27 ± 9 4 (20) 1 (5) 2 (10) 5 (25) 4 (20) 23.6 ± 21.1 28.9 ± 21.9 3.5 ± 4.2
42 ± 11 25 ± 8 5 (25) 0 (0) 2 (10) 4 (20) 3 (15) 21.9 ± 19.1 23.4 ± 18.8 6.0 ± 9.4
− 8.47 to 7.96 − 8.99 to 4.52 0.26 to 2.45 — 0.18 to 5.44 0.41 to 3.90 0.37 to 4.98 − 14.85 to 11.64 − 2.49 to 7.49 − 18 86 to 7.94
0.95 0.50 1.00 1.00 1.00 1.00 1.00 0.81 0.41 0.31
Abbreviations: CI, confidence interval; DOA, dopamine; DOB, dobutamine. Data are mean ± s.d. Percentages, given in parentheses, are calculated as a proportion of the total number. Blood pressure was measured by using oscillometric method.
DISCUSSION To our knowledge, this was the first report to test the noninferiority of efficacy of one-time umbilical cord milking after umbilical cord cutting compared with multiple-time umbilical cord milking before umbilical cord cutting in very low birth weight infants born between 24 and 28 weeks of gestation. This study showed that milking ~ 30 cm of segment of umbilical cord once into the infant resulted in similar hemoglobin levels, and was an equally important contributor to reducing RBC transfusions, compared with multiple-time umbilical cord milking. We often experienced the phenomenon that immediate reversed flow in umbilical arteries from an infant occurred after milking, when the operator unclamped the umbilical cord at the infant’s site to perform the next umbilical cord milking. This phenomenon led us to introduce the technique of one-time umbilical cord milking. Our hypothesis, when we introduced multiple-time umbilical cord milking, was that the umbilical cord vessels including both the arteries and the vein would be refilled due to the resulting self-inflating vessels' capability and negative pressure gradient in the placenta from the previous milking. However, the umbilical vessels rapidly refilled from the infant’s side as a result of the infant’s blood pressure itself, when the obstetricians released the compressed portion of umbilical cord closest to the infant first against the milking procedure. The correct procedure for multiple-time umbilical cord milking is as follows. It is little more complicated than one-time umbilical cord milking. After each milking, release the compressed portion of the umbilical cord closest to the placenta but keep the part of the umbilical cord closest to the infant compressed with your other Journal of Perinatology (2015), 590 – 594
hand. This will allow placental blood to refill the umbilical cord, which should be complete within a few seconds. After this, take your hand off the umbilical cord at closest to the infant and milk the blood into the infant with your free hand. Repeat the procedure as required. Recent studies provided a paradigm shift of a potential mechanism for the passage of blood flow from the placenta to the infant during DCC. The first report by Vain et al.16 showed the position of the infant before cord clamping does not seem to affect volume of placental transfusion. Boere et al.15 revealed that the net placental transfusion was probably the result of several factors of which breathing, particularly crying, could play a major role. However, the eligible infants in both studies were all healthy term infants. As is emphasized in the commentary by Raju,17 more research should be performed to address the mechanism of placental transfusion in the high-risk infants. Blood flow in the vessels after umbilical cord milking seems to be more complicated because of unknown mechanism of refilling. One important problem that seems insurmountable is determining the volume of placental blood that transfers to the infant during multiple-time umbilical cord milking. Our previous study demonstrated that the residual cord blood volume per kilogram of infants weight per 30 cm of segment of umbilical cord was 17.7 ± 5.5 (8.9 to 29.0) ml kg − 1.14 With an average hematocrit of 40%, this volume is equivalent to a transfusion of ~ 13 ml of packed RBC transfusion (hematocrit of 55%). This study demonstrated a similar effect of reduction in RBC transfusions within the 21 days after birth and during the hospital stay. Rabe et al.12 assumed that at least one-half to two-thirds of the cord length © 2015 Nature America, Inc.
One-time umbilical cord milking S Hosono et al
593 Table 4.
Major morbidity during NICU stay
Polycythemia RDS PDA Hyperkalemia IVH IVH ⩾ III Intestinal perforation PVL CLD at 4 weeks CLD at 36 weeks ROP ⩾ 2 ROP ⩾ 3
One-time milking (n = 20)
Multiple-time milking (n = 20)
1 (5) 13 (65) 6 (30) 4 (20) 4 (20) 0 (0) 1 (5) n = 19 0 (0) 3 (16) 1 (5) 9 (47) 4 (21)
0 (0) 14 (70) 5 (25) 3 (15) 3 (15) 2 (10) 1 (5) n = 18 1 (7) 3 (17) 0 (0) 6 (33) 2 (11)
95% CI
P-value
— to 1.40 to 3.28 to 5.00 to 5.00 to 4.98 to 9.44
1.00 1.00 1.00 1.00 1.00 0.47 1.00
0.00 to 3.57 0.24 to 3.82 — 0.65 to 3.20 0.45 to 8.46
0.98 0.71 0.98 0.81 0.71
0.62 0.45 0.37 0.37 0.37 0.11
Abbreviations: CI, confidence interval; CLD, chronic lung disease; IVH, intraventricular hemorrhage; NICU, neonatal intensive care unit; PDA, patent ductus arteriosus; PVL, periventricular leukomalacia; RDS, respiratory distress syndrome; ROP, retinopathy of prematurity. Percentages, given in parentheses, are calculated as the proportion of the total number. Polycythemia is defined as venous or arterial hemoglobin concentration over 22 g dl − 1.
