The Influence of the Timing of Cord Clamping on Postnatal Cerebral Oxygenation in Preterm Neonates: A Randomized, Controlled Trial
OBJECTIVE. Our goal was to investigate the effect of placentofetal transfusion on cerebral oxygenation in preterm infants by near-infrared spectroscopy.
SUBJECTS. A total of 39 preterm infants with a median gestational age of 30.4 weeks were randomly assigned to an experiment group (n = 15) and a control group (n = 24).
INTERVENTIONS. The delivery of the infants in the experiment group was immediately followed by maternal administration of syntocinon, the infant was placed 15 cm below the placenta, and cord clamping was delayed by 60 to 90 seconds. The infants in the control group were delivered conventionally. At the ages of 4 and 24 hours, cerebral hemoglobin concentrations, cerebral blood volume, and regional tissue oxygenation were measured by near-infrared spectroscopy.
RESULTS. Cerebral blood volume was not different between the 2 groups at the age of 4 hours (6.1 vs 5.8 mL/100 g of tissue) nor at the age of 24 hours (6.2 vs 6.2 mL/100 g of tissue). Mean regional tissue oxygenation of the experiment group was higher at the ages of 4 hours (69.9% vs 65.5%) and of 24 hours (71.3% vs 68.1%).
CONCLUSION. Delayed clamping of the umbilical cord improves cerebral oxygenation in preterm infants in the first 24 hours.
In recent years, delayed cord clamping and placentofetal transfusion (PFT) was advocated to reduce the rate of blood transfusion and improve hemodynamic stability by increasing the intravascular blood volume in preterm neonates.1–4 PFT was proven to be a safe and practicable procedure and effectively can reduce the need for blood transfusion in very low birth weight infants.5,6 The increased blood volume may have profound implications on cerebral blood flow and oxygen delivery to the brain and other organs.7,8 This is particularly interesting because neonatal brain injuries are the most important sequelae of premature birth.
The aim of our study was to investigate the effect of PFT on cerebral oxygenation in preterm infants measured by near-infrared spectroscopy (NIRS).
PATIENTS AND METHODS
A total of 39 preterm neonates expected to be delivered at 24 to 32 completed weeks' gestation at the University Hospital Zurich were enrolled onto the study. The women were enrolled by a local study coordinator who obtained written informed consent and informed the obstetrician about the grouping. The neonatologist was not aware of the timing of cord clamping. Multiple deliveries, children with perinatal asphyxia, major fetal malformations, and children whose parents refused consent were excluded.
Our study population was a part of a large international, randomized, multicenter trial that investigated the effects of PFT on blood volume, need for red cell transfusion, and respiratory and neurologic complications. The infants were selected randomly and assigned to an experiment group or a control group by a central study coordinator. The infants were enrolled between September 1996 and July 1997.
The delivery of the infants in the experiment group was immediately followed by maternal administration of syntocinon, the infant was placed 15 cm below the placenta in cesarean-section deliveries and as low as possible for vaginal deliveries, and umbilical cord clamping was delayed 60 to 90 seconds. The infants in the control group were delivered conventionally, with the cord clamped in <20 seconds. The following neonatal resuscitation was performed according to the standard protocol of the clinic of neonatology and was identical for both groups. Clinical data about the 39 infants are provided in Table 1. There were no differences between the 2 groups in birth weight, gestational age, Apgar scores, or complications during pregnancy.
Eleven infants from the experiment group were delivered by cesarean section, and 16 infants from the control group were delivered by cesarean section. Three infants subsequently died (2 because of complications from hyaline membrane disease and 1 because of neonatal sepsis); all 3 were in the control group and died after the age of 72 hours.
The study was approved by the local ethics committee, and written informed consent was obtained from the parents before the study.
