Effect of timing of umbilical cord clamping of term infants on maternal and neonatal outcomes

  • Review
  • Intervention

Authors

  • Susan J McDonald,

    Corresponding author
    1. La Trobe University/Mercy Hospital for Women, Midwifery Professorial Unit, Heidelberg, Victoria, Australia
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  • Philippa Middleton

    1. The University of Adelaide, ARCH: Australian Research Centre for Health of Women and Babies, Discipline of Obstetrics and Gynaecology, Adelaide, South Australia, Australia
    Search for more papers by this author

Abstract

Background

Policies for timing of cord clamping vary, with early cord clamping generally carried out in the first 60 seconds after birth, whereas later cord clamping usually involves clamping the umbilical cord greater than one minute after the birth or when cord pulsation has ceased.

Objectives

To determine the effects of different policies of timing of cord clamping at delivery of the placenta on maternal and neonatal outcomes.

Search methods

We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (December 2007).

Selection criteria

Randomised controlled trials comparing early and late cord clamping.

Data collection and analysis

Two review authors independently assessed trial eligibility and quality and extracted data.

Main results

We included 11 trials of 2989 mothers and their babies. No significant differences between early and late cord clamping were seen for postpartum haemorrhage or severe postpartum haemorrhage in any of the five trials (2236 women) which measured this outcome (relative risk (RR) for postpartum haemorrhage 500 mls or more 1.22, 95% confidence interval (CI) 0.96 to 1.55). For neonatal outcomes, our review showed both benefits and harms for late cord clamping. Following birth, there was a significant increase in infants needing phototherapy for jaundice (RR 0.59, 95% CI 0.38 to 0.92; five trials of 1762 infants) in the late compared with early clamping group. This was accompanied by significant increases in newborn haemoglobin levels in the late cord clamping group compared with early cord clamping (weighted mean difference 2.17 g/dL; 95% CI 0.28 to 4.06; three trials of 671 infants), although this effect did not persist past six months. Infant ferritin levels remained higher in the late clamping group than the early clamping group at six months.

Authors' conclusions

One definition of active management includes directions to administer an uterotonic with birth of the anterior shoulder of the baby and to clamp the umbilical cord within 30-60 seconds of birth of the baby (which is not always feasible in practice). In this review delaying clamping of the cord for at least two to three minutes seems not to increase the risk of postpartum haemorrhage. In addition, late cord clamping can be advantageous for the infant by improving iron status which may be of clinical value particularly in infants where access to good nutrition is poor, although delaying clamping increases the risk of jaundice requiring phototherapy.

Résumé

Effet sur les résultats maternels et néonatals du moment du clampage du cordon ombilical chez les nouveau-nés à terme

Contexte

Les politiques concernant le moment du clampage du cordon ombilical varient, le clampage précoce étant généralement effectué dans les 60 premières secondes après la naissance, alors qu’un clampage plus tardif est généralement pratiqué plus d'une minute après la naissance ou lorsque les pulsations du cordon ont cessé.

Objectifs

Déterminer les effets des différentes politiques relatives au moment du clampage et section du cordon lors de la délivrance du placenta sur les résultats maternels et néonatals.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans le registre des essais cliniques du groupe Cochrane sur la grossesse et la naissance (décembre 2007).

Critères de sélection

Essais comparatifs randomisés comparant le clampage précoce et le clampage tardif du cordon ombilical.

Recueil et analyse des données

Deux auteurs ont évalué, de manière indépendante, si les essais remplissaient les critères d’inclusion et de qualité et ont extrait les données.