would be available for milking before clamping, because this length represents 7 to 10 ml of blood, then ~ 30 to 40 ml of blood would be transfused into the infants. The mean hemoglobin value of premature infants who received multiple-time umbilical cord milking ranged from 14.9 to 17.5 g dl − 1.8,12 March et al.8 milked a 20-cm length of umbilical cord three times, whereas Rabe et al.12 did not provide numerical details concerning the length of the umbilical cord milked, but instead reported that the umbilical cord was milked for its entire length four times. In our study, the mean hemoglobin level for the one-time umbilical cord-milking group was 16.9 g dl − 1, which was midway in the minimum (14.9 g dl − 1) and the maximum (17.5 g dl − 1) ranges.8,12 One-time umbilical cord milking of a 30-cm length may potentially match the effectiveness of multiple-time umbilical cord milking. One-time umbilical cord milking has several advantages over multiple-time umbilical cord milking. First, one-time umbilical cord milking can easily be standardized. Second, this procedure is simple enough for the delivering obstetricians to understand an incorporation of this procedure into practice. All they have to do is to lower the infant at or below the level of the placenta and to clamp and cut the umbilical cord 30 cm of length from the umbilical stump. Third, one-time umbilical cord milking might have less of an impact on circulation dynamics compared with multiple-time umbilical cord milking, because during releasing the torsion of umbilical cord, umbilical cord blood flows into the infant gravitationally, and the neonatologist can milk the umbilical cord slowly without time pressure. Finally, one-time umbilical cord milking might deliver a steady supply of umbilical cord blood to the infant compared with multiple-time umbilical cord milking. The current study had several limitations. This study had a small sample size and was not a prospective randomized controlled study. Therefore, this study was not powered to estimate important outcomes, including a need for RBC transfusion and intraventricular hemorrhage. This study was a historical control study. The infants in the multiple-time umbilical cord-milking group were admitted to the NICU between 2001 and 2002, and the infants in the one-time umbilical cord-milking group were admitted between 2007 and 2008. There were no major changes in either the transfusion, respiratory or circulatory management policies during the two study periods, and the obstetric management was also similar, but there was a new strategy of early aggressive nutrition introduced after 2003, and there was also employee turnover. However, we might have overlooked the possibility of unrecognizable differences, which could have affected clinical variables and could also have contributed to © 2015 Nature America, Inc.
variations in the subjects’ conditions. Approximately, 20-cm length of umbilical cord was milked in multiple-time umbilical cordmilking group. However, in the one-time umbilical cord group ~ 30-cm length of umbilical cord was milked. In addition, umbilical cord-milking performers were changed from obstetricians to pediatricians. Finally, the resuscitation team and therapeutic team were aware of the infants’ grouping in both intervention periods. There are no data on the neurodevelopmental outcomes of infants received umbilical cord milking. We could find only one developmental outcome of very low birth weight infants received DCC, and this study showed that DCC seemed to be protective in very low birth weight male infants against motor disability at 7 months of corrected age.18 So we should analyze the neurodevelopmental outcomes near future. In conclusion, this report was the first study to evaluate the effects of one-time umbilical cord milking on the enhancement of placental transfusion in premature infants. The results demonstrated that there were similar beneficial effects between one-time umbilical cord milking after umbilical cord cutting and multipletime umbilical cord milking before umbilical cord cutting. Moreover, this procedure might be a less demanding method for obstetricians to perform. We believe that the results of our preliminary trial justify the need for a prospective randomized multicenter trial to evaluate further the potential benefits of one-time umbilical cord milking after umbilical cord cutting in premature infants. Needless to say, the aim of future research would be to examine the reduction of severe intraventricular hemorrhage and the long-term effects of these two umbilical cord-milking methods on neurodevelopment. CONFLICT OF INTEREST The authors declare no conflict of interest.
ACKNOWLEDGMENTS This work was supported by MEXT KAKENHI (Grant-in-Aid for Scientific Research (C) Grant Number 26461649.
REFERENCES 1 Rabe H, Diaz-Rossello JL, Duley L, Dowswell T. Effect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes. Cochrane Database Syst Rev 2012; 8: CD003248.
