The Influence of Cut-umbilical Cord Milking (C-UCM) on the Cerebral Oxygenation and Perfusion of Preterm and Term Infants
Phase: NA
Conditions: Preterm Infant, Term Infant, Transition
Sponsor: Medical University of Graz

C-UCM und zerebrale Oxygenierung und Perfusion 
Version 1.0 vom 12.06.2018 
 
 
1
 
The influence of cut-umbilical cord milking (C-UCM) on the cerebral 
oxygenation and perfusion of preterm and term infants 
 
 
 
Lukas Schober, MD 
Department of Pediatrics, Division of Neonatology, Medical University of Graz, 
Auenbruggerplatz 30, 8036 Graz, Austria 
 
Bernhard Schwaberger, MD, PhD 
Department of Paediatrics, Division of Neonatology, Medical University of Graz, 
Auenbruggerplatz 30, 8036 Graz, Austria 
 
Berndt Urlesberger, MD 
Department of Paediatrics, Division of Neonatology, Medical University of Graz, 
Auenbruggerplatz 30, 8036 Graz, Austria 
 
 
Keywords: preterm infant, newborn infant, (immediate) neonatal transition, cord 
milking, cut-umbilical cord milking, near-infrared spectroscopy (NIRS), cerebral 
regional oxygen saturation (crSO2), cerebral tissue oxygenation index (cTOI), 
cerebral blood volume (CBV), cerebral perfusion 
 
 
Address for correspondence: 
Univ. Prof. Dr. Berndt Urlesberger 
Division of Neonatology Department of Paediatrics Medical University of Graz 
Auenbruggerplatz 30 
8036 Graz, Austria 
Phone: +43-316-385-81133 
Fax: +43-316-385-2678 
Mail: berndt.urlesberger@medunigraz.at 
 

C-UCM und zerebrale Oxygenierung und Perfusion 
Version 1.0 vom 12.06.2018 
 
 
2
1 Introduction 
 
Fetal to neonatal transition is not only characterized by major changes in pulmonary 
perfusion, but hemodynamic changes as well. Both changes are strongly interrelated, 
and occur in a very short time period (first minutes of life).  
The method of immediate umbilical cord clamping (within 15 seconds) after delivery 
of the newborn became routine 50-60 years ago. It was introduced as a package of 
care for reducing maternal postpartum haemorrhage. (1) Although umbilical cord 
clamping is a quick and simple intervention, the timing of umbilical cord clamping 
may have a large impact on the infant’s health. (2) 
During postnatal stabilisation of the newborn one of the essential aims is to establish 
lung aeration and increase pulmonary blood flow to improve oxygen delivery to the 
brain to meet the tissue demand. The concept of placental transfusion is the transfer 
of residual placental blood to the newborn resulting in increased haemoglobin levels 
and increased cardiac output and thus improved oxygen delivery. (3) In the last 
decade “delayed cord clamping” (DCC) was introduced to accomplish placental 
transfusion, especially in term infants. (4) Recently, different new concepts for 
promoting placental transfusion were developed including the concept of 
“physiological based cord clamping” (PBCC) (5). PBCC is defined as an approach, in 
which the first lung ventilation is facilitated, and the umbilical cord is clamped only 
after the establishment of pulmonary blood flow. Whereas in DCC the main 
intervention criterion is only the withholding of the clamping for a certain amount of 
time (2-4 minutes), in PBCC adequate pulmonary aeration is the criterion for 
clamping the umbilical cord. The debate on the optimal timing and type of umbilical 
cord clamping is still ongoing. 
Besides DCC and PBCC, the alternative concept of “cord milking" was introduced(6) 
which includes “intact umbilical cord milking” (I-UCM) and “cut-umbilical cord milking” 
(C-UCM). I-UCM is based on grasping the unclamped umbilical cord and stripping 
the blood towards the neonate up to four times before clamping the cord. (3) In 
contrast, C-UCM is a procedure, in which the umbilical cord is clamped immediately 
after birth and cut with a cord length longer than 30 cm, and then it is manually 
milked once by the neonatologist simultaneously with the first breaths or with the 
initiation of respiratory support. (3,7) The blood volume administered to the preterm 
infant was 17.7 mL/kg/30cm. (8) Comparative prospective studies on the two 

C-UCM und zerebrale Oxygenierung und Perfusion 
Version 1.0 vom 12.06.2018 
 
 
3
different approaches of cord milking (I-UCM and C-UCM) have not been published 
yet, and therefore it is unclear whether one of the approaches is superior compared 
to the other. However, C-UCM is supposed to be fast and easy to perform, especially 
during caesarean section or in situations in which urgent postnatal stabilisation 
interventions are needed. Therefore, the effect of placental transfusion promoted by 
C-UCM on cerebral oxygenation and perfusion is of special interest. 
 
