Early versus delayed umbilical cord clamping in preterm infants
Abstract
Background
Optimal timing for clamping of the umbilical cord at birth is unclear. Early clamping allows for immediate resuscitation of the newborn. Delaying clamping may facilitate transfusion of blood between the placenta and the baby.
Objectives
To delineate the short‐ and long‐term effects for infants born at less than 37 completed weeks' gestation, and their mothers, of early compared to delayed clamping of the umbilical cord at birth.
Search methods
We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (2 February 2004), the Cochrane Neonatal Group's Trials Register (2 February 2004), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2004, Issue 1), PubMed (1966 to 2 February 2004) and EMBASE (1974 to 2 February 2004). We updated the search of the Cochrane Pregnancy and Childbirth Group's Trials Register on 30 November 2009 and added the results to the awaiting classification section
Selection criteria
Randomized controlled trials comparing early with delayed (30 seconds or more) clamping of the umbilical cord for infants born before 37 completed weeks' gestation.
Data collection and analysis
Three reviewers assessed eligibility and trial quality.
Main results
Seven studies (297 infants) were eligible for inclusion. The maximum delay in cord clamping was 120 seconds. Delayed cord clamping was associated with fewer transfusions for anaemia (three trials, 111 infants; relative risk (RR) 2.01, 95% CI 1.24 to 3.27) or low blood pressure (two trials, 58 infants; RR 2.58, 95% CI 1.17 to 5.67) and less intraventricular haemorrhage (five trials, 225 infants; RR 1.74, 95% CI 1.08 to 2.81) than early clamping.
Authors' conclusions
Delaying cord clamping by 30 to 120 seconds, rather than early clamping, seems to be associated with less need for transfusion and less intraventricular haemorrhage. There are no clear differences in other outcomes.
[Note: The 14 citations in the awaiting classification section of the review may alter the conclusions of the review once assessed.]
PICOs
Plain language summary
Early versus delayed umbilical cord clamping in preterm infants
Delayed cord clamping for babies born early improves their health.
In the womb, blood flows to and from the baby and the placenta bringing oxygen to the baby from the mother's blood. If the cord is left unclamped for a short time after the birth, some of the baby's blood from the placenta passes to the baby to help the flow of blood to the baby's lungs. In the review of studies on babies born prematurely, delaying cord clamping for just a very short time helped the babies to adjust to their new surroundings better. Further studies are needed on longer delays to see whether this brings even more benefits.
Authors' conclusions
Background
The comparative risks and benefits of early rather than late clamping of the umbilical cord for the preterm infant (fewer than 37 weeks' gestation) have been the subject of much debate, and the optimal timing to clamp the cord is unclear. Attempts to transfuse the baby from the placenta, by leaving the cord unclamped for longer at the time of birth, may conflict with a perceived need for immediate resuscitation, which usually takes place away from the mother.
Cord clamping is part of the third stage of labour, which is the time between delivery of the infant and the placenta. The cord is usually clamped by applying two clamps. The cord is cut between the clamps, without blood loss for either the infant or the mother, through the placenta. Before the clamps are applied the infant can either be placed on the mother's abdomen (above the level of the placenta), between the mother's thighs (at the level of the placenta) or held below the level of the placenta. Blood flow from the placenta to the infant will depend on which position is used. Some birth attendants also 'milk' the cord towards the infant before clamping, as it can contain up to 20 ml of placental blood (Brune 2002). Whether additional blood actually passes to the infant as a result of this practice is unclear.
Suggested advantages of delaying clamping of the umbilical cord and subsequent increased placental transfusion include less respiratory distress (Linderkamp 1978), less need for blood transfusion later and less requirement for respiratory support (Holland 1991; Hudson 1990; Kinmond 1993). Potential disadvantages include delay in resuscitation, hypothermia, polycythaemia, hyperbilirubinaemia needing treatment (Saigal 1972) and a possible risk of intraventricular haemorrhage (Hofmeyr 1988). There are different potential comparative effects of early rather then delayed cord clamping for term and preterm infants. For example, in term infants increasing placental transfusion by delaying cord clamping may increase respiratory morbidity after birth (Yao 1974). As a consequence the issue of timing of cord clamping is reviewed separately for preterm and term infants. There is a separate Cochrane review of this topic for term infants (McDonald 2008).
For developing countries, with limited resources and a high risk of transmitting infection through blood transfusion, the potential value of a reduced need for blood transfusion would be of particular interest. In more developed countries, 60% to 80% of preterm infants less than 32 completed weeks' gestation (Brune 2002; Ringer 1998) require transfusion, and strategies that might reduce this without risk would be desirable.