Journal of Perinatology (2015), 590 – 594
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594 2 Jelin AC, Kuppermann M, Erickson K, Clyman R, Schulkin J. Obstetricians' attitudes and beliefs regarding umbilical cord clamping. J Matern Fetal Neonatal Med 2013; 27: 1457–1461. 3 Hosono S, Mugishima H, Fujita H, Hosono A, Minato M, Okada T et al. Umbilical cord milking reduces the need for red cell transfusions and improves neonatal adaptation in infants born at less than 29 weeks' gestation: a randomised controlled trial. Arch Dis Child Fetal Neonatal Ed 2008; 93: F14–F19. 4 Hosono S, Mugishima H, Fujita H, Hosono A, Okada T, Takahashi S et al. Blood pressure and urine output during the first 120 h of life in infants born at less than 29 weeks' gestation related to umbilical cord milking. Arch Dis Child Fetal Neonatal Ed 2009; 94: F328–F331. 5 Erickson-Owens DA, Mercer JS, Oh W. Umbilical cord milking in term infants delivered by cesarean section: a randomized controlled trial. J Perinatol 2012; 32: 580–584. 6 Takami T, Suganami Y, Sunohara D, Kondo A, Mizukaki N, Fujioka T et al. Umbilical cord milking stabilizes cerebral oxygenation and perfusion in infants born before 29 weeks of gestation. J Pediatr 2012; 161: 742–747. 7 Upadhyay A, Gothwal S, Parihar R, Garg A, Gupta A, Chawla D et al. Effect of umbilical cord milking in term and near term infants: randomized control trial. Am J Obstet Gynecol 2013; 208: 120.e1–6. 8 March MI, Hacker MR, Parson AW et al. The effects of umbilical cord milking in extremely preterm infants: a randomized controlled trial. J Perinatol 2013; 33: 763–767. 9 Katheria AC, Leone TA, Woelkers D, Modest AM, de Veciana M. The effects of umbilical cord milking on hemodynamics and neonatal outcomes in premature neonates. J Pediatr 2014; 164: 1045–1050. 10 Alan S, Arsan S, Okulu E, Akin IM, Kilic A, Taskin S et al. Effects of umbilical cord milking on the need for packed red blood cell transfusions and early
Journal of Perinatology (2015), 590 – 594
11 12
13
14
15
16
17 18
neonatal hemodynamic adaptation in preterm infants born ≤ 1500 g: a prospective, randomized, controlled trial. J Pediatr Hematol Oncol 2014; 36: e493–e498. Katheria A, Blank D, Rich W, Finer N. Umbilical cord milking improves transition in premature infants at birth. PLoS One 2014; 9: e94085. Rabe H, Jewison A, Alvarez RF, Crook D, Stilton D, Bradley R et al. Brighton Perinatal Study Group. Milking compared with delayed cord clamping to increase placental transfusion in preterm neonates: a randomized controlled trial. Obstet Gynecol 2011; 117: 205–211. Patel S, Clark EA, Rodriguez CE, Metz TD, Abbaszadeh M, Yoder BA. Effect of umbilical cord milking on morbidity and survival in extremely low gestational age neonates. Am J Obstet Gynecol 2014; 211: 519.e1–7. Hosono S, Hine K, Nagano N, Taguchi Y, Yoshikawa K, Okada T et al. Residual blood volume in the umbilical cord of extremely premature infants. Pediatr Int 2015; 57: 68–71. Boere I, Roest AA, Wallace E, Ten Harkel AD, Haak MC, Morley CJ et al. Umbilical blood flow patterns directly after birth before delayed cord clamping. Arch Dis Child Fetal Neonatal Ed 2015; 100: F121–F125. Vain NE, Satragno DS, Gorenstein AN, Gordillo JE, Berazategui JP, Alda MG et al. Effect of gravity on volume of placental transfusion: a multicentre, randomised, non-inferiority trial. Lancet 2014; 384: 235–240. Raju TN. Delayed cord clamping: does gravity matter? Lancet 2014; 384: 213–214. Mercer JS, Vohr BR, Erickson-Owens DA, Padbury JF, Oh W. Seven-month developmental outcomes of very low birth weight infants enrolled in a randomized controlled trial of delayed versus immediate cord clamping. J Perinatol 2010; 30: 11–16.
© 2015 Nature America, Inc.
