Early Human Development (2008) 84, 195200 a v a i l a b l e a t w w w. s c i e n c e d i r e c t .

c o m

w w w. e l s e v i e r. c o m / l o c a t e / e a r l h u m d e v

Early versus late cord clamping: Effects on peripheral blood flow and cardiac function in term infants
Patrizia Zaramella a,, Federica Freato a , Valentina Quaresima b , Silvia Secchieri c , Anna Milan a , Davide Grisafi c , Lino Chiandetti a
Department of Pediatrics, Neonatal Intensive Care Unit, University of Padova, Via Giustiniani, 3, 35128 PADOVAItaly Department of Biomedical Sciences and Technologies, University of L'Aquila, 67100 L'Aquila, Italy c Department of Pediatrics, University of Padova, 35128 Padova, Italy
a b

Accepted 14 April 2007

KEYWORDS
Cord clamping; Regional blood flow; M-mode heart measurement; Newborn infant; Near-infrared spectroscopy

Abstract Background: In the debate on the best cord clamping time in newborn infants, we hypothesized that late cord clamping enables an increased volemia due to blood transfer to the newborn from the placenta. Aim: To assess whether clamping time can affect limb perfusion and heart hemodynamics in a group of 22 healthy term newborn infants. Study design: A case-control study. Subjects: Eleven early-clamped (at 30 s) vaginally-delivered newborn infants were compared with eleven late-clamped (at 4 min) newborns. Outcome measures: The two groups were studied using near-infrared spectroscopy and M-mode echocardiography. Results: Late cord clamping coincided with a higher hematocrit (median 62% versus 54%) and hemoglobin concentration (median 17.2 versus 15 g/dL), whilst there were no changes in bilirubin level. Echocardiography showed a larger end-diastolic left ventricle diameter (1.7 cm median value versus 1.5) coupled with unvaried shortening and ejection fraction values. There were no changes in calf blood flow, oxygen delivery, oxygen consumption or fractional oxygen extraction calculated from the NIRS measurements, or in foot perfusion index. Conclusions: Our results demonstrated that late cord clamping coincides with an increased placental transfusion, expressed by higher hematocrit and hemoglobin values, and larger left ventricle diameter at the end of the diastole, with no changes in peripheral perfusion or oxygen metabolism. 2007 Elsevier Ireland Ltd. All rights reserved.

Abbreviations: BF, blood flow; DO2, oxygen delivery; EF, ejection fraction; FOE, fractional oxygen extraction; Hb, hemoglobin concentration; HHb, deoxyhemoglobin; LVD(D), end-diastolic ventricle diameter; LVD(S), end-systolic left ventricle diameter; O2Hb, oxyhemoglobin; PaO2, oxygen arterial pressure; PI, perfusion index; SaO2, arterial oxygen saturation; SF, shortening fraction; SvO2, mixed venous oxygen saturation; tHb, total hemoglobin content; VO2, oxygen consumption. Corresponding author. Tel.: +39 049 8213573/05/06, 347 6782927 (mobile); fax: +39 049 8213502. E-mail address: zaramella@pediatria.unipd.it (P. Zaramella). 0378-3782/$ - see front matter 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.earlhumdev.2007.04.003

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P. Zaramella et al. for exclusion: eclampsia, hypertension, intrauterine growth retardation, diabetes, diuretic or vasoactive medication, cardiotocographic anomalies, cesarean section or twin pregnancy. Newborn infants delivered vaginally in the lateclamped group were held in their mothers' arms while waiting supine for the cord to be clamped. Echocardiographic and NIRS measurements were taken by staff blinded to the clamping times.