At the ages of 4, 24, and 72 hours, cerebral oxygenation was evaluated by measuring deoxyhemoglobin (μM), oxyhemoglobin (μM), their sum of the total hemoglobin (tHb; μM), and the regional tissue oxygen saturation (Sto2; %) by NIRS. From the tHb and the hematocrit, the cerebral blood volume (CBV; mL/100g) was calculated. The measurements were performed by trained study personal (Mr Keel and Drs Stolkin and Wolf) who participated in numerous NIRS studies, including studies on data quality and interobserver variability. At the same time heart rate, arterial blood pressure, hematocrit, arterial oxygen saturation, Pao2, and Paco2 were recorded. For mechanically ventilated children, an oxygenation index was calculated by using the following formula:
For our study, we used a Critikon 2020 Cerebral RedOx Monitor (Johnson & Johnson, New Brunswick, NJ), which is based on a 2-channel sensor and a coupling compensation system. It uses 4 laser diodes with wavelengths at 776.5, 819.0, 871.4, and 908.7 nm. The silicon photodiode detectors are placed 10 and 37 mm from the emitter window for the neonatal sensor. In the middle between the 2, a light emitting diode is placed. The light intensity of the light emitting diode should be the same at both detectors. Hence, differences in coupling can be compensated.
The goal of the Critikon algorithm is to determine the cerebral concentrations of hemoglobin without the influence of the superficial layers: skin, skull, and cerebrospinal fluid. The signal from detector 1 is mainly affected by the superficial layers, whereas the signal at detector 2 has a substantial component that refers to brain. A ratio of the signals at detector 2 and detector 1 is calculated, which reduces the influence of the outer layers.9–11 The algorithm has been described in detail8 and yields absolute oxyhemoglobin, deoxyhemoglobin, tHb, and Sto2 values. In previous studies, it was shown that the Sto2 values obtained by this instrument reflect physiologic changes, although the instrument underestimates the size of the changes.12 The tHb has been compared with other methods of measurement.13
Differences between the groups were analyzed by using unpaired nonparametric tests (Mann-Whitney U); the results are expressed as mean and SD. The analyses were performed by using SPSS 7.5.1 (SPSS Inc, Chicago, IL).
Hematocrit was higher for infants in the experiment group compared with the control group at 4, 24, and 72 hours of age (Table 2). Mean arterial blood pressure was higher in the experiment group compared with the control group at 4 hours but did not differ at 24 and 72 hours (Table 2). Arterial oxygen saturation was lower in infants in the experiment group at the age of 4 hours but not in older infants. There was no difference between the experiment group and the control group regarding heart rate and Paco2 at either age group.
Six infants from the experiment group and 12 infants from the control group needed mechanical ventilation. The oxygenation index between the 2 groups did not differ (13.63 ± 7.68 vs 16.0 ± 15.24).
A total of 15 infants in the experiment group and 24 infants in the control group were measured at the age of 4 hours. Because of movement artifacts or clinical instability of the child, 1 measurement at 24 hours (control group) and 3 measurements at age 72 hours (1 in the experiment group, 2 in the control group) could not be performed or the data set had to be excluded. At the age of 36 weeks, 12 measurements in the experiment group and 18 in the control group were performed (3 deaths in the control group or transfer to other neonatal units for the other infants).
The values of deoxyhemoglobin, oxyhemoglobin, CBV, and Sto2 are given in Table 2. Sto2 was higher at ages 4 and 24 hours in the experiment group but not at 72 hours (Table 3). There was a trend toward higher oxyhemoglobin values at the age of 4 hours (80.09 ± 34.91 vs 67.66 ± 29.32 μmol/L; P = .08), whereas there was no difference between the 2 groups in older infants. CBV and deoxyhemoglobin did not differ between the 2 groups at any age groups (Table 3).
The late clamping procedure led to a higher hematocrit measurement. Because the concentration of the oxygen carrier is higher, the oxygen extraction is lower, which led to the significantly higher Sto2 in the experiment group.
Delayed clamping of the umbilical cord allows PFT and improves oxygen delivery to the tissues by increasing systemic blood volume.1 Increased blood volume was advocated to facilitate pulmonary adaptation5 with a decrease for medical interventions, particularly mechanical ventilation.