ORIGINAL ARTICLE
One-time umbilical cord milking after cord cutting has same effectiveness as multiple-time umbilical cord milking in infants born at o 29 weeks of gestation: a retrospective study S Hosono1, H Mugishima1, S Takahashi1, S Takahashi1, N Masaoka2,3, T Yamamoto3 and M Tamura4 OBJECTIVE: To compare two strategies to potentiate the effects of placental transfusion in infants born at o29 weeks of gestation. STUDY DESIGN: Twenty infants who received one-time umbilical cord milking after umbilical cord cutting were compared with 20 infants from a previous study group who received multiple-time umbilical cord milking. The primary outcome measurements were the probability of not needing a red blood cell (RBC) transfusion during the hospital stay and the total number of RBC transfusions within 21 days after birth. RESULT: There was no significant difference in the probability of not needing a transfusion during the hospital stay (P = 0.75) and the mean number of RBC transfusions given within the first 21 days of life (1.1 ± 1.8 for the one-time umbilical cord-milking group vs 0.7 ± 1.2 for the multiple-time umbilical cord-milking group, P = 0.48). CONCLUSION: One-time umbilical cord milking after umbilical cord cutting had similar beneficial effects to multiple-time umbilical cord milking before umbilical cord cutting in very premature infants. Journal of Perinatology (2015) 35, 590–594; doi:10.1038/jp.2015.15; published online 12 March 2015
INTRODUCTION The most recent evidence has shown benefits of delayed cord clamping (DCC) in premature infants.1 However, the survey of the members of the American College of Obstetricians and Gynecologists revealed that obstetricians often preferred immediate cord clamping due to the fear of delaying resuscitation.2 In Japan, as in the United States, DCC is not the usual practice in both term infants and preterm infants, and umbilical cord milking in premature infants has become an alternative procedure in place of DCC. We first described that umbilical cord milking reduced the need for red blood cell (RBC) transfusions and improved neonatal adaptation in premature infants.3,4 Nine studies on umbilical cord milking5–13 have been published in the years following the initial report. However, there is no welldesigned, standardized protocol for umbilical cord milking. Our original procedure for umbilical cord milking, performed by the obstetrician, was to place the infant at or below the level of the placenta and to milk vigorously ~ 20 cm of the umbilical cord toward the umbilicus two to three times before clamping the umbilical cord. The milking speed was ~ 20 cm per 2 s.3 After January 2007, we changed the umbilical cord-milking procedure from multiple-time umbilical cord milking before umbilical cord cutting by the obstetrician to one-time umbilical cord milking after umbilical cord cutting by the neonatologist. This procedure was adopted because we found that a 30-cm length of umbilical cord contained 17.7 ± 5.5 (8.9 to 29.0) ml per birth weight (kg) of whole blood in preterm infants14 and that this transfused volume might be adequate for placental transfusion. Another reason for this change in procedure was that obstetricians were occupied
with surgery, they often felt it was a hindrance to perform multiple-time umbilical cord milking. Therefore, we introduced the technique of one-time umbilical cord milking by the neonatologist after cutting the umbilical cord as an alternative to management by obstetrician. In 2013 Upadhyay et al.7 first reported one-time umbilical cord milking in term and near term infants. There might be theoretically a large difference in the placental transfusion volume between the procedure of one-time umbilical cord milking, which involved milking the umbilical cord once after umbilical cord cutting, and other procedures that involved milking the umbilical cord two to four times before umbilical cord cutting. If umbilical cord milking after umbilical cord cutting is performed, the maximum blood volume of the placental transfusion is the residual blood volume in the remaining segment of the umbilical cord. In contrast, it is unclear that placental transfusion volume might depend on the number of umbilical cord milking because there was no data whether enough umbilical vessels refilling from placenta occur after umbilical cord milking. The recent study by Boere et al.15 revealed no flow or reversed flow in a vein during expiration, and unidirectional or bidirectional flow in arteries during DCC by using ultrasound machine. Blood flow in the cord vessels is very complex and depends on the many factors. The aims of this study were to test the equivalence or noninferiority of one-time umbilical cord milking after cutting the umbilical cord long by the obstetrician compared with multipletime umbilical cord milking before umbilical cord cutting by the neonatologist and to obtain preliminary data prior to conducting a multicenter prospective randomized trial in Japan.
1 Division of Neonatology, Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan; 2Department of Obstetrics and Gynecology, Tokyo Women’s Medical University Yachiyo Medical Center, Chiba, Japan; 3Department of Obstetrics and Gynecology, Nihon University School of Medicine, Tokyo, Japan and 4Division of Neonatal Medicine, Center for Maternal, Fetal and Neonatal Medicine, Saitama Medical University Kawagoe Medical Center, Saitama, Japan. Correspondence: Dr S Hosono, Division of Neonatology, Department of Pediatrics and Child Health, Nihon University School of Medicine, 30-1 Oyaguchi Itabashi, Tokyo 173-8610, Japan. E-mail: [email protected] Received 22 October 2014; revised 3 February 2015; accepted 4 February 2015; published online 12 March 2015
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This study was a retrospective study comparing two treatment arms. We evaluated 40 very low birth weight infants born between 24 and 28 weeks of gestation who were admitted to the level III neonatal intensive care unit (NICU) at Nihon University Itabashi Hospital in Tokyo, Japan. Twenty infants, admitted between 2007 and 2008, who received one-time umbilical cord milking, were compared with 20 infants from a previous study group who received multiple-time umbilical cord milking.3 For all cases of intervention with one-time umbilical cord milking after delivery, infants were placed at or below the level of the placenta, and within 30 s of birth, the umbilical cord was clamped and cut at 30 cm of length from the umbilical stump before moving the infant to the radiant warmer. Next, a neonatologist raised the cut end of the umbilical cord, released umbilical cord torsion, milked the umbilical cord once from the cut end toward the infant at a speed of 10 cm s − 1, and clamped the cord at 1 to 2 cm from the umbilical stump. In contrast, for multiple-time umbilical cord milking, the infant was placed at or below the level of the placenta, and ~ 20 cm of the umbilical cord was vigorously milked toward the umbilicus two to three times before clamping of the cord by the obstetrician. The milking speed was ~ 10 cm per 1 s as same speed as one-time umbilical cord milking. The primary outcome measurements were the probability of not needing an RBC transfusion during the hospital stay and the total number of RBC transfusions within 21 days after birth. The secondary outcome variables were hemoglobin level and morbidity. Diagnosis and treatment strategies including RBC transfusion criteria were described in a previous study,3 and there was no change in the RBC transfusion criteria during the care of two study cohorts. Prenatal, delivery and infant data were collected from medical charts. This study was approved by the hospital investigation committee (RK-140314-4).