This review will be of interest to obstetricians, midwifes, neonatologists as well as pregnant women. In the six trials reported in a previous systematic review (Elbourne 1995), there was considerable variation in transfusion strategies, intervention and outcomes and it was recommended that further, larger trials should be initiated before firm recommendations could be made. Since then, additional trials have been reported and a reappraisal of the available data is warranted.
Objectives
To delineate the short‐ and long‐term effects in infants less than 37 completed weeks' gestation of placental transfusion at birth by delayed umbilical cord clamping and/or positioning below the introitus and/or milking of the umbilical cord.
Methods
Criteria for considering studies for this review
Types of studies
Randomized controlled trials. Quasi‐randomized trials were not included.
Types of participants
Preterm infants born before 37 completed weeks' gestation and their mothers.
Types of interventions
Delayed (30 seconds or more) versus immediate umbilical cord clamping. This could be with or without oxytocin, with or without the baby held below the level of the placenta, and with or without milking of the cord towards the infant.
Subgroup analyses
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By position relative to the level of the placenta: infant below the level of the placenta before clamping or infant at or above the level of the placenta before clamping;
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by use of oxytocin: with or without oxytocin;
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by milking of the cord: with or without milking;
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by route for delivery: vaginal or abdominal route;
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by gestational age: less than 32 completed weeks' gestation or 32 or more completed weeks.
Sensitivity analyses
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By quality of studies.
Types of outcome measures
Overall (infant)
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Requirement for resuscitation;
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Apgar score at five and ten minutes;
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hypothermia during first hour of life on admission or in labour ward;
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death.
Respiratory
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Respiratory distress syndrome (assessed by clinical signs, oxygen requirement, respiratory support, chest x‐ray) during first 36 hours of life;
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use of exogenous surfactant;
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days of oxygen dependency;
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oxygen dependency at 28 days after birth;
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oxygen dependency at equivalent of 36 completed weeks' gestational age;
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chronic lung disease (Northway Stage 2, 3 or 4).
Cardiovascular
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Volume (colloid, sodium chloride 0.9 %, blood transfusion) administration for hypotension during the first 24 hours of life;
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inotropic support for hypotension during the first 24 hours of life;
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treatment for patent ductus arteriosus.
Haematological
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Anaemia, number or volume of blood transfusions;
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treatment for hyperbilirubinaemia with phototherapy;
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treatment for hyperbilirubinaemia with blood exchange transfusion;
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blood counts at 6 and 12 months of age.
Central nervous system
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Intraventricular haemorrhage (IVH) all grades;
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IVH grades three and four;
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periventricular leukomalacia.
Gastrointestinal
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Necrotizing enterocolitis.
Overall (mother's)
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Death;
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postpartum haemorrhage;
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complications with delivery of placenta;
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effects on rhesus‐isoimmunization;
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psychological well‐being;
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bonding to the infant;
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anxieties;
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mother's views.
Overall (father's)
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Psychological well‐being;
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bonding to the infant;
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anxieties;
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father's views.
Search methods for identification of studies
Electronic searches
We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register by contacting the Trials Search Co‐ordinator (2 February 2004). We updated this search on 30 November 2009 and added the results to Studies awaiting classification.
The Cochrane Pregnancy and Childbirth Group’s Trials Register is maintained by the Trials Search Co‐ordinator and contains trials identified from:
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quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);
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weekly searches of MEDLINE;
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handsearches of 30 journals and the proceedings of major conferences;
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weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.
Details of the search strategies for CENTRAL and MEDLINE, the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service can be found in the ‘Specialized Register’ section within the editorial information about the Cochrane Pregnancy and Childbirth Group.
Trials identified through the searching activities described above are each assigned to a review topic (or topics). The Trials Search Co‐ordinator searches the register for each review using the topic list rather than keywords.
In addition, we searched the Cochrane Neonatal Group's Trials Register (2 February 2004), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2004, Issue 1), PubMed (1966 to 2 February 2004) and EMBASE (1974 to 2 February 2004) using the following terms:
umbilical‐cord AND clamp* AND (preterm OR premature OR infant, premature).
Data collection and analysis
We used the methods described in the Cochrane Reviewers' Handbook (Clarke 1999). In addition, we assessed the methodological quality of each study in terms of selection, performance, attrition and detection as described by the Neonatal Review Group. See Review Group's details for more information. This includes the independent evaluation of each trial by all reviewers.
