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Early versus delayed umbilical cord clamping in preterm infants

RHL Commentary by Ceriani Cernadas JM

1. EVIDENCE SUMMARY

The main objective of the review was to assess the short- and long-term effects of placental transfusion according to the timing of cord clamping and/or the position of the neonate relative to the level of the placenta and/or the milking of the umbilical cord in infants born at less than 37 completed weeks' gestation. Delayed cord clamping was defined as cord clamping between 30–120 seconds after birth.

Of the 16 trials identified, the authors selected seven and requested additional information for three. Blood transfusion for anemia and the risk of intraventricular haemorrhage were the two variables for which delayed cord clamping was beneficial. For most other outcomes there were insufficient data to evaluate the effects reliably. The trial by Mercer et al. (1) is listed as 'ongoing' but this trial has recently been published and should be eligible for inclusion in this review.

The authors correctly identify several inconsistencies within the evaluated trials. These mainly relate to the use of different definitions of terms (“intervention”, “immediate cord clamping” and “delayed cord clamping”) and to the outcome variables included. Most trials did not state whether the timing of cord clamping was measured and whether any guidelines were followed with respect to the indication of blood transfusion in neonates; the latter makes it difficult to know whether the indication of blood transfusion in neonate was dealt with in a similar manner in all the trials. Finally, the trials did not define many of the variables included. These limiting factors affect the reliability of the results.

Although the authors of the review had defined stratification categories, taking into account possible confounding factors, this was not possible to implement the stratification due to the limited number of papers and their marked heterogeneity. Also, not all the trials considered all the outcome variables. Consequently, the review had to rely on a limited number of trials that included the different outcome variables. Therefore, even though the conclusions of the review do not reliably indicate any benefits of delayed cord clamping, it would be plausible to assert that delayed cord clamping would not result in any conditions that become a risk for infants born at less than 37 completed weeks'.

Another aspect of the trials that needs to be emphasized is that not all included trials achieved their estimated required sample size. Considering the main outcomes—need of blood transfusion and intraventricular hemorrhage—the sample size obtained after combining the trials was enough in the first case (n=111), taking into account 52% and 55% frequencies of need of blood transfusion in each arm of the trial. In the case of intraventricular hemorrhage, the sample size obtained in the review (n=225) was close to that required.

2. RELEVANCE TO UNDER-RESOURCED SETTINGS

2.1. Magnitude of the problem

The umbilical cord is often clamped immediately or within the first 15 s after delivery of the baby. There is no sound scientific evidence to support this practice, which probably is based on, among other reasons, the belief that delayed cord clamping causes adverse effects in the neonate as a consequence of placental transfusion. This thinking is supported by a limited number of small observational trials, most of which were carried out in the 1960s and 1970s (2, 3, 4, 5, 6, 7). These trials reported a higher frequency of cardiopulmonary diseases and hyperbilirubinemia in newborn infants with delayed cord clamping. The more recent randomized controlled trials included in (and excluded from) the present review did not observe any harmful or adverse events with this practice. Despite the limitations of the trials noted in the review, it is highly likely that delayed cord clamping is a safe practice, although some precautions (see below) will need to be followed. A key advantage of delayed cord clamping is that postnatal placental transfusion allows newborn infants to increase their red cell count and iron stores (8, 9). In preterm infants, this is especially relevant, as they are exposed to multiple circumstances that increase the risks of experiencing severe disorders. Newborn anemia associated with preterm birth is a common problem and has considerable implications for the clinical outcome, especially in under-resourced settings.

In preterm newborns there are three main causes of anemia: physiological mechanisms inherent to preterm birth; neonatal diseases or disorders; and, more importantly, the frequent blood extractions for laboratory tests during intensive care. In spite of some specific strategies to limit transfusions, the great majority of preterm infants born at less than 32 completed weeks' gestation receive at least one blood transfusion. The problems associated with anemia in preterm infants, as well as with its treatment (blood transfusions), are multiple and involve significant risks. Anemia hinders normal growth and contributes to postnatal malnutrition in most very-low-birth-weight preterm infants who are hospitalized for a long time. Also, anemia interferes with the process of recovery from respiratory diseases (particularly bronchopulmonary dysplasia), congenital heart diseases, and bacterial infections. On the other hand, blood or blood product transfusions may represent a significant risk for the transmission of infections and other diseases, especially in under-resourced settings.

2.2. Applicability of the results

The results observed in the Cochrane Review would be applicable to under-resourced settings. In fact, it is very likely that certain beneficial effects of delayed cord clamping in preterm infants may yield even greater benefits in settings where access to hear care is limited. In all settings, but particularly in under-resourced ones, it is important to reduce the number of blood transfusions to preterm infants.