Statistical analysis Normally distributed continuous outcome variables were compared using the Student's unpaired t-test, and non-parametric continuous variables were analyzed using the Mann–Whitney U-test. Categorical variables were compared using the chi-square test. Fisher’s exact test was used for contingency tables showing expected cell counts o5. Kaplan–Meier analysis and the log-rank test were used to evaluate the transfusion-free duration. In patients who did not require RBC transfusion, the time from birth to hospital discharge was used as the transfusion-free duration. The data are expressed as the mean ± s.d. All of the analyses were conducted with two-tailed tests. P-values o0.05 were considered significant. The statistical analysis was performed using SPSS (Statistical Package for the Social Science) software, version 20 (Chicago, IL, USA).
RESULTS Table 1 lists the infants’ characteristics and clinical data on admission, which were not significantly different between the
Table 1.
two groups. One infant in the one-time umbilical cord-milking group died on day 45 due to intestinal perforation, and two infants in the multiple-time umbilical cord-milking group died, one at 15 days due to sepsis and one at 35 days due to intestinal perforation. Therefore, there was no significant difference in mortality between the two groups (P = 0.67). Each of these three infants received at least one RBC transfusion within 21 days after birth. There was no significant difference in the probability of being free from transfusion during the hospital stay between the two groups by the log-rank test (P = 0.60; Figure 1). Table 2 shows the clinical characteristics of the infants. The initial mean hemoglobin values were 16.9 ± 2.7 g l − 1 for the one-time umbilical cordmilking group and 16.5 ± 1.4 g l − 1 for the multiple-time umbilical cord-milking group (P = 0.46). There was no significant difference in the mean number of transfusions within the first 21 days of life (one-time umbilical cord-milking group 1.1 ± 0.8; multiple-time umbilical cord-milking group 0.7 ± 1.2; P = 0.79) or during the hospital stay (one-time umbilical cord-milking group 1.8 ± 2.8; multiple-time umbilical cord-milking group 1.7 ± 3.0; P = 0.91). Mean peak bilirubin and the duration of phototherapy were comparable between the two groups. Table 3 shows the cardiopulmonary status of the infant. No differences in systolic or diastolic blood pressure were observed between the two groups. Table 4 provides the information about major morbidities during the hospital stay. The morbidities during the hospital stay were similar between the two groups. One infant in the one-time umbilical cord-milking group whose weight was appropriate for dates, born to a mother with a non-complicated pregnancy, had non-symptomatic polycythemia with a hemoglobin value of 23.1 g dl − 1 on day 0.
Probability of being free from transfusion
METHODS
1.0 0.8
Multiple-time milking
0.6 0.4
One-time milking
Log-rank test p=0.60
0.2 0 0
50 Day after birth
100
Figure 1. There was no significant difference in the probability of being free from transfusion between the two groups by the log-rank test (P = 0.60).
Baseline characteristics
Characteristics Gestational age (weeks) Birth weight (g) Male Antenatal steroids PROM Chorioamnionitis Small for gestational age 1-min Apgar 5-min Apgar Cesarean delivery Death
One-time milking (n = 20)
Multiple-time milking (n = 20)
95% CI
P-value
27.0 ± 1.6 24–28 852 ± 234 453–1404 7 (35) 5 (25) 6 (30) 9 (45) 5 (25) 5 7 18 (90) 1 (5)
27.0 ± 1.5 24–28 836 ± 223 494–1198 10 (50) 7 (35) 6 (30) 10 (50) 6 (30) 6 8 14 (70) 2 (10)
− 0.85 to 1.15
0.77
− 164 to 131
0.83
0.34 0.27 0.39 0.47 0.31
0.36 0.73 1.00 0.76 1.00 0.11 0.11 0.24 1.00
to to to to to
1.44 1.82 2.55 1.71 2.24
0.31 to 2.24 0.07 to 3.66
Abbreviations: CI, confidence interval; PROM, premature rupture of membranes. Data are expressed as mean ± s.d. except Apgar score. Apgar scores are expressed as median. Percentages, given in parentheses, are calculated as a proportion of the total number.
© 2015 Nature America, Inc.