Three reviewers extracted data independently using previously prepared data extraction forms. We resolved any discrepancies by discussion. Whenever the disagreement could not be resolved by consensus, the trial was referenced as one that is awaiting assessment until additional information is obtained. We extracted data presented in graphs and figures whenever possible, but were only included if three reviewers independently had the same results. We double‐checked all data for discrepancies. We requested additional data from the authors of each trial. Authors provided additional data for three trials (McDonnell 1997; Oh 2002; Rabe 2000). We entered data into the Review Manager software developed by The Cochrane Collaboration (RevMan 2003).
The statistical methods used were as follows:
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Analysis: We described adverse outcomes as adverse event rates (AER) and relative risk (RR), the ratio of adverse events in the treated and control groups. For measures of treatment effect we gave RR, relative risk reduction (1‐RR), risk difference and number needed to treat (1/RD). For continuous data, we used mean and standard deviations with reference to the original data if necessary. We calculated weighted mean difference (WMD) where appropriate. For the WMD, the weight given to each study (i.e. how much influence each study has on the overall results of the meta‐analysis) as determined by the precision of its estimate of effect which in the Review Manager statistical software is equal to the inverse of the variance. This method assumes that all of the trials have measured the outcome on the same scale.
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Heterogeneity: We tested clinically and statistically important heterogeneity at the p < 0.05 level and used subgroup analysis to explain heterogeneous data if possible.
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We specified subgroup analysis before review.
Results
Description of studies
See: 'Characteristics of included studies' for more detail, such as gestational age, mode of delivery, positioning of the infant and length of cord clamping time.
Seven trials qualified for inclusion into this review. We excluded nine studies (see 'Characteristics of excluded studies'). The trials enrolled preterm babies between 24 and 33 weeks' gestation. There was some inconsistency in both the intervention and the control procedures between studies and wide variation in outcome measures. This limited the utility of each of the studies.
The women recruited into the trials were all expecting to deliver their infants prematurely. The infants in the study of Kinmond 1993 were all delivered vaginally, while those in the trial of Nelle 1998 were delivered by caesarean section only. All other trials allowed both ways of delivery.
(Thirteen reports from an updated search in November 2009 have been added to Studies awaiting classification.)
Early or immediate umbilical cord clamping
The definition of early umbilical cord clamping has not been made clear in any study except McDonnell (McDonnell 1997) where the exact time to cord clamping in the immediate group is five seconds. It seems likely that there is a time lag between delivery and cord clamping and that variation may be up to 10 seconds or more. In Rabe 2000 early cord clamping was defined as clamping at 20 seconds and there was no immediate clamped group for comparison. We have included this study in this review because we believe that there is close proximity to the immediate clamped groups, and that in clinical practice such delays may occur. Furthermore, it allows the review to focus on at least 20 seconds interval between early and late cord clamping.
Delayed umbilical cord clamping
The definition of delayed umbilical cord clamping varies between studies. McDonnell 1997 had a mean timed delay of 31 seconds, Rabe 2000 45 seconds, and Hofmeyr 1988 and Hofmeyr 1993 60 and 120 seconds. The exact time to clamping is not given in other studies, nor is there an adequate description of how the timing was done and by whom. The number of babies allocated to delayed cord clamping but in whom resuscitation was considered necessary before the allocated time is described in only two studies. In Hofmeyr 1988 for example, 8 of 24 babies in the delayed clamping group required earlier intervention. There are insufficient data to determine whether there is any additional benefit for delay in cord clamping beyond 30 to 60 seconds.
Position in relation to the placenta
The position in relation to the placenta or uterus varies between studies. It is accepted that positioning the baby below the placenta during caesarean section is difficult and that for most studies the baby lies on the mother's thighs above the level of the uterus whilst waiting to clamp the umbilical cord. Most studies have positioned the baby at the level of the introitus for vaginal deliveries. Only in one study (Rabe 2000) was the baby kept at or more than 20 cm below the placenta. Subgroup analysis based on position of the baby in relation to the placenta has not therefore been possible.
Syntocinon or ergometrine
The use of pharmacologic stimulants to the uterus after delivery is not consistent between studies or is ill defined. However, Hofmeyr had shown that there is no significant difference in the two groups allocated to delayed umbilical cord clamping with or without ergometrine (Hofmeyr 1988). We have therefore not attempted a subgroup analysis on this variable.
Umbilical cord blood analysis
No study has described how and when the cord blood was obtained (whether from placenta, cord, isolated segment, etc).