1. Introduction
Although the World Health Organisation stated that late cord clamping or not clamping represent a more physiological method of neonatal care in the delivery room [1], there is still debate on the best cord clamping time in newborn infants. The current obstetric approach is to clamp the cord within the first 1015 s after birth, while delayed clamping involves clamping the cord after a palpable pulse has ceased, i.e. after up to 10 min [2,3]. About 35 mL of blood/kg of body weight are transfused from the placenta to the baby held at vaginal level if clamping is done after 3 min or more in term infants [4]. When the newborn infant is laid on the mother's abdomen and clamping is delayed until the beats cease, the neonatal blood volume increases by about 32% [5]. Placental blood flow seems to be related to: 1) clamping time, 2) the newborn's position with respect to the placenta, 3) uterine contractions, 4) oxytocin infusion, and 5) mode of delivery. Cord clamping time seems to be particularly crucial to the baby's pulmonary adaptation to extrauterine life. It has been reported that the hematocrit benefits from late cord clamping in both preterm [6] and term neonates [5,7], which is likely to mean a lower prevalence of iron-deficiency anemia in infancy [8]. Systolic blood pressure increases in both term and preterm neonates [9,10] as a consequence of an increased atrial pressure and pulmonary blood flow [11]. It has also been reported that skin and renal blood flow increase [11], as well as vascular resistance and blood viscosity [5]. Limb perfusion/oxygenation can be evaluated by nearinfrared spectroscopy (NIRS) [12]. NIRS is combined with arterial/venous occlusion maneuvers to measure local muscle blood flow (BF), oxygen consumption (VO2), oxygen delivery (DO2) and venous saturation (SVO2). Many significant clinical studies have demonstrated the usefulness of this technique [1321]. The development of pulse oximetry has also made it possible to calculate the perfusion index (PI) [22], which varies with the quantity of red blood cells in the skin microvasculature and is a reliable indicator of changes in skin blood flow in humans [23] and animals [24]. The aim of this study was to assess whether umbilical cord clamping time (early vs late) can affect limb perfusion and heart hemodynamics in a group of healthy term newborn infants. We hypothesized that late cord clamping would enable an increased volemia, due to blood transfer to the newborn from the placenta.

2.1. NIRS measurements

NIRS measurements were obtained using the NIRO-300 oximeter (Hamamatsu Photonics, Hamamatsu City, Japan). In the optical probe, the two optodes (the distal end of the emitter and the detector) were kept a constant distance apart and in the same position by means of a black rubber shell firmly attached to the skin of the main part of the calf (2 cm above the outer tibial malleolus) with double-sided adhesive tape. To prevent ambient light from reaching the optodes, a dark felt cloth covered the neonate's leg. No sliding of the probes was observed at the end of the measurements in any of the neonates. The NIRO-300 is based on the spatially-resolved spectroscopy approach and provides relative concentration changes (expressed in M) of oxyhemoglobin (O2Hb), deoxyhemoglobin (HHb), and the derived total hemoglobin content (tHb = O2Hb + HHb), while O2Hb and HHb concentration changes are calculated [25]. The procedure involved minimal disturbance to the neonate. If necessary, the child was calmed with a glucose-coated pacifier. In the case of venous occlusion, the child's leg was raised 5 cm above heart level with a foam rubber wedge to facilitate venous drainage after the occlusion. A disposable non-invasive blood pressure cuff for neonates (No. 4 or 5, depending on the diameter of the thigh) (Agilent Technologies GmbH, Boeblingen, Germany) was positioned in the proximal part of the thigh. A pressure-inducing device (DP 903, Tenno Laboratories; Trento, Italy) was used to obtain standardized and rapid cuff inflation. Briefly, this device enables a sudden increase in pressure to be induced by a suitably adapted machine, as described by Zaramella et al [26]. After positioning and fixing the optical probe, the NIRO-300 was initialized and measurements could start. The NIRO-300 data were collected at a frequency of 6 Hz and transferred online to a computer for storage and subsequent analysis. Occlusions were considered unsatisfactory if artifact movements were recorded, in which case the initialization and occlusions were repeated in stable conditions.