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Clinical characteristics
Hemoglobin value at birth (g dl − 1; range) Phlebotomy loss per birth weight (ml kg − 1) First day of EPO (day) Hemoglobin value at the start of EPO (g dl − 1) No RBC transfusion ⩽ 21 days No RBC transfusion during hospital stay Number of blood transfusions ⩽ 21 days Total number of blood transfusions Maximum serum bilirubin (mg dl Duration of phototherapy (day)
−1
)
One-time milking (n = 20)
Multiple-time milking (n = 20)
16.9 ± 2.7 (11.7–23.1) 18.3 ± 1.5 19.9 ± 1.4 12.4 ± 2.7 12 (60) 11 (55) 1.1 ± 1.8 0–4 1.8 ± 2.8 0–9 8.5 ± 2.2 7.7 ± 2.0
16.5 ± 1.4 (13.7–19.6) 16.7 ± 4.8 19.3 ± 4.9 12.0 ± 2.0 13 (65) 13 (65) 0.7 ± 1.2 0–4 1.7 ± 3.0 0–9 8.2 ± 2.6 8.2 ± 2.6
95% CI − 1.93 − 5.40 − 4.28 − 1.51 0.59 0.52 − 1.34
to to to to to to to
P-value
0.90 2.19 3.11 0.74 1.47 1.39 0.64
0.46 0.40 0.75 0.50 1.00 0.75 0.48
− 1.95 to 1.75
0.91
− 1.83 to 1.25 − 1.04 to 1.94
0.71 0.54
Abbreviations: CI, confidence interval; EPO, erythropoietin; RBC, red blood cell. Data are expressed as mean ± s.d. Percentages, given in parentheses, are calculated as a proportion of the total number.
Table 3.
Cardiopulmonary status
Systolic blood pressure at admission (mmHg) Diastolic blood pressure at admission (mmHg) Hypotension at admission Blood transfusion for hypotension Volume expander DOA+DOB ⩽ 5 μg kg − 1 min − 1 DOA+DOB 45 μg kg − 1 min − 1 Duration of mechanical ventilation (days) Duration of O2 (days) Duration of O2 ⩾ 30% (days)
One-time milking (n = 20)
Multiple-time milking (n = 20)
95% CI
P-value
42 ± 10 27 ± 9 4 (20) 1 (5) 2 (10) 5 (25) 4 (20) 23.6 ± 21.1 28.9 ± 21.9 3.5 ± 4.2
42 ± 11 25 ± 8 5 (25) 0 (0) 2 (10) 4 (20) 3 (15) 21.9 ± 19.1 23.4 ± 18.8 6.0 ± 9.4
− 8.47 to 7.96 − 8.99 to 4.52 0.26 to 2.45 — 0.18 to 5.44 0.41 to 3.90 0.37 to 4.98 − 14.85 to 11.64 − 2.49 to 7.49 − 18 86 to 7.94
0.95 0.50 1.00 1.00 1.00 1.00 1.00 0.81 0.41 0.31
Abbreviations: CI, confidence interval; DOA, dopamine; DOB, dobutamine. Data are mean ± s.d. Percentages, given in parentheses, are calculated as a proportion of the total number. Blood pressure was measured by using oscillometric method.
DISCUSSION To our knowledge, this was the first report to test the noninferiority of efficacy of one-time umbilical cord milking after umbilical cord cutting compared with multiple-time umbilical cord milking before umbilical cord cutting in very low birth weight infants born between 24 and 28 weeks of gestation. This study showed that milking ~ 30 cm of segment of umbilical cord once into the infant resulted in similar hemoglobin levels, and was an equally important contributor to reducing RBC transfusions, compared with multiple-time umbilical cord milking. We often experienced the phenomenon that immediate reversed flow in umbilical arteries from an infant occurred after milking, when the operator unclamped the umbilical cord at the infant’s site to perform the next umbilical cord milking. This phenomenon led us to introduce the technique of one-time umbilical cord milking. Our hypothesis, when we introduced multiple-time umbilical cord milking, was that the umbilical cord vessels including both the arteries and the vein would be refilled due to the resulting self-inflating vessels' capability and negative pressure gradient in the placenta from the previous milking. However, the umbilical vessels rapidly refilled from the infant’s side as a result of the infant’s blood pressure itself, when the obstetricians released the compressed portion of umbilical cord closest to the infant first against the milking procedure. The correct procedure for multiple-time umbilical cord milking is as follows. It is little more complicated than one-time umbilical cord milking. After each milking, release the compressed portion of the umbilical cord closest to the placenta but keep the part of the umbilical cord closest to the infant compressed with your other Journal of Perinatology (2015), 590 – 594
hand. This will allow placental blood to refill the umbilical cord, which should be complete within a few seconds. After this, take your hand off the umbilical cord at closest to the infant and milk the blood into the infant with your free hand. Repeat the procedure as required. Recent studies provided a paradigm shift of a potential mechanism for the passage of blood flow from the placenta to the infant during DCC. The first report by Vain et al.16 showed the position of the infant before cord clamping does not seem to affect volume of placental transfusion. Boere et al.15 revealed that the net placental transfusion was probably the result of several factors of which breathing, particularly crying, could play a major role. However, the eligible infants in both studies were all healthy term infants. As is emphasized in the commentary by Raju,17 more research should be performed to address the mechanism of placental transfusion in the high-risk infants. Blood flow in the vessels after umbilical cord milking seems to be more complicated because of unknown mechanism of refilling. One important problem that seems insurmountable is determining the volume of placental blood that transfers to the infant during multiple-time umbilical cord milking. Our previous study demonstrated that the residual cord blood volume per kilogram of infants weight per 30 cm of segment of umbilical cord was 17.7 ± 5.5 (8.9 to 29.0) ml kg − 1.14 With an average hematocrit of 40%, this volume is equivalent to a transfusion of ~ 13 ml of packed RBC transfusion (hematocrit of 55%). This study demonstrated a similar effect of reduction in RBC transfusions within the 21 days after birth and during the hospital stay. Rabe et al.12 assumed that at least one-half to two-thirds of the cord length © 2015 Nature America, Inc.
