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COMMENTARY |
Emeritus Professor, Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Palo Alto, California
Abbreviations: RDS, respiratory distress syndrome • DCC, delayed cord clamping • LOS, late-onset sepsis • IVH, intraventricular hemorrhage • ICC, immediate cord clamping
During the 1960s and 1970s, there were multiple studies of the effects on the neonate of varying the time of umbilical cord clamping. Interest in this area of investigation lay dormant for 
15 years, but in the past decade there has been renewed investigation of this topic, particularly in the preterm infant. In a recent article, Dr Saroj Saigal and I reviewed the history and implications of early and late umbilical cord clamping in both term and preterm infants,1 noting that definitions have varied widely over the years. More than a century ago, "early" was sometimes considered to be within 1 minute, whereas "late" may have been after 5 minutes. Currently, "early" is generally defined as "immediate," which may take up to 15 seconds, and "late" as 45 to 60 seconds after delivery of the body, by which time the majority of available blood in the placenta will have been transferred to the infant in the form of a "placental transfusion." In our article we suggested that lack of interest in the timing of umbilical cord clamping in preterm infants might have been a result of the introduction of surfactant as therapy for respiratory distress syndrome (RDS).1 A recent Cochrane review also evaluated the effects of different times of umbilical cord clamping in preterm infants.2
In an earlier era, the possibility that RDS (also called pulmonary syndrome of the newborn) might be ameliorated by delayed cord clamping (DCC) in preterm infants was proposed.3 Similar pathologic findings had been documented in foals born "in captivity" that had their umbilical cords clamped soon after birth.4 Subsequent studies suggested that early cord clamping might prevent placental transfusion and result in RDS. The most persuasive study was performed in 1975 by Usher et al,5 who showed significant differences in circulating blood volume in neonates with or without RDS. The same group had shown earlier that hyperbilirubinemia was more likely in preterm infants when a placental transfusion was allowed to occur.6 A deficiency of red cell mass was also noted in preterm infants with respiratory distress by Linderkamp et al.7
Renewed interest in the timing of cord clamping has been directed primarily at preventing the need for blood transfusion with donated blood.8 The Cochrane review points to the decreased need for blood transfusions with DCC.2 Additional interest has been directed at conserving or "harvesting" placental blood to use for autologous blood transfusion.9,10
In this issue of Pediatrics, additional possible benefits of DCC are described by Mercer et al.11 In the abstract, the primary outcome variables were stated to be BPD and suspected necrotizing enterocolitis (although BPD was the only primary outcome variable noted in their methods section). Secondary outcomes are stated to have been late-onset sepsis (LOS) and intraventricular hemorrhage (IVH), as well as retinopathy of prematurity. Other outcomes were evaluated also. In their introduction, they review the results of several recent randomized studies of cord clamping and mention some of the shortcomings of those studies. Among the purported benefits noted was a decrease in IVH. This was noted in the Cochrane review, although it should be said that this was really only true for all IVH. No differences were noted for severe IVH. It should be mentioned that the second (and larger) of 2 studies by Hofmeyer et al12,13 did not show a significant decrease in IVH with DCC.
In their study, Mercer et al demonstrated no significant difference in the frequency of BPD or suspected necrotizing enterocolitis but did document a decrease in all IVH (but not severe IVH, which was rare) and LOS with DCC.11 The former is easier to understand, with a possible relationship to decreased total blood volume and reduced cerebral blood flow. Additional documentation of this effect on IVH is needed. The effect on LOS is not so intuitively obvious, although the authors speculate on the protective role of primitive hematopoietic progenitor cells, present in high concentration in extremely preterm infants. These cells might be increased with DCC.
Although my personal bias is that DCC may be beneficial for preterm infants, I have some reservations about the study of Mercer et al and other recent randomized studies of cord clamping in preterm infants. Why should this be? To demonstrate a difference between immediate cord clamping (ICC) and DCC, I believe that there should be a demonstration that a placental transfusion occurred; this could come from (1) a change in hematocrit from cord blood to a central sample (venous or arterial) taken 4 hours after birth, (2) blood or plasma volume studies, or (3) measurement of residual placental blood volume. None of these methods were used in the present study or in most other recent studies.
This kind of study is not easy to perform. Obtaining the cooperation of the delivering physician is not always possible, which is reflected in the number of protocol violations encountered. Results were analyzed by "intention to treat," which is admirable, and statistical differences were found, but 1 infant in the ICC group (immediate) was clamped at 25 seconds and 6 in the DCC group (intention to clamp at 30–45 seconds) were clamped between 2 and 18 seconds. It is hard to imagine that these infants received a significant placental transfusion. Furthermore, placental transfusion may be influenced greatly by respiration, so that timing of cord clamping alone is not enough. We need to know about the time to onset of respiration or first cry. Certainly the transfer of blood from placenta to infant in term infants is influenced strongly by respiration.14–16 When the lungs expand, there is a large vascular bed into which blood may flow. Many of these very preterm infants require endotracheal intubation, not just stabilization. Although placental respiration may continue after delivery, placental transfusion may not occur.
Despite my reservations about documentation that a placental transfusion occurred in individual infants, the results of this study11 are provocative. Because there was no significant difference in the levels of bilirubin between the groups and other outcomes tended to favor the DCC group (although not statistically significant), there do not seem to be obvious disadvantages to DCC. Additional studies, which deserve to be performed, may provide compelling evidence of its advantages. In the meantime, the potential advantages of DCC suggest that neonatologists should recommend that obstetricians defer cord clamping for a short time after delivery. Our previous suggestion to "wait a minute,"1 a long time when one is counting off the seconds, might result in cords being clamped somewhere between 30 and 45 seconds, which probably allows a placental transfusion to occur, especially if the infant has established respiration.
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FOOTNOTES |
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Address correspondence to Alistair G.S. Philip, MD, FRCPE, Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, 750 Welch Rd, Palo Alto, CA 94304. E-mail: aphilip{at}stanford.edu
The author has indicated he has no financial relationships relevant to this article to disclose.
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REFERENCES |
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 TOP REFERENCES |
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This article has been cited by other articles:
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  R. K. Ohls Transfusions in the Preterm Infant NeoReviews, September 1, 2007; 8(9): e377 - e386. [Abstract] [Full Text] [PDF]
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