2. Subjects and methods

An observational case-control study was conducted at the delivery room and nursery of the Padova University Obstetrics and Pediatrics Departments between January and June 2005. Eleven early-clamped newborn infants (at 30 s) were compared with 11 late-clamped babies (at 4 min). They were enrolled by a physician taking part in the research, who decided the clamping time at random (not based on any clinical indication) and timed cord clamping with a stopwatch. Babies with life-threatening congenital malformations, metabolic or infectious diseases, or chromosomal abnormalities were ruled out and the following were further reasons

2.2. NIRS and venous occlusion to calculate blood flow, VO2 and DO2
Automatic rapid cuff inflation (3040 mm Hg for 10 s) on the thigh proved essential to obtain a venous occlusion, adapting the method first applied in adults [27]. During venous occlusion, hemoglobin flow (Hb flow) equates to the rate of tissue tHb accumulation during the initial part of the occlusion (first 6 s). Hb flow was derived, according to Wardle and Weindling [13], from the slope of a line through the tHb values (Hb flow = tHb dt) during the first 3 s of occlusion. Calf BF was calculated by dividing Hb flow by Hb concentration (M/mL).

Early versus late cord clamping Table 1 groups Variable Physiological data in the early- and late-clamped Early clamping Median (range) Late clamping Median (range)

197 a luminous source to a photodetector through a translucent and perfused site like the neonate's hand, finger or foot. The PI is expressed as a percentage of the absorbed arterial inflow light (AC) divided by the non-pulsatile absorbed light (venous and non-pulsatile blood/tissue) (DC), PI = AC/DC. This value and arterial saturation (SaO2) were obtained using a Masimo SET radical pulse oximeter (Masimo Corp., Irvine, CA) with a sensor placed on the foot contralateral to the side of the NIRS measurements. PI measurements were collected just before venous occlusion, averaging 30 s of data.

Gestational 39 (3742) 40 (3741) age (wk) Birth weight (g) 3250 (30503855) 3410 (32303960) 1st min Apgar 9 (79) 9 (910) 5th min Apgar 10 (910) 10 (1010) Evaluation 72 (6174) 72 (5274) age (hours) Heart rate (bpm) 137 (121152) 140 (110164) Breathing 48 (3662) 44 (4052) rate (breaths/min) 98 (9799) 99 (98100) SaO2 (%)

2.5. Other physiological variables

Capillary hematocrit (Ht%) was measured on day 3 of life in blood drawn from a heel-prick; blood was collected in a tube sealed at one end, filled and centrifuged (Biofuge Haemo, Heraeus Instruments, Milano, Italy) for 5 min: hematocrit was measured on a graded scale provided by the manufacturer (Haematocrit Tube Reader ALC, Elmed Ginevri, Roma, Italy). Hemoglobin concentration (Hb, g/dL) was calculated by multiplying the hematocrit value (Htc, %) by 0.34 [28,29]. Total bilirubin (TB, mg/dL) was assessed in the same tube after centrifugation (Bilirubin meter GB 13/A, G. Bertocchi, Cremona, Italy).

SvO2 was calculated during the first 6 s of venous occlusion according to Yoxall and Weindling [14]: SvO2 = [O2Hb] / [tHb], i.e. change in O2Hb concentration divided by change in tHb during the same interval as for the calculation of Hb flow. DO2 and VO2 were calculated as follows; DO2 = BF [Hb] 4 SaO2 and VO2 = BF [Hb] 4 (SaO2SvO2), where 4 corresponds to the molar ratio due to 4 moles of oxygen being carried by each mole of Hb. Fractional oxygen extraction (FOE) was calculated as the ratio VO2/DO2 = (SaO2SvO2)/ SaO2.