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Major morbidity during NICU stay
Polycythemia RDS PDA Hyperkalemia IVH IVH ⩾ III Intestinal perforation PVL CLD at 4 weeks CLD at 36 weeks ROP ⩾ 2 ROP ⩾ 3
One-time milking (n = 20)
Multiple-time milking (n = 20)
1 (5) 13 (65) 6 (30) 4 (20) 4 (20) 0 (0) 1 (5) n = 19 0 (0) 3 (16) 1 (5) 9 (47) 4 (21)
0 (0) 14 (70) 5 (25) 3 (15) 3 (15) 2 (10) 1 (5) n = 18 1 (7) 3 (17) 0 (0) 6 (33) 2 (11)
95% CI
P-value
— to 1.40 to 3.28 to 5.00 to 5.00 to 4.98 to 9.44
1.00 1.00 1.00 1.00 1.00 0.47 1.00
0.00 to 3.57 0.24 to 3.82 — 0.65 to 3.20 0.45 to 8.46
0.98 0.71 0.98 0.81 0.71
0.62 0.45 0.37 0.37 0.37 0.11
Abbreviations: CI, confidence interval; CLD, chronic lung disease; IVH, intraventricular hemorrhage; NICU, neonatal intensive care unit; PDA, patent ductus arteriosus; PVL, periventricular leukomalacia; RDS, respiratory distress syndrome; ROP, retinopathy of prematurity. Percentages, given in parentheses, are calculated as the proportion of the total number. Polycythemia is defined as venous or arterial hemoglobin concentration over 22 g dl − 1.
would be available for milking before clamping, because this length represents 7 to 10 ml of blood, then ~ 30 to 40 ml of blood would be transfused into the infants. The mean hemoglobin value of premature infants who received multiple-time umbilical cord milking ranged from 14.9 to 17.5 g dl − 1.8,12 March et al.8 milked a 20-cm length of umbilical cord three times, whereas Rabe et al.12 did not provide numerical details concerning the length of the umbilical cord milked, but instead reported that the umbilical cord was milked for its entire length four times. In our study, the mean hemoglobin level for the one-time umbilical cord-milking group was 16.9 g dl − 1, which was midway in the minimum (14.9 g dl − 1) and the maximum (17.5 g dl − 1) ranges.8,12 One-time umbilical cord milking of a 30-cm length may potentially match the effectiveness of multiple-time umbilical cord milking. One-time umbilical cord milking has several advantages over multiple-time umbilical cord milking. First, one-time umbilical cord milking can easily be standardized. Second, this procedure is simple enough for the delivering obstetricians to understand an incorporation of this procedure into practice. All they have to do is to lower the infant at or below the level of the placenta and to clamp and cut the umbilical cord 30 cm of length from the umbilical stump. Third, one-time umbilical cord milking might have less of an impact on circulation dynamics compared with multiple-time umbilical cord milking, because during releasing the torsion of umbilical cord, umbilical cord blood flows into the infant gravitationally, and the neonatologist can milk the umbilical cord slowly without time pressure. Finally, one-time umbilical cord milking might deliver a steady supply of umbilical cord blood to the infant compared with multiple-time umbilical cord milking. The current study had several limitations. This study had a small sample size and was not a prospective randomized controlled study. Therefore, this study was not powered to estimate important outcomes, including a need for RBC transfusion and intraventricular hemorrhage. This study was a historical control study. The infants in the multiple-time umbilical cord-milking group were admitted to the NICU between 2001 and 2002, and the infants in the one-time umbilical cord-milking group were admitted between 2007 and 2008. There were no major changes in either the transfusion, respiratory or circulatory management policies during the two study periods, and the obstetric management was also similar, but there was a new strategy of early aggressive nutrition introduced after 2003, and there was also employee turnover. However, we might have overlooked the possibility of unrecognizable differences, which could have affected clinical variables and could also have contributed to © 2015 Nature America, Inc.
variations in the subjects’ conditions. Approximately, 20-cm length of umbilical cord was milked in multiple-time umbilical cordmilking group. However, in the one-time umbilical cord group ~ 30-cm length of umbilical cord was milked. In addition, umbilical cord-milking performers were changed from obstetricians to pediatricians. Finally, the resuscitation team and therapeutic team were aware of the infants’ grouping in both intervention periods. There are no data on the neurodevelopmental outcomes of infants received umbilical cord milking. We could find only one developmental outcome of very low birth weight infants received DCC, and this study showed that DCC seemed to be protective in very low birth weight male infants against motor disability at 7 months of corrected age.18 So we should analyze the neurodevelopmental outcomes near future. In conclusion, this report was the first study to evaluate the effects of one-time umbilical cord milking on the enhancement of placental transfusion in premature infants. The results demonstrated that there were similar beneficial effects between one-time umbilical cord milking after umbilical cord cutting and multipletime umbilical cord milking before umbilical cord cutting. Moreover, this procedure might be a less demanding method for obstetricians to perform. We believe that the results of our preliminary trial justify the need for a prospective randomized multicenter trial to evaluate further the potential benefits of one-time umbilical cord milking after umbilical cord cutting in premature infants. Needless to say, the aim of future research would be to examine the reduction of severe intraventricular hemorrhage and the long-term effects of these two umbilical cord-milking methods on neurodevelopment. CONFLICT OF INTEREST The authors declare no conflict of interest.