2 Background 
 
2.1 Physiology of neonatal transition and the effects of umbilical cord 
clamping or milking 
 
The fetal circulation is characterized by a high pulmonary vascular resistance and a 
low placental vascular resistance. Approximately 30-50% of fetal cardiac output 
perfuses the placenta, thus 30-50% of the venous return comes from the placenta. 
As most of the oxygenated blood coming from the placenta is preferentially shunted 
through the foramen ovale towards the left atrium, preload of the left ventricle is 
largely dependent on placental venous return in the fetus. At birth lung aeration 
results in a drop in pulmonary vascular resistance resulting in a simultaneous 
increase in pulmonary blood flow. The consecutive increase in pulmonary venous 
return gradually replaces the loss of placental venous return (following cord 
clamping). A delay in cord clamping (DCC or PBCC) or I-UCM may result in an 
increase in cardiac output, as the increase in pulmonary venous return is assisted by 
placental venous return for 2-3 minutes on the one hand, and the increase in 
neonatal blood volume due to placental transfusion on the other hand. Recent 
experimental studies in lambs have shown that immediate cord clamping (prior to 
lung aeration or lung ventilation) resulted in unstable hemodynamic parameters with 
an initial increase in carotid arterial flow and pressure, followed by a decrease in 
carotid arterial flow and pressure, accompanied with a significant increase in heart 
rate. (9) (Polglase et al 2015, =7neu) Instability of cerebral perfusion and oxygenation 
may be associated with brain damage in preterm infants.  

C-UCM und zerebrale Oxygenierung und Perfusion 
Version 1.0 vom 12.06.2018 
 
 
4
The concept of C-UCM may substitute the adverse effects of immediate cord 
clamping by supplying additional placental blood to the infant, which is mostly 
performed during caesarean section or in the critically ill neonate. 
 
2.2 Near-Infrared Spectroscopy 
 
Near-infrared spectroscopy (NIRS) enables non-invasive measurement of tissue 
oxygenation in regions of interest e.g. cerebral, renal and peripheral muscle tissue. In 
1977 the principle was described by Jöbsis. (10) NIRS is based on two fundamental 
facts: the relative transparency of biological tissue to near-infrared light (wavelength 
700-1000 nm) and the presence of chromophores (colour bearing compounds) in the 
biological tissue, which have oxygenation-dependent absorption properties (e.g. 
haemoglobin and cytochrome oxidase) in the near-infrared region. Therefore, NIRS 
enables the non-invasive continuous measurement (of changes in the concentration) 
of oxygenated haemoglobin (HbO2), deoxygenated haemoglobin (Hb) and 
cytochrome oxidase (CytOx). 
Regional tissue oxygen saturation depends on the local balance of oxygen delivery 
and oxygen consumption, and the regional arterial/venous volume ratio, reflecting 
oxygen saturation in veins (70-80%), capillaries (5%) and arteries (15-25%). (11) The 
main component of tissue oxygen saturation is venous blood, thus representing 
oxygen saturation after oxygen consumption by the tissue. Therefore, the values for 
regional oxygen saturation tend to be close to venous oxygen saturation, but do not 
equate venous saturation. (11) 
In the field of neonatology different NIRS devices are in clinical use, most of them are 
based on the method of  “spatially resolved spectroscopy”. This NIRS method was 
introduced for the evaluation of regional tissue oxygen saturation and is widely used 
for measurements on the cerebral tissue oxygenation (crSO2). (12) Moreover this 
technology enables measurements of changes in total haemoglobin which can be 
converted to changes in cerebral blood volume (ΔCBV). The disadvantage of this 
technique is that it is only possible to measure relative changes of these parameters. 
Very recently, a new NIRS technology was introduced for clinical use. The tNIRS 
device of Hamamatsu (Japan) uses the method of the so called “time resolved 
spectroscopy”. This technology is able to measure absolute values for total 
haemoglobin (Hb(tot)) and does enable the calculation of absolute CBV.  