Résultats Principaux

Nous avons inclus 11 essais portant sur 2 989 mères et leurs bébés. Aucune différence significative entre le clampage précoce et le clampage tardif du cordon ombilical n’a été observée en ce qui concerne les hémorragies post-partum ou les hémorragies sévères post-partum dans aucun des cinq essais (2 236 femmes) ayant évalué ces résultats (Risque relatif (RR) pour les hémorragies post-partum supérieures ou égales à 500 ml = 1,22, intervalle confiance (IC) à 95 % 0,96 à 1,55). Pour les résultats néonatals, notre revue a mis en évidence à la fois des effets bénéfiques et des effets nocifs associés au clampage tardif du cordon ombilical. Après la naissance, une augmentation significative du nombre de nouveau-nés nécessitant une photothérapie pour ictère (RR = 0,59, IC à 95 % 0,38 à 0,92; cinq essais portant sur 1 762 nouveau-nés) a été observée dans le groupe du clampage tardif comparativement au groupe du clampage précoce. Cela s’est accompagnée d'une augmentation significative du taux d'hémoglobine des nouveau-nés dans le groupe du clampage tardif comparativement au groupe du clampage précoce (différence moyenne pondérée = 2,17 g/dl, IC à 95 % 0,28 à 4,06 ; trois essais portant sur 671 nouveau-nés), bien que cet effet n'ait pas persisté après six mois. Le taux de ferritine chez les nouveau-nés restait plus élevé à six mois dans le groupe du clampage tardif que dans le groupe du clampage précoce.

Conclusions des auteurs

Une définition de la prise en charge active prévoit l’administration d’un utérotonique, une fois dégagée l’épaule antérieure du nouveau-né et le clampage du cordon ombilical dans les 30 à 60 secondes suivant la naissance (ce qui n'est pas toujours réalisable dans la pratique). Dans cette revue, le fait de retarder le clampage du cordon ombilical pendant au moins deux à trois minutes ne semble pas augmenter le risque d'hémorragie post-partum. En outre, bien que le clampage tardif du cordon soit associé à une augmentation du risque d'ictère nécessitant une photothérapie, il peut s'avérer bénéfique pour le nouveau-né en améliorant son statut en fer, ce qui pourrait être cliniquement important en particulier pour les nouveau-nés des milieux défavorisés ayant difficilement accès à une nutrition de bonne qualité.

Plain language summary

Effect of timing of umbilical cord clamping at birth of term infants on mother and baby outcomes

At the time of birth, the infant is still attached to the mother via the umbilical cord, which is part of the placenta. The infant is usually separated from the placenta by clamping the cord. The timing of this clamping is one part of the third stage of labour (the time from birth until delivery of the placenta) which can vary according to clinical policy and practice. Early cord clamping is believed to lead to a reduced risk of bleeding after birth (postpartum haemorrhage). This review of 11 trials showed no significant difference in postpartum haemorrhage rates when early and late cord clamping were compared. For neonatal outcomes it is important to weigh the growing evidence that delayed cord clamping confers improved iron status in infants up to six months after birth, with a possible additional risk of jaundice that requires phototherapy.

Résumé simplifié

Effet sur les résultats maternels et néonatals du moment du clampage du cordon ombilical chez les nouveau-nés à terme

Effet sur les résultats maternels et néonatals du moment du clampage du cordon ombilical chez les nouveau-nés à terme

Au moment de la naissance, le nourrisson est encore relié à sa mère par le cordon ombilical, qui fait partie du placenta. Le nouveau-né est généralement séparé du placenta par clampage et section du cordon ombilical. Le moment de ce clampage est une partie de la délivrance (temps entre la naissance et l'expulsion du placenta) qui peut varier en fonction de la politique et de la pratique clinique. Le clampage précoce du cordon ombilical est censé entraîner une réduction du risque de saignements après l'accouchement (hémorragie post-partum). Cette revue de 11 essais n'a montré aucune différence significative en ce qui concerne le taux d'hémorragies post-partum lors de comparaisons entre clampage précoce et clampage tardif. Pour les résultats néonatals, il est important de soupeser les preuves croissantes selon lesquelles le clampage tardif du cordon ombilical améliore le statut en fer du nourrisson jusqu'à six mois après la naissance, avec un risque potentiel supplémentaire d’ictère nécessitant une photothérapie.

Notes de traduction

Traduit par: French Cochrane Centre 12th November, 2012
Traduction financée par: Ministère du Travail, de l'Emploi et de la Santé Français

Background

At the time of birth, the infant is still attached to the mother via the umbilical cord, which is part of the placenta. The infant is usually separated from the placenta by putting the umbilical cord between two clamps. One clamp is placed close to the infant's navel and the second is placed further along the umbilical cord; then the cord is cut between the two clamps. This takes place during the third stage of labour, which is that period of time from birth of the infant until delivery of the placenta.

Active management and expectant management of the third stage of labour
There are two contrasting approaches to managing the third stage of labour: active management and expectant or physiological management. A comparison of these approaches is the subject of a separate Cochrane review (Prendiville 2000).