PFT does increase total blood volume in preterm infants delivered by cesarean section.3 In infants in our experiment group, hematocrit and mean arterial blood pressure were increased compared with those in the control group, which suggests better systemic oxygen delivery to the tissue. It is well known that heart rate and arterial blood pressure only poorly correlate with blood volume, and that hematocrit does not completely match the adequacy of the oxygen transport capacity. However, our results demonstrate that the delayed cord clamping had its effect on systemic oxygen delivery to the tissues.
Optimizing tissue perfusion by PFT should also influence cerebral perfusion7 and potentially reduce the risk of hypoxic ischemic brain damage in these infants.2 We measured absolute cerebral hemoglobin concentrations by using NIRS and calculated a Sto2 that reflects tissue oxygenation of the brain.10,11 Our results demonstrate a higher Sto2 for the infants after delayed clamping of the umbilical cord. These results are supported by the data from studies using NIRS after red blood transfusion in older preterm infants.14,15 Transfusing red blood cells to anemic preterm infants resulted in an increase of oxyhemoglobin, deoxyhemoglobin, and the calculated Sto2. The main difference between our study and the above-mentioned study is that in the second study, adult red blood cells were transfused to anemic infants, whereas in our study, the transfusion was with the infant's own fetal hemoglobin containing red blood cells.
The higher Sto2 measurement clearly demonstrates a higher cerebral tissue oxygenation in the experiment group. Even if the absolute values of Sto2 did not completely match the in vivo values of the tissue oxygenation, the difference between the 2 groups shows a greater reserve of cerebral oxygenation for the experiment group. This reserve potentially reduces the risk of hypoxic ischemic events to the brain.
Most authors suggest practicing PFT to reduce the need for transfusion of packed red cells. However, our data suggest that it may be beneficial to reduce the risk of disturbed cerebral oxygenation. Inadequate cerebral oxygenation is an important factor in the development of neonatal brain injury. In the preterm infant, it may play a role in the development of intracranial hemorrhages and periventricular leukomalacia.8 Our study demonstrates an increased tissue oxygenation in the neonatal brain after delayed cord clamping. We do not know whether this effect really has an impact on the development of neonatal brain injury or on the neurologic outcome of these infants, but reducing the risk of inadequate tissue oxygenation by a simple technique, such as delayed cord clamping, would be very advantageous.
Because the randomization for our study was performed by a central study coordinator for a larger randomized, multicenter trial and the primary outcome of the study was not cerebral oxygenation, the experiment group and the control group were not equal in size. They did not differ in their clinical data, such as birth weight, gestational age, head circumference, or Apgar scores. Therefore, the small study size and the uneven distribution should not affect the results in regards to cerebral oxygenation. However, it remains a limitation of our trial. A confirmation of the results by a larger, multicenter trial is desirable.
We conclude that delayed cord clamping increases cerebral oxygenation for the first 24 hours after birth.
- Accepted November 10, 2006.
- Address correspondence to Oskar Baenziger, MD, Department of Pediatric Intensive Care and Neonatology, University Children's Hospital, Steinwiesstrasse 75, 8032 Zurich, Switzerland. E-mail:
The authors have indicated they have no financial relationships relevant to this article to disclose.
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- ↵Nelle M, Hocker C. Effects of red cell transfusion on cardiac output and blood flow velocities in cerebral and gastrointestinal arteries in premature infants. Arch Dis Child Fetal Neonatal Ed.1994;71 :F45– F48
- ↵Volpe JJ. Hypoxic-ischemic encephalopathy. In: Volpe J, ed. Neurology of the Newborn. 3rd ed. Philadelphia, PA: WB Saunders; 1995:279– 313
- ↵Okada E, Delpy DT. The effect of overlying tissue on NIR light propagation in neonatal brain. Adv Opt Imaging Photon Migr.1996;338– 343
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- Copyright © 2007 by the American Academy of Pediatrics