C-UCM und zerebrale Oxygenierung und Perfusion 
Version 1.0 vom 12.06.2018 
 
 
5
 
In animal experiments it has been shown, that immediate and delayed cord clamping 
influences cerebral oxygenation and perfusion measured non-invasively with NIRS. 
Human NIRS data in regard to different cord clamping procedures are not yet 
published at all. I-UCM has been introduced several years ago in preterm infants with 
need for respiratory support. It was shown, that this approach may improve short 
term and long term outcome of the preterm infants. (6) Furthermore, it was proven, 
that C-UCM was as effective as I-UCM in regard to the need of blood transfusions 
(4). Detailed analyses of the effects of such an approach on cerebral oxygenation 
and perfusion in preterm and term infants are still missing. Thus, further research on 
this topic is warranted. 
 
2.3 Monitoring during immediate neonatal transition 
 
Transition from fetus to extra-uterine life is a complex physiological process. Within 
the recent years interest has grown in the use of pulse oximetry to monitor arterial 
oxygen saturation (SpO2) and to guide medical interventions during the transitional 
period. (13-16) Immediately after birth, most of the newborn infants show oxygen 
desaturation with SpO2 values in the range of 40-70%. Newborn infants although 
undergoing normal postnatal transition frequently need more than 5 minutes to attain 
a SpO2 >80% and almost 10 minutes to reach 90%.  
There is an ongoing discussion about the use of supplemental oxygen during 
neonatal stabilisation, since it is unknown which oxygen concentration may be 
appropriate for preterm and term infants. As the brain is the most vulnerable organ 
system of the infant, a more direct way to assess its oxygenation status in a simple 
non-invasive way would be potentially useful. A promising approach to assess 
cerebral oxygenation is the measurement of the regional tissue oxygen saturation by 
using NIRS.  
Our research unit published data on cerebral oxygen saturation in newborn infants 
during immediate postnatal transition demonstrating a significant increase within the 
first 10 minutes after birth(17). Furthermore, we presented crSO2 data comparing 
vaginal delivery versus caesarean delivery. (18) Moreover, our group was the first to 
publish percentiles of cerebral regional oxygen saturation during the first 15 minutes 
after birth for the two most widely used NIRS devices (Medtronic INVOS 5100C(19) 

C-UCM und zerebrale Oxygenierung und Perfusion 
Version 1.0 vom 12.06.2018 
 
 
6
and Hamamatsu NIRO 200NX(20)). Very recently, our group published data on the 
clinical use of these percentiles during neonatal transition in preterm infants 
with/without respiratory support. (21,22) Furthermore, we published data of the 
transitional behaviour of cerebral blood volume using NIRS in healthy term infants 
demonstrating a significant decrease of CBV during the first 15 minutes after birth. 
(23) Recently, we added CBV data of preterm and term infants with and without 
respiratory support, demonstrating differences in the postnatal course of CBV in 
those patients. 
 
3 Aims of the present study 
 
The aim of the study is to analyse whether C-UCM in preterm and term infants 
results in an improvement of cerebral oxygenation and perfusion during immediate 
neonatal transition measured with NIRS.  
 
3.1 Hypotheses 
 
Infants undergoing C-UCM after birth compared to infants without C-UCM show 
differences in cerebral oxygenation and perfusion in the first 15 min after birth. 
 
3.1.1 Hypothesis I: C-UCM and CBV 
In infants with C-UCM there is more CBV decrease immediately after birth, compared 
to infants without C-UCM, due to improved cerebral oxygen delivery.  
 
3.1.2 Hypothesis II: C-UCM and crSO2 
Infants with C-UCM have higher crSO2 values during immediate neonatal transition, 
compared to infants without C-UCM, again due to improved cerebral oxygen delivery. 
3.1.3 Hypothesis III: C-UCM and stroke volume  
In infants with C-UCM the stroke volume (SV) at 15 minutes after birth is higher, 
compared to infants without C-UCM. 