Expectant management is a non-interventionist approach, which involves waiting for signs of placental separation and allowing the placenta to deliver spontaneously or aided by gravity, maternal effort or nipple stimulation. This strategy is popular in some northern European countries, in some units in the United States and Canada and in some low-income countries (McDonald 1996), although active management is becoming more common in lower income countries. Active management usually involves the clinician intervening in the process through three interrelated processes: the administration of a prophylactic uterotonic drug; cord clamping and cutting; and controlled traction of the umbilical cord. An injection of an uterotonic drug, an agent that stimulates the uterus to contract, is given as a precautionary measure, aimed at reduction in the risk of postpartum haemorrhage. This injection is usually given to the mother at about the same time as the infant's shoulders are born. There are several different types of uterotonic drugs that may be given and the relative advantages and disadvantages of these different drugs are the subject of separate reviews (see Cotter 2001 (oxytocin); Gülmezoglu 2007 (prostaglandins and misoprostol); McDonald 2004 (ergometrine-oxytocin and oxytocin)). In an active management strategy the umbilical cord is usually clamped shortly following birth of the infant, although there can be substantial variation in the application of policies for active management.

Active management is widely practised in high-income countries, although relative timing of each individual component of the strategy varies. Most maternity units in Australia and the United Kingdom administer the uterotonic prior to placental delivery, whereas some units in the United States (Brucker 2001) and Canada (Baskett 1992) advocate withholding uterotonic administration until after the placenta is delivered. A recent survey of active management policies in Europe showed considerable differences, including the timing of cord clamping, with eight countries clamping the cord immediately in 66% to 90% of units, and five countries mostly waiting until the cord stopped pulsating (Winter 2007).

A major reason for practising active management is its association with reduced risk of postpartum haemorrhage (PPH), the major complication of the third stage of labour (Prendiville 2000). The usual definition of PPH is that given by the World Health Organization (WHO): blood loss of equal to or more than 500 mls from the genital tract during the first 24 hours postpartum (WHO 1990; WHO 2000). Stricter definitions of 600 ml (Beischer 1986) and 1000 ml (Burchell 1980) have been suggested although the assessment of blood loss is often significantly underestimated and is based on a clinical estimation of blood loss (Kwast 1991; WHO 1998a). The 500 ml limit is intended to be a warning and blood loss up to 1000 ml in healthy women may still be considered physiological, not necessitating treatment other than uterotonics. In low-income countries, where the prevalence of severe anaemia is high, a 500 ml blood loss can be life threatening for many women (WHO 1996). PPH is the most common fatal complication of pregnancy and childbirth in the world (UNICEF 2002; WHO 2007) and is a major contributor to the conservatively estimated 500,000 maternal deaths occurring throughout the world annually (Adamson 1996; UNICEF 2002; WHO 1990; WHO 2005). Whilst the majority of maternal deaths (99%) occur in low-income countries (WHO 2002), the risk of PPH haemorrhage should not be underestimated for any birth (McDonald 2003). Effects on maternal morbidity are less well documented, but are likely to include interrelated outcomes such as anaemia and fatigue (Patterson 1994). Complications that can arise from major blood loss include shock, the widespread formation of blood clots in the microcirculation, renal failure, liver failure and adult respiratory distress syndrome (Bonnar 2000).

Although active management leads to reduced risk of PPH, it is important to establish which components of the strategy lead to this reduced risk. It can be difficult to adhere to an active management strategy. For instance, in one definition of the strategy, the uterotonic drug is given at the time of the birth of the anterior shoulder of the infant, whereas it is often given after birth of the infant. This may be due to the number of staff available in the room at the time of birth and unexpected occurrences such as malpresentation (for example, a breech presentation) or shoulder dystocia (difficulty in delivering the infant's shoulders, McDonald 1996). Furthermore, some women have preferences for expectant management (McDonald 2003). Thus, it is important to examine the relative importance of each component of an active management strategy.