Subgroup analysis
Subgroup analysis on position, milking of the cord, effects on mothers and fathers is not possible for lack of data. Stratification by gestational age has only been possible for a limited number of criteria.
Outcome measures
No two studies are similar in their outcome objectives and there is a wide and varied definition of the type of outcome measured. Similarly, the manner of reporting the same outcome varies between studies. We have requested raw data from all authors in order to clarify and normalize our evaluation more effectively, in line with the clinical outcomes that, a priori, we considered important. The authors of most recent studies have declared that they have performed a pilot or feasibility study and have been powered to answer short term specific questions only. In general the studies that we have included are not powered to answer the range of clinical questions that we feel are important in day‐to‐day neonatal practice.
Risk of bias in included studies
Randomization
Randomization was largely appropriate and well described except for the study of Nelle 1998, which has only been published in abstract format. Most studies claim to pilot a certain cord clamping time and an intervention and have therefore not been powered to detect small differences. The study of Hofmeyr 1993 is the largest of the seven included studies with 86 infants. Randomization was largely by sealed envelope, after allocation by random number table in later studies (McDonnell 1997; Rabe 2000) or by card shuffling in earlier studies (Hofmeyr 1988; Hofmeyr 1993). These methods are appropriate to use.
Concealment of allocation was adhered to in all studies. Blinding towards the allocation of intervention after delivery of the baby was not possible, as the intervention has to be performed openly after birth.
Effects of interventions
Seven studies involving 297 infants were included.
(a) For the baby
Haematological outcome
There was no clear effect on haematocrit at birth or one hour (three trials, 112 infants; weighted mean difference (WMD) ‐3.24%, 95% confidence interval (CI) ‐5.66 to 0.83) and haematocrit at four hours (four trials, 134 infants; WMD ‐5.31%, 95% CI ‐7.19 to ‐3.42). Fewer infants allocated delayed clamping were transfused for anaemia of prematurity (three trials, 111 infants; 29/55 versus 14/55; relative risk (RR) 2.01, 95% CI 1.24 to 3.27). Peak bilirubin concentration is also higher for infants allocated delayed rather than early clamping (three trials, 111 infants, WMD 21.49 mmol/litre, 95% CI 38.04 to 4.94). Treatment for hyperbilirubinaemia is reported by only one study, which was too small for reliable conclusions (39 infants, RR 0.95, 95% CI 0.58 to 1.56). Data on exchange transfusion are not reported by any of the studies.
Cardiovascular effects
Infants allocated delayed clamping were also less likely to need transfusion for low blood pressure at birth (two trials, 58 infants, RR 2.58, 95% CI 1.17 to 5.67). There was insufficient evidence for any firm conclusions on the effect of timing of cord clamping on the need for inotropic support at birth, or treatment for patent ductus arteriosus.
Intraventricular haemorrhage
There was reduction in the relative risk of intraventricular haemorrhage associated with delayed, rather than early, cord clamping (five trials, 225 infants; RR 1.74, 95% CI 1.08 to 2.81). For severe intraventricular hemorrhage (Grade 3 and 4) the numbers of events (two versus three) were too small for any firm conclusions (three trials, 161 infants; RR 0.86, 95% CI 0.15 to 4.75). Only one study (31 infants) reported periventricular leucomalacia.
Respiratory effects
Even taken together, these trials were too small for any firm conclusion about possible respiratory effects of the alternative strategies for timing of umbilical cord clamping. Respiratory distress syndrome is reported only in two studies (75 infants, RR 0.83, 95% CI 0.59 to 1.15), and only one trial reports severe respiratory distress (39 infants, RR 1.27, 95% CI 0.33 to 4.93). Use of surfactant was reported in two trials (85 infants; RR 0.78, 95% CI 0.34 to 1.79) and ventilation for respiratory distress by three trials (121 infants, RR 0.91, CI 95% 0.65 to 1.28). There was insufficient evidence for any reliable conclusions about the effects on days on oxygen, oxygen dependency at day 28 of life (one trial 36 infants, RR 6.30, 95% CI 0.35 to 113.81), or chronic lung disease at 36 weeks' corrected age (two trials, 65 infants; RR 0.97, CI 95% 0.35 to 2.69).
Gastrointestinal effects
There were insufficient data for any reliable conclusion about possible differential effects on necrotizing enterocolitis (two trials, 72 infants, RR 2.08, 95% CI 0.52 to 8.37).