C-UCM und zerebrale Oxygenierung und Perfusion 
Version 1.0 vom 12.06.2018 
 
 
7
3.1.4 Hypothesis IV: C-UCM and cardiac output  
In infants with C-UCM the cardiac output (CO) at 15 minutes after birth is higher, 
compared to infants without C-UCM. 
3.1.5 Hypothesis V: C-UCM and mean arterial blood pressure (MABP) 
In infants with C-UCM the MABP at 5, 10 and 15 minutes after birth is higher, 
compared to infants without C-UCM. 
 
4 Methods 
 
4.1 Study population 
4.1.1 Preterm infants 
Neonates with a gestational age >28 - 37 weeks delivered by caesarean section at 
the Department of Obstetrics and Gynaecology, Medical University of Graz, will be 
enrolled into the study, provided written informed consent is obtained from parents 
prior to birth. Neonates with severe congenital malformations will be excluded. 
4.1.2 Term Infants 
Neonates with a gestational age >37 weeks delivered by caesarean section at the 
Department of Obstetrics and Gynaecology, Medical University of Graz, will be 
enrolled into the study, provided written informed consent is obtained from parents 
prior to birth. Neonates with severe congenital malformations will be excluded. 
 
4.2 Study design 
 
The present study is designed as a randomized controlled pilot trial. As there have 
not been prior human studies investigating C-UCM regarding the outcome measures 
cerebral oxygenation and perfusion, a randomized controlled pilot study is the 
appropriate first step to be able to calculate sample size for a bigger trial.  
 
4.3 Sample Size 
 
Sample size calculations were not performed, since there are no data from previous 
human studies available, and this pilot study needs to be conducted to generate data 

C-UCM und zerebrale Oxygenierung und Perfusion 
Version 1.0 vom 12.06.2018 
 
 
8
for the sample size calculation of a consecutive main study. For this pilot study a 
sample size of 80 infants (20 subjects in the intervention group of preterm infants, 20 
subjects in the intervention group of term infants, 20 subjects in each of the two 
control groups) is arbitrary designated.  
 
4.4 Randomization 
 
Based on a computer-generated randomization software (www.randomizer.at) the 
included neonates will be randomly assigned to the intervention group in which 
C-UCM will be performed or the control group without C-UCM. The randomization of 
the two different study populations (preterm/term infants) will be done separately. 
Blocked randomization with a block size of 8 will be used. 
 
4.5 Procedure 
 
The medical history focussing on any pathologic findings during pregnancy and 
delivery will be collected and stored anonymously.  
After delivery of the neonate via caesarean section, in the intervention group the 
umbilical cord will be clamped within 30 seconds and cut long at least 30 cm by the 
obstetrician. The neonate is then placed under an overhead heater by the midwife. 
There, the umbilical cord must be untwisted and held in a vertical position. It is milked 
once by the neonatologist towards the baby at a speed of approximately 10 cm/s and 
then clamped 3 cm from the umbilicus by one member of the clinical team. In 
contrast, in the control group the umbilical cord is cut according to the standard 
procedure and no C-UCM is performed. The further treatment procedure is the same 
in both groups. 
A NIRS transducer will be placed on the newborn’s left forehead, and fixed with a 
modified neonatal CPAP cap or gauze bandage by a scientific staff member without 
disturbing routine medical care. Furthermore, a pulse oximeter sensor will be 
attached on the right wrist or palm to monitor preductal SpO2 and heart rate. 
Moreover 4 electrodes are fixed on the skin for the non-invasive cardiac output 
monitoring (NICOM) to evaluate SV and CO. All the measurements will be performed 
within the first 15 minutes after birth.  
 

C-UCM und zerebrale Oxygenierung und Perfusion 
Version 1.0 vom 12.06.2018 
 
 
9
The pneumatic cuff for the oscillometric measurements of the arterial blood pressure 
will be placed around the left upper arm (or alternatively on the left lower leg) at 5, 10 
and 15 minutes after birth. A capillary blood gas check 15 minutes after birth will be 
performed in all the patients; However infants in need for respiratory support during 
postnatal stabilisation receive this blood gas check routinely. Moreover, rectal 
temperature will be measured at 15 minutes after birth. 
A stopwatch is started at delivery, the time points of umbilical cord clamping, C-UCM 
in the intervention group, establishment of NIRS measurement, establishment of 
SpO2 measurement, and blood drawing for the gas check will be noted. 
 