Early cord clamping as part of active management
In an active management strategy the umbilical cord is usually clamped shortly following birth of the infant. This is generally carried out in the first 30 seconds after birth, regardless of whether the cord pulsation has ceased (McDonald 2003). The infant may be placed on the mother's abdomen, put to the breast or be more closely examined on a warmed cot if resuscitation is required. Once the placenta is felt to have separated from the wall of the uterus, downward traction may be applied to the remaining length of the umbilical cord to assist delivery of the placenta. Controlled cord traction is believed to reduce blood loss, shorten the third stage of labour and therefore minimise the time during which the mother is at risk from haemorrhage (McDonald 2003).

Arguments against early cord clamping include the reduction in the amount of placental transfusion and thus forgo any associated benefits of extra blood volume. Early cord clamping may increase the likelihood of feto-maternal transfusion (the amount of blood that is forced back across the placental barrier into the maternal circulation), as a larger volume of blood remains in the placenta. This would have been considered a potential issue prior to the introduction of Rh D immunoglobulin prophylaxis, since early clamping of the cord was considered to increase the risk. However, little work appears to have been undertaken since findings from small non-randomised studies (Lapido 1972) suggested there may be a reduction in feto-maternal transfusion if cord clamping was delayed (Smith 2006). Early clamping has also been associated with some higher risks for the pre-term infant. This topic is the subject of a Cochrane systematic review (Rabe 2004), which is currently being updated, and a non-Cochrane systematic review (Rabe 2008).

Delayed cord clamping
Late cord clamping, or delayed clamping, a physiological approach, involves clamping the umbilical cord when cord pulsation has ceased. However, definitions of what constitutes early and late cord clamping vary (Prendiville 1989). If the cord is not clamped, the umbilical circulation usually ceases when the umbilical arteries close and the cord stops pulsating.

Delaying clamping allows time for a transfer of the fetal blood in the placenta to the infant at the time of birth. This placental transfusion can provide the infant with an additional 30% more blood volume and up to 60% more red blood cells (McDonald 2003; Mercer 2001; Mercer 2006). The amount of blood returned to the infant depends on when the cord is clamped and at what level the infant is held (above or below the mother's abdomen) prior to clamping (Yao 1974).

The suggested neonatal benefits associated with this increased placental transfusion include higher haemoglobin levels (Prendiville 1989), additional iron stores and less anaemia later in infancy (Chaparro 2006; WHO 1998b), higher red blood cell flow to vital organs, better cardiopulmonary adaptation, and increased duration of early breastfeeding (Mercer 2001; Mercer 2006). There is growing evidence that delaying cord clamping confers improved iron status in infants up to six months post birth (Chaparro 2006; Mercer 2006; van Rheenen 2004).

Delayed cord clamping has been linked to an increase in the incidence of jaundice (Prendiville 1989) which, in severe cases, could have longer term effects on the health and development of the infant. In addition, early cord clamping has been associated with a reduction in the length of the third stage of labour. One of the aims of active management is to reduce the length of the third stage because the longer the placenta remains undelivered, the greater is the likelihood of maternal bleeding (Inch 1985). A delay in time before clamping the umbilical cord in healthy term infants appears be less crucial as the cord ceases pulsation within the first two minutes of birth in the majority of cases (McDonald 2003).

Rationale for this review

The World Health Organization has recently updated its guidelines on preventing postpartum haemorrhage (WHO 2007) and the International Confederation of Midwives and the International Federation of Gynaecology and Obstetrics also updated its statement on postpartum haemorrhage in 2006 (ICM/FIGO 2006). While both statements refer to benefits of delaying cord clamping, evidence has still been unclear as to whether one timing of cord clamping policy is preferable to another. This review seeks to explore this issue further. Since evidence suggests that the effects of early versus late cord clamping may differ in pre-term and term infants, these are the subjects of separate reviews (see Rabe 2004 (Cochrane review); Rabe 2008 (non-Cochrane systematic review) for reviews of delayed cord clamping in pre-term infants). This review will concentrate on the effect of early versus late cord clamping on maternal and neonatal outcomes.

Objectives

The objective of this review was to determine the maternal and neonatal effects of different policies for the timing of cord clamping in the third stage of labour.

Methods

Criteria for considering studies for this review

Types of studies

We considered all randomised comparisons of different strategies for the timing of umbilical cord clamping of term infants during the third stage of labour for inclusion. We excluded quasi-randomised studies.

Types of participants

Women who:

  1. have given birth to a term infant (equal to or greater than 37 completed weeks' gestation); and

  2. have been involved in a birth where clamping of the umbilical cord is applied.