2.6. Echocardiography
Echocardiography was performed on day 3 of life, prior to the NIRS measurements, when the patent ductus arteriosus is assumed to have closed in term infants [30]. End-diastolic ventricle diameter, LVD(D) (cm), end-systolic left ventricle diameter, LVD(S) (cm), ejection fraction (EF, %, [LV diastolic volume LV systolic volume] / [LV diastolic volume]) and shortening fraction (SF, %, [LVD(D) LVD(S)] / [LVD(D)]) were assessed by M-mode echocardiographic imaging modalities in accordance with American Society of Echocardiography recommendations [31], using a HDI 3000 CV (Advanced Technology Laboratories, Bothell, WA, USA). End-diastolic diameter was measured at the beginning of the QRS complex, while the endsystolic phase was identified as when the interventricular septum reached the maximum systolic shift towards the lower edge. Ventricular volume was calculated from M-mode diameter value using Teicholtz equation (V = [7/ (2.4 + D) D3]) [32].

2.3. NIRS and arterial occlusion to calculate VO2

Automatic rapid cuff inflation to 100 mm Hg was applied on the thigh for 3040 s to obtain an arterial occlusion (blood supply to the muscle ceases and the drop in O2Hb reflects oxygen consumption). VO2 was then calculated from the slope of the drop in O2Hb (O2Hb dt) [16,27]. The time interval between a series of occlusions was set to 5 min to ensure a sufficient recovery period.

2.4. Perfusion index

The principle behind pulse oximetry relies on the quantity of red (660 nm) and near-infrared (940 nm) light transmitted by Table 2 Variable
Hematocrit (%) Hemoglobin (g/dL) Total bilirubin (mg/dL) Calf VO2 by venous occlusion (M/100 ml/min) Calf BF (ml/100 g/min) Calf DO2 (M/100 mL/min) Calf VO2 by arterial occlusion (M/100 ml/min) SvO2 (%) Calf FOE Foot PI
ns: not significant.

Physiological and NIRS data in the early- and late-clamped groups Early clamping Median (range)
54 15 8.1 4.12 1.00 9.03 0.73 52 0.48 1.24 (5062) (13.817.2) (2.313.2) (1.836.97) (0.551.74) (5.5814.44) (0.481.15) (4468) (0.300.55) (0.501.68)

Late clamping Median (range)

62 (5874) 17.2 (16.120.5) 7.9 (1.710.3) 3.25 (2.217.14) 0.67 (0.451.33) 8.41 (4.9813.70) 0.64 (0.440.94) 48 (4263) 0.52 (0.360.57) 1.11 (0.691.78)

p
0.001 0.001 ns ns ns ns ns ns ns ns

198 Table 3 Echocardiographic data in the early- and lateclamped groups Variable
Shortening fraction (SF, %) Ejection fraction (EF, %) LVD(D) cm LVD(S) cm

P. Zaramella et al. change in peripheral (leg) blood flow but a higher enddiastolic left ventricular diameter in the late-clamped infants, suggesting a greater filling of the left ventricle with no increase in peripheral perfusion. This result seems to contrast with a recent study on preterm vaginally delivered newborns that demonstrated an increased volemia in late (median time 90 s) clamped infants due to placental transfusion [37]. This discrepancy may be related to a peripheral vasodilation in our healthy term newborn infants, and thus have to do with a different gestational age: placental transfusion seems to be more pronounced in lower gestational age groups than in more mature infants [37]. We found no change in PI values in our groups, suggesting that there was no difference in skin circulatory status. The PI values were in the range (1.2 0.3) previously reported [26]. Peripheral limb BF was unchanged in our late-clamped group, which demonstrates that, if clamping is done at 4 min, placental transfusion to the infant does not affect the peripheral tissue circulation. There was also no difference in FOE and VO2 or DO2 between our two groups. The increase in LVD(D) in the late-clamped group suggests that clamping the cord after the transfer of an additional volume of blood increases the volemia [37], although no increase in left ventricular output was documented [5]. Since there are no non-invasive techniques for measuring volemia, it is difficult to diagnose hypovolemia or hypervolemia in newborn infants [38]. To investigate the hemodynamic and presumable volemic changes in relation to clamping time, we studied peripheral blood flow as well as heart function. The larger LVD(D) with no change in BF and oxygen demand might be a sign of neonatal competence in redistributing blood towards capillary beds in relative hypoperfusion [5], thanks to the autoregulation of vascular control essential in brain perfusion [39] and in the prevention of passive pressure brain circulation. A recent randomized trial in brain hemodynamics demonstrated that delaying clamping (by 60 to 90 sec) improves cerebral oxygenation in the first 24 hours of life [40]. Weaknesses of this study include the underpowered significance of our limited numbers and the lack of a peripheral blood pressure value, but the main purpose of this observational study was the NIRS assessment of peripheral tissue perfusion and heart function using two cord clamping times. Moreover, although hemodynamic adjustments following placental transfusion occur mainly in the first hours of life [37], we were unable to study our neonates quite so promptly. Delaying cord clamping by 30120 s seems to be associated with a lesser need for transfusion and less intraventricular hemorrhage. There are no clear differences in other outcomes in preterm newborn infants, according to the Rabe et al's meta-analysis [41]. The lack of any change in peripheral BF (presumably due to vasodilation) could be even more important for extrauterine adaptation in preterm infants, given their higher risk of hypovolemia, IVH and sepsis and their immature cerebral flow autoregulation [42].