4.6 Materials 
 
Immediately after birth initial medical care is performed in a ‘Giraffe’ incubator (GE 
Healthcare; United Kingdom) or on a resuscitation cot (‘CosyCot’, Fisher&Paykel 
Healthcare; New Zealand). If necessary, respiratory support is applied by using a 
‘Neopuff Infant T- Piece Resuscitator’ (Perivent, Fisher& Paykel Healthcare; New 
Zealand) and a round face mask of appropriate size (LSR Silicon mask no. 0/0 or 
0/1, Laerdal; Norway). NIRS measurements were carried out by using ‘t-NIRS’ or 
‘NIRO 200-NX’ tissue oxygenation monitor (Hamamatsu; Japan). The ‘Aesculon 
Electrical Velocimetry monitoring system’ (Osypka, Berlin, Germany) is used to 
assess CO and SV non-invasively. Vital signs (HR, SpO2, arterial blood pressure 
and rectal body temperature) were recorded by using an ‘IntelliVue MP70 or MP30 
Neonatal Monitor’ (Philips; The Netherlands). For later analysis all parameters and 
the video recordings were stored using a multichannel system ‘alpha-trace digital 
MM’ (BEST Medical Systems; Austria). The Axis P1354 video camera (Axis 
Communications, Sweden) is positioned in such a way, that no person can be 
identified (only hands can be seen). The recorded sequences allow 
identification of artefacts, and secure correct data analysis during the 
intervention. 
 
4.7 Primary and secondary outcome measures 
 
The primary outcome parameters for this study are the changes in CBV within the 
first 15 minutes after birth. 

C-UCM und zerebrale Oxygenierung und Perfusion 
Version 1.0 vom 12.06.2018 
 
 
10
 
Secondary outcome parameters include cTOI, SpO2, HR, SV, CO and MABP within 
the first 15 minutes after birth. 
 
4.8 Statistical Analysis 
 
The measurement will take place in the first 15 minutes after birth. Especially in the 
first three minutes missing values are very common. Therefore the analysis of 
continuous measured data will start at that first minute with <50% of newborns having 
missing values. To include all newborn infants with valid measurements after this 
time point a linear mixed models will be used to analyse the difference in CBV, cTOI, 
SpO2, HR, SV and CO between newborn infants with and without C-UCM. 
Categorical secondary outcome parameters (MABP) will be analysed using χ² or 
Fisher’s exact Test. Patient’s characteristics will be compared using t-Test or Mann 
Whitney U-Test for continuous variables and χ² or Fisher’s exact Test for categorical 
variables. 
 
5 Research plan and time table 
 
The study may start in 2018. Recruitment will take one to two years. 
The study is designed for an approximately three year running time.  
 
 