Exclusions:

  1. Women who have given birth to a pre-term infant (less than 37 weeks' gestation; as these are the subject of separate reviews, see Rabe 2004 (Cochrane review); Rabe 2008 (non-Cochrane systematic review).

  2. Breech presentation.

  3. Multiple pregnancies.

Exclusions 2 and 3 were due to the lack of control over the timing of cord clamping in these conditions.

Types of interventions

  1. Early cord clamping, defined as application of a clamp to the umbilical cord within 60 seconds of the birth of the infant.

  2. Later (delayed) cord clamping, defined as application of a clamp to the umbilical cord greater than one minute after birth or when cord pulsation has ceased.

Types of outcome measures

The outcome measures chosen in this review were based on those factors that were likely to be seen as clinically relevant in terms of an outcome changing clinical practice, as well as what factors would be most likely to advantage or disadvantage a woman's recovery from childbirth and the wellbeing of her infant.

Maternal outcomes
  1. Postpartum haemorrhage (PPH, clinically estimated blood loss of 500 mls to 999 mls)

  2. Severe PPH (blood loss of 1000 mls or greater)

  3. Mean blood loss (ml)

  4. Maternal haemoglobin concentration (after birth and longer term)

  5. Maternal ferritin levels (after birth and longer term)

  6. Need for blood transfusion

  7. Need for manual removal of the placenta

  8. Length of the third stage of labour

  9. Need for therapeutic uterotonics

Neonatal and infant outcomes
  1. Apgar score less than seven at five minutes

  2. Admission to special care nursery (SCN) or neonatal intensive care unit (NICU)

  3. Respiratory distress

  4. Jaundice requiring phototherapy

  5. Clinical jaundice

  6. Polycythaemia (haematocrit greater than 65%)

  7. Infant haemoglobin levels (at birth and longer term)

  8. Infant ferritin levels (at birth and longer term)

  9. Exclusive breastfeeding

Cord measures

Cord haemoglobin levels

In future versions of this review, we will seek for and include mortality for the baby and longer term outcomes such as neonatal and child neurodevelopment.

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 (December 2007). 

The Cochrane Pregnancy and Childbirth Group’s Trials Register is maintained by the Trials Search Co-ordinator and contains trials identified from:

  1. quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);

  2. weekly searches of MEDLINE;

  3. handsearches of 30 journals and the proceedings of major conferences;

  4. 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 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.

We did not apply any language restrictions.

Data collection and analysis

Selection of studies

At least two review authors independently assessed the full text of potential studies for the appropriateness of inclusion and methodological quality.

Data extraction and management

Review authors performed data extraction separately and double checked data for discrepancies. Careful assessment and data extraction of the McDonald 1996 trial was made independently by three people not involved with this trial (J Abbott, S Higgins and P Middleton). We undertook thorough discussions between review authors (S McDonald and P Middleton) about the appropriateness of all other studies for inclusion. We contacted individual investigators if we required clarification before deciding if a trial met the inclusion criteria.

Assessment of methodological quality of included studies

We assessed the validity of each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2006). Methods used for generation of the randomisation sequence were described for each trial.

1. Selection bias (randomisation and allocation concealment)

We assessed selection bias as follows:
A. adequate concealment of allocation: such as telephone randomisation, consecutively numbered, sealed opaque envelopes;
B. unclear whether adequate concealment of allocation: such as list or table used, sealed envelopes, or study does not report any concealment approach.

We excluded quasi-randomised trials.

2. Attrition bias (loss of participants, for example, withdrawals, dropouts, protocol deviations)

We assessed completeness to follow up by describing loss of participants and recording reasons for losses where available.

3. Performance bias (blinding of participants, researchers and outcome assessment)

We assessed blinding using the following criteria:
A. blinding of participants (yes/no/unclear);
B. blinding of caregiver (yes/no/unclear);
C. blinding of outcome assessment (yes/no/unclear).

Measures of treatment effect

We carried out statistical analysis using the Review Manager software (RevMan 2003). We used fixed-effect analysis for combining data in the absence of significant heterogeneity and when trials were sufficiently similar. If heterogeneity was found this was explored by sensitivity analysis followed by random effects analysis if required.

Dichotomous data

For dichotomous data, we used relative risks with 95% confidence intervals.