ACKNOWLEDGMENTS This work was supported by MEXT KAKENHI (Grant-in-Aid for Scientific Research (C) Grant Number 26461649.
REFERENCES 1 Rabe H, Diaz-Rossello JL, Duley L, Dowswell T. Effect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes. Cochrane Database Syst Rev 2012; 8: CD003248.
Journal of Perinatology (2015), 590 – 594
One-time umbilical cord milking S Hosono et al
594 2 Jelin AC, Kuppermann M, Erickson K, Clyman R, Schulkin J. Obstetricians' attitudes and beliefs regarding umbilical cord clamping. J Matern Fetal Neonatal Med 2013; 27: 1457–1461. 3 Hosono S, Mugishima H, Fujita H, Hosono A, Minato M, Okada T et al. Umbilical cord milking reduces the need for red cell transfusions and improves neonatal adaptation in infants born at less than 29 weeks' gestation: a randomised controlled trial. Arch Dis Child Fetal Neonatal Ed 2008; 93: F14–F19. 4 Hosono S, Mugishima H, Fujita H, Hosono A, Okada T, Takahashi S et al. Blood pressure and urine output during the first 120 h of life in infants born at less than 29 weeks' gestation related to umbilical cord milking. Arch Dis Child Fetal Neonatal Ed 2009; 94: F328–F331. 5 Erickson-Owens DA, Mercer JS, Oh W. Umbilical cord milking in term infants delivered by cesarean section: a randomized controlled trial. J Perinatol 2012; 32: 580–584. 6 Takami T, Suganami Y, Sunohara D, Kondo A, Mizukaki N, Fujioka T et al. Umbilical cord milking stabilizes cerebral oxygenation and perfusion in infants born before 29 weeks of gestation. J Pediatr 2012; 161: 742–747. 7 Upadhyay A, Gothwal S, Parihar R, Garg A, Gupta A, Chawla D et al. Effect of umbilical cord milking in term and near term infants: randomized control trial. Am J Obstet Gynecol 2013; 208: 120.e1–6. 8 March MI, Hacker MR, Parson AW et al. The effects of umbilical cord milking in extremely preterm infants: a randomized controlled trial. J Perinatol 2013; 33: 763–767. 9 Katheria AC, Leone TA, Woelkers D, Modest AM, de Veciana M. The effects of umbilical cord milking on hemodynamics and neonatal outcomes in premature neonates. J Pediatr 2014; 164: 1045–1050. 10 Alan S, Arsan S, Okulu E, Akin IM, Kilic A, Taskin S et al. Effects of umbilical cord milking on the need for packed red blood cell transfusions and early
Journal of Perinatology (2015), 590 – 594
11 12
13
14
15
16
17 18
neonatal hemodynamic adaptation in preterm infants born ≤ 1500 g: a prospective, randomized, controlled trial. J Pediatr Hematol Oncol 2014; 36: e493–e498. Katheria A, Blank D, Rich W, Finer N. Umbilical cord milking improves transition in premature infants at birth. PLoS One 2014; 9: e94085. Rabe H, Jewison A, Alvarez RF, Crook D, Stilton D, Bradley R et al. Brighton Perinatal Study Group. Milking compared with delayed cord clamping to increase placental transfusion in preterm neonates: a randomized controlled trial. Obstet Gynecol 2011; 117: 205–211. Patel S, Clark EA, Rodriguez CE, Metz TD, Abbaszadeh M, Yoder BA. Effect of umbilical cord milking on morbidity and survival in extremely low gestational age neonates. Am J Obstet Gynecol 2014; 211: 519.e1–7. Hosono S, Hine K, Nagano N, Taguchi Y, Yoshikawa K, Okada T et al. Residual blood volume in the umbilical cord of extremely premature infants. Pediatr Int 2015; 57: 68–71. Boere I, Roest AA, Wallace E, Ten Harkel AD, Haak MC, Morley CJ et al. Umbilical blood flow patterns directly after birth before delayed cord clamping. Arch Dis Child Fetal Neonatal Ed 2015; 100: F121–F125. Vain NE, Satragno DS, Gorenstein AN, Gordillo JE, Berazategui JP, Alda MG et al. Effect of gravity on volume of placental transfusion: a multicentre, randomised, non-inferiority trial. Lancet 2014; 384: 235–240. Raju TN. Delayed cord clamping: does gravity matter? Lancet 2014; 384: 213–214. Mercer JS, Vohr BR, Erickson-Owens DA, Padbury JF, Oh W. Seven-month developmental outcomes of very low birth weight infants enrolled in a randomized controlled trial of delayed versus immediate cord clamping. J Perinatol 2010; 30: 11–16.
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