C-UCM und zerebrale Oxygenierung und Perfusion 
Version 1.0 vom 12.06.2018 
 
 
11
(1) Farrar D, Tuffnell D, Airey R, Duley L. Care during the third stage of labour: a 
postal survey of UK midwives and obstetricians. BMC Pregnancy Childbirth 2010 
May 21;10:23-2393-10-23. 
(2) Knol R, Brouwer E, Vernooij ASN, Klumper FJCM, DeKoninck P, Hooper SB, et 
al. Clinical aspects of incorporating cord clamping into stabilisation of preterm infants. 
Arch Dis Child Fetal Neonatal Ed 2018 Apr 21. 
(3) Katheria AC, Lakshminrusimha S, Rabe H, McAdams R, Mercer JS. Placental 
transfusion: a review. J Perinatol 2017 Feb;37(2):105-111. 
(4) Yao AC, Moinian M, Lind J. Distribution of blood between infant and placenta 
after birth. Lancet 1969 Oct 25;2(7626):871-873. 
(5) Hooper SB, Polglase GR, te Pas AB. A physiological approach to the timing of 
umbilical cord clamping at birth. Arch Dis Child Fetal Neonatal Ed 2015 
Jul;100(4):F355-60. 
(6) 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 Jan;93(1):F14-9. 
(7) Hosono S, Mugishima H, Takahashi S, Takahashi S, Masaoka N, Yamamoto T, 
et al. One-time umbilical cord milking after cord cutting has same effectiveness as 
multiple-time umbilical cord milking in infants born at  
(8) 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(1):68-71. 
(9) Polglase GR, Dawson JA, Kluckow M, Gill AW, Davis PG, Te Pas AB, et al. 
Ventilation onset prior to umbilical cord clamping (physiological-based cord clamping) 
improves systemic and cerebral oxygenation in preterm lambs. PLoS One 2015 Feb 
17;10(2):e0117504. 
(10) Jobsis FF. Noninvasive, infrared monitoring of cerebral and myocardial oxygen 
sufficiency and circulatory parameters. Science 1977 Dec 23;198(4323):1264-1267. 
(11) Watzman HM, Kurth CD, Montenegro LM, Rome J, Steven JM, Nicolson SC. 
Arterial and venous contributions to near-infrared cerebral oximetry. Anesthesiology 
2000 Oct;93(4):947-953. 
(12) Susumu S, Sumio T, Takeo O, Yukio K. Tissue oxygenation monitor using NIR 
spatially resolved spectroscopy. Proc SPIE 1999;3597:582-592. 
(13) Kamlin CO, O'Donnell CP, Davis PG, Morley CJ. Oxygen saturation in healthy 
infants immediately after birth. J Pediatr 2006 May;148(5):585-589. 
(14) Rabi Y, Yee W, Chen SY, Singhal N. Oxygen saturation trends immediately after 
birth. J Pediatr 2006 May;148(5):590-594. 

C-UCM und zerebrale Oxygenierung und Perfusion 
Version 1.0 vom 12.06.2018 
 
 
12
(15) Finer N, Leone T. Oxygen saturation monitoring for the preterm infant: the 
evidence basis for current practice. Pediatr Res 2009 Apr;65(4):375-380. 
(16) Dawson JA, Davis PG, O'Donnell CP, Kamlin CO, Morley CJ. Pulse oximetry for 
monitoring infants in the delivery room: a review. Arch Dis Child Fetal Neonatal Ed 
2007 Jan;92(1):F4-7. 
(17) Urlesberger B, Grossauer K, Pocivalnik M, Avian A, Muller W, Pichler G. 
Regional oxygen saturation of the brain and peripheral tissue during birth transition of 
term infants. J Pediatr 2010 Nov;157(5):740-744. 
(18) Urlesberger B, Kratky E, Rehak T, Pocivalnik M, Avian A, Czihak J, et al. 
Regional oxygen saturation of the brain during birth transition of term infants: 
comparison between elective cesarean and vaginal deliveries. J Pediatr 2011 
Sep;159(3):404-408. 
(19) Pichler G, Binder C, Avian A, Beckenbach E, Schmolzer GM, Urlesberger B. 
Reference ranges for regional cerebral tissue oxygen saturation and fractional 
oxygen extraction in neonates during immediate transition after birth. J Pediatr 2013 
Dec;163(6):1558-1563. 
(20) Baik N, Urlesberger B, Schwaberger B, Schmolzer GM, Mileder L, Avian A, et al. 
Reference Ranges for Cerebral Tissue Oxygen Saturation Index in Term Neonates 
during Immediate Neonatal Transition after Birth. Neonatology 2015;108(4):283-286. 
(21) Schwaberger B, Pichler G, Binder C, Avian A, Pocivalnik M, Urlesberger B. Even 
mild respiratory distress alters tissue oxygenation significantly in preterm infants 
during neonatal transition. Physiol Meas 2014 Oct;35(10):2085-2099. 
(22) Baik N, Urlesberger B, Schwaberger B, Schmolzer GM, Avian A, Pichler G. 
Cerebral haemorrhage in preterm neonates: does cerebral regional oxygen 
saturation during the immediate transition matter? Arch Dis Child Fetal Neonatal Ed 
2015 Sep;100(5):F422-7. 
(23) Schwaberger B, Pichler G, Binder-Heschl C, Baik N, Avian A, Urlesberger B. 
Transitional Changes in Cerebral Blood Volume at Birth. Neonatology 
2015;108(4):253-258.