Continuous data

For continuous data, we used the weighted mean difference with 95% confidence intervals.

Dealing with missing data

We analysed data on all participants with available data in the group to which they were allocated, regardless of whether or not they received the allocated intervention. If in the original reports participants were not analysed in the group to which they were randomised, and there was sufficient information in the trial report, we attempted to restore them to the correct group.

Assessment of heterogeneity

We used the I2 statistic to test for statistical heterogeneity. We explored high levels of heterogeneity among the trials (exceeding 50%).

Subgroup analyses

It was stated in the protocol for this review that subgroup analyses would be considered on the basis of:
1. whether uterotonics (oxytocic drugs used to stimulate the uterus to contract) were used as part of the third stage management;
2. whether the infant was held above or below the abdomen prior to cord clamping;
3. the extent of control for selection bias.

The uterotonic subgroup was presented as part of the analysis structure.

There was insufficient information or variation to present subgroup analyses by placement of infant (however this was noted in the 'Characteristics of included studies' table) or selection bias.

Results

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of ongoing studies.

Participants

Participants generally were healthy pregnant women expected to give birth vaginally. However, in Gupta 2002, the women were anaemic and the van Rheenen 2007 trial was conducted in a malaria-endemic area. Cernadas 2006 included some women who gave birth by caesarean section.

Settings

Studies were conducted in Argentina, Australia, Canada, India (two studies), Libya, Mexico, UK, USA (two studies) and Zambia.

Interventions

Timing of cord clamping

While the timing of early clamping was relatively consistent between studies at less than one minute (mostly within 15 seconds of birth), the timing of late clamping was quite variable:

The one-minute and three-minute arms of Cernadas 2006 were combined to give data for late cord clamping; as were the one-minute and five-minute arms in Saigal 1972.

Use and timing of uterotonic

McDonald 1996 used a factorial design with four arms, randomising not only by early and late cord clamping but also by whether uterotonics were administered early or late. Early uterotonic administration involved administration at the time of birth of the anterior shoulder of the baby; late uterotonic administration was after the birth of the baby (literally) and if the cord clamping allocation was early, then it was allocated to be after the cord was clamped (i.e., not within 30 seconds). The uterotonic used was intramuscular oxytocin 10 IU.

van Rheenen 2007 also used intramuscular oxytocin, but this was administered after clamping of the cord and no dosage was recorded.

In the Oxford Midwives 1991 trial, uterotonic was given at the time of birth of the anterior shoulder of baby in both arms; in Emhamed 2004 it was given when the cord was clamped and in Saigal 1972 it was given after the cord was clamped.

The remaining six trials did not specify either use or timing of any uterotonic (Cernadas 2006; Chaparro 2006; Geethanath 1997; Gupta 2002; Nelson 1980; Spears 1966)

See table of 'Characteristics of included studies' for further details of the included trials.

Studies which involved pre-term infants were excluded since this review focuses on term infants (see Rabe 2004 (Cochrane review); Rabe 2008 (non-Cochrane systematic review) for reviews focusing on pre-term infants).

Risk of bias in included studies

Allocation concealment

Five trials (Cernadas 2006; Chaparro 2006; McDonald 1996; Oxford Midwives 1991; van Rheenen 2007) all had adequate allocation concealment in the form of sequentially numbered sealed opaque envelopes. The remaining trials had unclear allocation concealment - opaque envelope systems (Emhamed 2004; Geethanath 1997; Gupta 2002) - and not specified (Nelson 1980; Saigal 1972; Spears 1966).

Blinding

The nature of the intervention precluded blinding of women and caregivers. However at least some form of blinding of outcome assessment was reported in three trials (Cernadas 2006; McDonald 1996; van Rheenen 2007).

Losses to follow up

Losses to follow up were generally low (when reported). Chaparro 2006 had 29% of participants lost to follow-up at six months and van Rheenen 2007 had lost about 33% of participants (including post-randomisation exclusions) by six months.

Effects of interventions

We included 11 trials involving a total of 2989 women and infant pairs.

Results are presented by whether uterotonics were given before or after cord clamping, or whether it was not stated whether a uterotonic was used.