It is important to keep in mind that there are some situations in which it is advisable to perform cord clamping within the first seconds of delivery, regardless of the setting. During fetal distress and intrauterine asphyxia there is a greater than normal transfer of blood from the placenta to the fetus prior to delivery (8, 10, 11), so delayed cord clamping may not be indicated in such cases. This, however, does not apply to fetal distress occurring in later stages of labor (second stage of labor or delivery). Hence, in such cases delayed cord clamping may not be contraindicated, as observed by Liderkamp et al. (8). On the contrary, in this situation the passage of blood in the first minute can contribute to a better resuscitation in preterm infants with low Apgar score at birth. Other situations in which delayed cord clamping is not recommended include: if the mother has immunity to Rh factor; the newborn is suffering from intrauterine growth restriction; or if the mother has diabetes.

2.3. Implementation of the intervention

Delayed cord clamping would be a feasible intervention in under-resourced settings. However, two main factors should be considered in implementing this intervention in preterm infants: (i) institution of measures that ensure that the practice is safe and does not cause any harm to the newborn; and (ii) development of strategies that promote a change in the routine practice for physicians and other health-care workers to help adopt the intervention. With regard to the first factor, it would be necessary to ensure that in the delivery room all precautions are taken to provide appropriate care to prevent alterations in the extrauterine adaptation and maintain physiological variables within normal ranges. In the case of the second factor, it is worth noting that changing established practices requires considerable effort over a period of time and needs to go beyond making rational evidence available to heath-care workers.

In Argentina, a UNICEF-supported trial was conducted in 31 maternity hospitals to ascertain the best timing for cord clamping. The exact timing of cord clamping was measured in 3738 births. The median of the timing of cord clamping was 25 seconds for the general population and of 10 s for infants with birth weight less than 2500 g (Carroli G, personal communication). Based on these data a series of actions were taken to promote delayed cord clamping to not before the first minute of life in term infants, with the main objective of increasing iron stores of the infant and preventing anemia in the first months of life. Likewise, UNICEF decided to support the development of a randomized controlled trial to evaluate the possible risks of this intervention in newborns and their mothers. A total of 276 mothers–infant pairs were randomly allocated to three groups with different timing of cord clamping; the first 15 seconds (early cord clamping), at one minute, or at three minutes (both groups defined as delayed cord clamping). The trial demonstrated that delayed cord clamping increased haematocrit during the first six hours of life within physiological ranges and did not cause any risks in either the newborn or the mothers. Also, delayed cord clamping significantly decreased the incidence of neonatal anemia, defined as a venous haematocrit value less than 45% (12). A second phase of the trial (still not published), assessing hemoglobin and ferritin in infants at six months of age has found that the levels of serum ferritin are significantly higher in the group with delayed cord clamping, even after controlling for confounding variables.

3. RESEARCH

It would be ideal to carry out randomized controlled trials of sufficient statistical power in under-resourced settings to evaluate the feasibility of implementation of delayed cord clamping and its benefits and potential risks.

References

• Mercer JS, McGrath MM, Hensman A, et al. Immediate and delayed cord clamping in infants born between 24 and 32 weeks: a pilot randomized controlled trial. Journal of Perinatology 2003;23:446–472.
• Oh W, Lind J, and Gessner IH. The circulatory and respiratory adaptation to early and late cord clamping in neonate infants. Acta Paediatrica Scandinavica 1966;55:17–25.
• Oh W, Wallgren G, Hanson JS, and Lind J. The effects of placental transfusion on respiratory mechanics of normal term neonate infants. Pediatrics 1967;40:6–12.
• Saigal S, and Usher RH. Symptomatic neonatal plethora. Biology of the Neonate 1977;32:62–72.
• Yao AC, Lind J, and Vuorenkoski V. Expiratory grunting in the late clamped normal neonate. Pediatrics 1971;48:865–870.
• Saigal S, O'Neill A, Surainder Y, Chua LB, and Usher R. Placental transfusion and hyperbilirubinemia in the premature. Pediatrics 1972;49:406–419.
• Yao AC, and Lind J. Placental transfusion. American Journal of the Diseases of the Childhood 1974;127:128–141.
• Linderkamp O, Nelle M, Kraus M, and Zilow EP. The effect of early and late cord-clamping on blood viscosity and other hemorheological parameters in full-term neonates. Acta Paediatrica 1992;81:745–750.
• van Rheenen P, Brabin BJ. Late umbilical cord-clamping as an intervention for reducing iron deficiency anaemia in term infants in developing and industrialised countries: a systematic review. Annals Tropical Paediatrics 2004;24:3–16.
• Flod NE, Ackerman BD. Perinatal asphyxia and residual placental volume. Acta Paediatric Scandinavian 1971;60:433.
• Yao A, Lind J. Blood volume in the asphyxiated term neonate. Biology of the Neonate 1972;21:199.
• Ceriani Cernadas JM, Carroli G, Otaño L, Pellegrini L et al. Effect of timing of cord clamping on postnatal hematocrit values and clinical outcome in term infants. A randomized controlled trial. Pediatric Research 2004;55:462.

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This document should be cited as: Ceriani Cernadas JM. Early versus delayed umbilical cord clamping in preterm infants: RHL commentary (last revised: 7 March 2006). The WHO Reproductive Health Library; Geneva: World Health Organization.

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