Other outcomes
There was insufficient evidence for any reliable conclusions about the effect on the risk of the baby dying (six trials, 278 infants; RR 1.05 95% CI 0.41 to 2.73).
Data on the analysis of cord pH did not show a significant difference between early and delayed umbilical cord clamping (three trials, 123 infants, WMD 0.01, 95% CI 0.03 to 0.05). Similarly, there was no difference in temperature on admission (one trial, 39 infants; WMD 0.20, 95% CI 0.43 to 0.03) or in Apgar scores at five minutes (three trials, 161 infants, RR 1.17, 95% CI 0.62 to 2.20).
(b) For the mothers
No trials reported outcome for the women.
Discussion
The trials included in this review varied in respect of positioning of the infant, how quickly the umbilical cord was clamped for the early group, how long it was delayed for the delayed group and in other aspects of management of the third stage of labour. Data are not available for a number of our prespecified outcomes, and similarly the planned subgroup analyses were not feasible. In particular, there were no data on the potential effects on psychological well‐being of the mothers and fathers, and their bonding with the infants.
Overall, even when taking all trial results together, most outcomes had wide confidence intervals, so the results should be interpreted with caution. Nevertheless, later umbilical cord clamping for the preterm infant appears to be associated with a reduction in the relative risk of intraventricular haemorrhage (IVH) and the need for transfusion, either for anaemia or for low blood pressure. These effects may be related to an improvement in the circulating blood volume, and better control of blood pressure, secondary to greater placental transfusion if the umbilical cord is not clamped too quickly. Even though no direct studies on circulating blood volume in the control and intervention groups have been performed, the higher blood pressure and the less need for blood transfusions later suggest a higher circulating blood volume in infants when umbilical cord clamping is delayed by at least 30 seconds. Perhaps this issue could be addressed in future trials.
Surprisingly, as the rationale for early clamping is to provide respiratory support, there are few data on respiratory outcomes. As one clinical concern about delayed umbilical cord clamping is hypothermia, it is also surprising that this outcome is only addressed by one small trial.
The trials were too small for any reliable conclusions about the possible comparative effects on the risk of death. Nevertheless, there are problems with death as an outcome for this review. Variations in clinical practice over time have substantially influenced the risk of death for preterm infants. These background variations in clinical practice may alter the risk of death more than the intervention itself. The five neonatal deaths in Hofmeyr's study (Hofmeyr 1988), for example, are quoted as being "< 1300 g birthweight". This study was performed in the late eighties in South Africa, where access to ventilatory support for very preterm infants would have been, and still is, limited. In more recent years, and in most intensive care units in high‐income countries, ventilatory support for these babies would have been offered. In the Hofmeyr 1988 study it is not clear whether ventilation was possible for these babies, but the comment in the report suggests that survival at this low birthweight was more the exception than the rule.
There is a strikingly high rate of intraventricular haemorrhage in both studies by Hofmeyr et al (Hofmeyr 1988; Hofmeyr 1993), which were conducted in South Africa. Other studies conducted in high‐income countries have less IVH, and therefore less power to demonstrate any clinically important effects on the risk of IVH. Recent reports in the literature on even major grade 3 or 4 intraventricular haemorrhage suggest that these might not always be associated with major neurological impairment (Schmidt 2001).
On the questions about optimal positioning of the infant, milking of the cord and combination of these with a delay of umbilical cord clamping, this review cannot give any analysis because of lack of data. Further studies should include these issues.
Comparison 1 Early versus delayed cord clamping, Outcome 1 Death of the baby.
Comparison 1 Early versus delayed cord clamping, Outcome 2 Transfused for anaemia.
Comparison 1 Early versus delayed cord clamping, Outcome 3 Transfused for low blood pressure.
Comparison 1 Early versus delayed cord clamping, Outcome 4 Number of transfusions.
Comparison 1 Early versus delayed cord clamping, Outcome 5 Haematocrit at birth or 1 hour (%).
Comparison 1 Early versus delayed cord clamping, Outcome 6 Haematocrit at 4 hours of life (%).
Comparison 1 Early versus delayed cord clamping, Outcome 8 Serum bilirubin peak (mmol/litre).
Comparison 1 Early versus delayed cord clamping, Outcome 9 Hyperbilirubinemia (treated).
Comparison 1 Early versus delayed cord clamping, Outcome 11 Inotropics for low blood pressure.
Comparison 1 Early versus delayed cord clamping, Outcome 12 Patent ductus arteriosus.