Early clamping Late clamping p Median (range) Median (range)

38 (1959) 72 (4388) 1.5 (1.41.7) 1 (0.71.5) 38.5 (3567) 72 (5793) 1.7 (1.52.1) 1.1 (0.61.2) ns ns 0.03 ns

LVD(D) = end-diastolic left ventricle diameter, LVD(S) = end-systolic left ventricle diameter.

2.7. Data analysis and statistics

Data are given as median (range). The MannWhitney test was used to compare the two groups. The relationship between DO2 and VO2 was analyzed using Pearson's correlation coefficient. A p value b 0.05 was considered statistically significant. The regression coefficient (r) was determined for arterial and venous occlusions and those producing an r of less than 0.8 were excluded. The reported data for each subject were the average of the remaining occlusions.

3. Results
The findings are summarized in Tables 13. Table 1 shows physiological data in the early- and late-clamped groups. No significant differences emerged for BW, GA, 1st and 5th min Apgar scores, heart and breathing rate, SaO2 or age at assessment. Physiological NIRS-derived and echocardiographic data are summarized in Tables 2 and 3. The lateclamped group had significantly higher hematocrit and hemoglobin values (p = 0.001), whilst there was no difference in bilirubin. Calf BF and DO2 did not change in the lateclamped group. There were no differences in calf VO2 or SvO2, FOE or foot PI. The LVD(D) was larger in the late-clamped group (p = 0.03), whilst end-diastolic left ventricle diameter shortening fraction and ejection fraction did not change.

4. Discussion
Immediate cord clamping seems to be the most common clamping practice, in spite of the lack of any randomized trials reporting any negative side effects of late clamping in newborn infants. It is also not clear whether late clamping affords benefits in terms of blood volume, iron, and other parameters [33]. A recent randomized trial on term newborn infants reported: 1) an increased hematocrit value (N 65%) in late (3 min) versus early (1 min) clamped newborn; 2) a greater frequency of anemia (hematocrit b 45%) in the early versus late clamped group. The same Authors also said that bilirubin levels in three time-dependent clamping groups were similar, according to the literature [3335]. Our data confirm that late clamping is unassociated with any increased risk of hyperbilirubinemia, whilst it does coincide with a higher hematocrit value, which might increase the risk of polycythemia [36]. We also found no

5. Conclusion
Our results demonstrate that late cord clamping coincides with a greater placental transfusion, expressed by an increase in hematocrit and hemoglobin, and a larger left

Early versus late cord clamping ventricle diameter at the end of the diastole without any change in peripheral perfusion or oxygen metabolism. Late clamping does not seem to increase the risk of jaundice, however. The increased LVD(D) with no change in BF might improve the extrauterine adaptation of newborn infants, mainly redistributing the capillary blood toward alternative vascular beds, preventing a relative ischemia and hypovolemia.

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