Clamping and cutting of the umbilical cord is the most prevalent of all operations, but the optimal timing of cord clamping is controversial, with different timings offering advantages and disadvantages. This study, for the first time, compares the influence of early and late cord clamping in correlation with oxidative stress and inflammation signaling, Because cord clamping timing may have a significant influence on placenta-to-infant blood transfer, thereby modifying oxygenation of maternal and fetal tissues, and on the transfer of inflammatory mediators throughout the placenta.
Sixty-four pregnant subjects were selected at the Gynecology and Obstetrics Services Department of the Clinico San Cecilio Hospital, Granada, Spain, based on disease-free women who experienced a normal course of pregnancy and a spontaneous, vaginal, single delivery. Half of the subjects had deliveries with early-clamped newborn infants (at 10 s), and the other half had late-clamped deliveries (at 2 min).
Erythrocyte catalase activity was significantly greater in the late-clamped group than in the early-clamped group (P < .01 for the umbilical vein and P < .001 for the artery). The values for superoxide dismutase, total antioxidant status, and soluble tumor necrosis factor receptor II were all significantly higher in the late-clamped group compared with the early-clamped group (P < .01, P < .001, and P < .001, respectively).
The results suggest a beneficial effect of late cord clamping, produced by an increase in antioxidant capacity and moderation of the inflammatory-mediated effects induced during delivery of term neonates.
Dear Editor:
It is logical to think that high concentrations of oxygen can increase the activity of the antioxidant enzymes, but in addition, the antioxidant enzymes studied do not act or are activated exclusively by the existence of a higher pressure of oxygen, though this fact could influence their activity, but as a consequence of the utilization of this oxygen and the generation of free radicals, therefore, more than a major oxygen pressure, it is more important to consider an increase in the sources of free radicals, something that happens during the parturition and the first moments of postnatal life. Definitively, this major pro-oxidant activity activates the antioxidan) defenses and these they are in full activity when the neonates face to an oxygen burst after birth, as we commented to Dr. Diaz-Rosello.
In addition, as it has been previously commented, there are several results obtained in our study and not only the activity of the SOD and Catalase in erythrocytes of umbilical cord artery. The total plasma antioxidant capacity, biomarkers of oxidative damage not only in artery but also in vein of cord have been assessed, which gives us an information of the mother?s contribution and she does not face any oxygen burst. On the basis of these findings, we think that the mother contribution is much higher than the oxygen burst.
It is also important to indicate that our subjects are newborn children with normal and totally healthy childbirth and their behavior should not be compared with the obtained one with other studies based on term newborn babies with suffocation needing resuscitation with air or with 100 % of oxygen; in this case the behavior of the antioxidant system is totally different, since it has been demonstrated by the Dr. Vento, as well as by other research groups, including our research group.
In some of these studies, it is observed even in vein a major activity of antioxidant enzymes in babies that need resuscitation in comparison with healthy children without need of this resuscitation; definitively, there is a factor in the pregnancy or childbirth that induces a major activity in the newborn child before the oxygen burst (Vento et al., 2003). In addition, if we compare this antioxidant enzymatical activity between the artery of umbilical cord and the observed 24h after, it is not observed in healthy children, and neither in those who need resuscitation, which indicates that they birth with a certain enzymatical activity and is kept, though the oxygen burst exists later.
In conclusion, we indicate again that the hypothesis proposed by Dr. Diaz Rosello and Dr. Vento, probably could be more accurate in preterm babies, especially those with resuscitation, or in cytosolic antioxidant enzymes of lung cells, which features, before the birth, a lower blood irrigation and is the first tissue in being exposed to this major oxygen concentration. We think that our results, therefore support the conclusions being made.
Conflict of Interest:
None declared
Dear Editor, it is with great interest that we have read the paper by J Diaz-Castro et al (Pediatrics 2014 134:257-264; doi:10.1542/peds.2013-3798). However, we agree with Dr Diaz Rosello that from the results expressed in this study it is cannot be confirmed that delaying cord clamping enhances antioxidant defenses and thus the ability of diminishing oxidative stress. Enzymatic activity is a normal response to an oxygen burst as occurs after birth. Prolonging the time of transfusion permits erythrocyte's to be a longer period of time in contact with a higher oxygen concentration and as a response increase antioxidant enzymes' activities. Enzymatic activity is not a surrogate of oxidative stress, it only indicates that enzymes get activated when confronted to a higher oxygen concentrations as it occurs immediately after birth. The biochemical methods employed to assess enzymatic activity do not infer a higher gene expression and transcription, only activity.
We have shown in repeated publications that control term babies increase their antioxidant enzyme activity during fetal to neonatal transition as a normal response to increased arterial blood oxygenation when breathing is initiated (1,2,3). In order to demonstrate that delaying cord clamping enhances antioxidant capacity the authors of this paper should have assessed biomarkers of oxidative damage especially related to increased oxygen concentration such as isoprostanes and isofurans several hours after birth. By not doing so they only show that a more prolonged contact of erythrocytes with higher oxygen increases the activity of enzymatic antioxidants. This is a physiologic reaction with no clinical implications.