Comparison 1 Early versus delayed cord clamping, Outcome 13 Intraventricular haemorrhage.
Comparison 1 Early versus delayed cord clamping, Outcome 14 Severe intraventricular haemorrhage.
Comparison 1 Early versus delayed cord clamping, Outcome 15 Periventricular leucomalacia.
Comparison 1 Early versus delayed cord clamping, Outcome 16 Respiratory distress syndrome.
Comparison 1 Early versus delayed cord clamping, Outcome 17 Severe respiratory distress syndrome.
Comparison 1 Early versus delayed cord clamping, Outcome 18 Ventilated for respiratory distress syndrome.
Comparison 1 Early versus delayed cord clamping, Outcome 19 Surfactant treatment.
Comparison 1 Early versus delayed cord clamping, Outcome 21 Oxygen supplementation at 28 days.
Comparison 1 Early versus delayed cord clamping, Outcome 22 Oxygen supplementation at 36 weeks.
Comparison 1 Early versus delayed cord clamping, Outcome 23 Necrotizing enterocolitis.
Comparison 1 Early versus delayed cord clamping, Outcome 24 Cord pH.
Comparison 1 Early versus delayed cord clamping, Outcome 25 Apgar score at 5th minute < 8.
Comparison 1 Early versus delayed cord clamping, Outcome 26 Temperature on admission (degrees Celsius).
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Death of the baby Show forest plot | 6 | 278 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.05 [0.41, 2.73] |
| 2 Transfused for anaemia Show forest plot | 3 | 111 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.01 [1.24, 3.27] |
| 3 Transfused for low blood pressure Show forest plot | 2 | 58 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.58 [1.17, 5.67] |
| 4 Number of transfusions Show forest plot | 3 | 98 | Mean Difference (IV, Fixed, 95% CI) | 1.28 [0.58, 1.98] |
| 5 Haematocrit at birth or 1 hour (%) Show forest plot | 3 | 112 | Mean Difference (IV, Fixed, 95% CI) | ‐3.21 [‐5.62, ‐0.80] |
| 6 Haematocrit at 4 hours of life (%) Show forest plot | 4 | 134 | Mean Difference (IV, Fixed, 95% CI) | ‐5.40 [‐7.28, ‐3.52] |
| 8 Serum bilirubin peak (mmol/litre) Show forest plot | 3 | 111 | Mean Difference (IV, Fixed, 95% CI) | ‐21.49 [‐38.04, ‐4.94] |
| 9 Hyperbilirubinemia (treated) Show forest plot | 1 | 39 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.95 [0.58, 1.56] |
| 11 Inotropics for low blood pressure Show forest plot | 3 | 118 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.17 [0.51, 9.12] |
| 12 Patent ductus arteriosus Show forest plot | 3 | 118 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.79 [0.36, 1.72] |
| 13 Intraventricular haemorrhage Show forest plot | 5 | 225 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.74 [1.08, 2.81] |
| 14 Severe intraventricular haemorrhage Show forest plot | 3 | 161 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.86 [0.15, 4.75] |
| 15 Periventricular leucomalacia Show forest plot | 1 | 31 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.31 [0.01, 7.15] |
| 16 Respiratory distress syndrome Show forest plot | 2 | 75 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.83 [0.59, 1.15] |
| 17 Severe respiratory distress syndrome Show forest plot | 1 | 39 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.27 [0.33, 4.93] |
| 18 Ventilated for respiratory distress syndrome Show forest plot | 3 | 121 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.91 [0.65, 1.28] |
| 19 Surfactant treatment Show forest plot | 2 | 85 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.78 [0.34, 1.79] |
| 21 Oxygen supplementation at 28 days Show forest plot | 1 | 36 | Risk Ratio (M‐H, Fixed, 95% CI) | 6.3 [0.35, 113.81] |
| 22 Oxygen supplementation at 36 weeks Show forest plot | 2 | 65 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.97 [0.35, 2.69] |
| 23 Necrotizing enterocolitis Show forest plot | 2 | 72 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.08 [0.52, 8.37] |
| 24 Cord pH Show forest plot | 3 | 123 | Mean Difference (IV, Fixed, 95% CI) | 0.01 [‐0.03, 0.05] |
| 25 Apgar score at 5th minute < 8 Show forest plot | 3 | 161 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.17 [0.62, 2.20] |
| 26 Temperature on admission (degrees Celsius) Show forest plot | 1 | 39 | Mean Difference (IV, Fixed, 95% CI) | ‐0.20 [‐0.43, 0.03] |