As Dr Diaz Rosello states, delaying cord clamping has enourmous advantages for the newborn infant, but with the present data we cannot conclude that reduction of oxidative stress is one of them.
1) Vento M et al Pediatrics 2001; 107(4):642-7.
2) Vento M et al J Pediatr. 2003;142(3):240-6.
3) Vento M et al Am J Respir Crit Care Med. 2005;172(11):1393-8
Conflict of Interest:
None declared
To the Editor: As many other plausible explanations that might discuss the obtained results, the hypothesis of Dr. Diaz-Rosello has a logical base, provided that the antioxidant defense (especially the antioxidant enzymes) can modify their activity in presence of oxygen. Nevertheless, this would be a partial and not completely correct hypothesis that would explain just part of the results and, in addition, it does not consider other aspects related to the childbirth that also induce the antioxidant defenses of the newborn, as well as other previous existing studies in relation to the oxidative stress in the neonate. The reasons that we report are the following ones: 1. It is not completely correct that in all the newborn with early clamping, this clamping is performed before the first breathing. Because they are totally healthy children, without need of resuscitation, normal delivery, this first breathing happens in the first seconds and therefore it could take place in many of them. 2. Not only the antioxidant activity of the cytosolic enzymes is modified, but also a higher antioxidant total plasmatic capacity is observed, which has their main source in the mother and not due to stimulation for oxygen. 3. The exposition to a higher oxygen pressure would have an effect in the newborn child but not in the mother and therefore this would not explain the changes observed in umbilical cord vein. 4. If a major exposition to oxygen were the only cause of the activation of cytosolic antioxidant enzymes, it would be expected to observe in the available studies in term newborn different activities of these enzymes when comparing umbilical cord blood (obtained after the clamping) with the blood in the first hours of life. Nevertheless, diverse studies, including those carried out by our research group, show that the activity of the erythrocyte cytosolic antioxidant enzymes of blood from umbilical cord do not show differences with the erythrocytes of newborn in the first hours of life, demonstrating that these newborn are perfectly prepared to face this major exposition to oxygen. 5. Newborn suffers multiple aggressions during the parturition. Oxygen consumption is increased during pregnancy and parturition, and therefore, there is an increase in mitochondrial respiration, facts that result in the formation of reactive oxygen species. In addition, during the progression of normal parturition, powerful contractions of the myometrium and the associated increase in intrauterine pressure periodically suppress uteroplacental blood flow giving rise to alternating cycles of ischemia and reperfusion. In addition, the inflammatory signalling is over- expressed in mother and neonate. Therefore, if we consider the reasons mentioned above, we can conclude that our results support perfectly our conclusions and the hypothesis of Dr. Diaz-Rosello, though logic, is difficult to apply to our data in its entirety. In addition, they exclude the need to take an extra sample of blood from the newborn with early clamping at two minutes of life, something that we consider would not be approved, on the basis of the existing precedents, for the Ethical Committee of the Hospital and in addition it would damage unnecessarily the neonate. Finally, our conclusions, encourages the practice of late clamping, that should be used as a routine practice in hospitals.
Conflict of Interest:
None declared
To the Editor
Diaz-Castro et al, suggest a beneficial effect of delayed cord clamping, produced by an increase in antioxidant capacity and moderation of the inflammatory-mediated effects induced during delivery of term neonates.
The study design has a major flaw and their conclusions are not supported by their results: the biological measurements in the early cord- clamping group were done before the newborn infants started breathing and in the late cord clamping group the blood was collected after two minutes of regular breathing. The exposure to higher oxygen levels in the late cord-clamping group may explain their results.
Although the blood volume of the late cord-clamping group may be larger than in the early cord clamping group, erythrocyte catalase activity, superoxide dismutase and total antioxidant status, are activated by the available concentration of oxygen. In order to study if any relevant and beneficial differences are determined by the timing of cord clamping and independently of the postnatal increase in oxygen availability, the study should have included a second blood sample in the early cord-clamping group at similar oxygen concentrations, 2 minutes after birth. We acknowledge that an invasive experimental design drawing blood from a normal neonate may not feasible under current ethical research standards.
We consider that after the initiation of breathing, newborn infants with early cord clamping may reach levels of antioxidant defenses similar to those in the delayed cord-clamping group. This study cannot reject this hypothesis. Therefore, the authors do not present valid proofs to support their conclusion that delaying cord clamping increases antioxidant defenses. Nevertheless, there is enough evidence for the benefits of delayed cord clamping. We should continue stimulating research on the physiology of the newborn infant during the third stage of labor, while the placenta is still functioning. For decades this period has been a blind spot of our clinical practice, while we were empirically interrupting the umbilical blood flow by unjustified early cord-clamping.
Conflict of Interest:
None declared