Maternal outcomes

Postpartum haemorrhage ≥ 500 mls

(four trials - Cernadas 2006; McDonald 1996; Oxford Midwives 1991; van Rheenen 2007: 1878 women)

The timing of cord clamping was not shown to be of any statistical significance with regard to postpartum haemorrhage of 500 mls or more (RR 1.22, 95% CI 0.96 to 1.55).

Severe postpartum haemorrhage ≥ 1000 mls

(four trials - Cernadas 2006; Chaparro 2006; McDonald 1996; van Rheenen 2007: 1684 women)

No significant differences between early and late cord clamping groups were seen for the outcome of severe postpartum haemorrhage (RR 0.84, 95% CI 0.48 to 1.49).

Mean blood loss

No significant differences in mean blood loss between early and late cord clamping were seen in McDonald 1996 (weighted mean difference (WMD) 6.36 mls; 95% confidence interval (CI) -34.94 to 47.66; 963 women).

Maternal postpartum haemoglobin

(three trials - Geethanath 1997; Gupta 2002; McDonald 1996: 1128 women)

Maternal haemoglobin values were similar between the early and late cord clamping groups (WMD -0.12 g/dL; 95% CI -0.30 to 0.06) at 24 to 72 hours after birth.

Need for blood transfusion

In McDonald 1996, there were no statistically significant differences in need for blood transfusion between the early and late cord clamping groups (RR 0.79, 95% CI 0.20 to 3.15; 963 women).

Need for manual removal of placenta

(two trials - McDonald 1996; Oxford Midwives 1991: 1515 women)

No clear difference was seen between the early and late cord clamping groups for manual removal of placenta (RR 1.59, 95% CI 0.78 to 3.26).

Length of third stage of labour

In McDonald 1996, neither instances of third stage greater than 30, nor 60 minutes, were significantly different between the early and late cord clamping groups (963 women).

Therapeutic uterotonics

McDonald 1996 showed no significant differences in need for therapeutic administration of uterotonics between the early and late cord clamping groups (RR 0.94, 95% CI 0.74 to 1.20; 963 women).

Maternal ferritin levels at birth

In Geethanath 1997, maternal ferritin levels at birth were significantly higher in the early clamping group than the late clamping group (WMD 9.10 ug/L; 95% CI 7.86 to 10.34; 107 women).

Neonatal outcomes

Apgar score

Apgar score less than seven at five minutes did not show significant differences between the early and late cord clamping groups in McDonald 1996 and Spears 1966 (RR 1.23, 95% CI 0.73 to 2.07; 1342 neonates).

Admission to special care baby nursery (SCN) or neonatal intensive care unit (NICU)

(three trials - Cernadas 2006; McDonald 1996; Nelson 1980: 1293 infants)

None of the early versus late cord clamping comparisons showed statistically significant differences for SCN or NICU admission (RR 1.03, 95% CI 0.56 to 1.90).

Respiratory distress

(four trials - McDonald 1996; Nelson 1980; Saigal 1972; Spears 1966: 1387 infants)

The number of infants admitted to any level of NICU (1, 2 or 3) for respiratory distress was similar between the early and late cord clamping groups (RR 1.01, 95% CI 0.18 to 5.75; 3 trials of 1008 infants).

In Spears 1966 similar numbers of infants showed signs of respiratory distress (RR 1.11, 95% CI 0.65 to 1.89; 379 infants).

Jaundice requiring phototherapy

(five trials - Emhamed 2004; McDonald 1996; Nelson 1980; Oxford Midwives 1991; van Rheenen 2007: 1762 infants)

Significantly fewer infants in the early cord clamping group required phototherapy for jaundice than in the late cord clamping group (RR 0.59, 95% CI 0.38 to 0.92). This equates to 3% of infants in the early clamping group and 5% in the late clamping group, a risk difference of 2% (95% CI -0.04 to 0.00).

Clinical jaundice

(five trials - Cernadas 2006; Emhamed 2004; McDonald 1996; Nelson 1980; Oxford Midwives 1991: 1828 infants)

The difference between early and late cord clamping for clinical jaundice did not reach statistical significance (RR 0.84, 95% CI 0.66 to 1.07).

Polycythaemia

(three trials - Cernadas 2006; Emhamed 2004; van Rheenen 2007: 463 infants)

No difference between the early and late cord clamping groups was detected for polycythaemia (RR 0.39, 95% CI 0.12 to 1.27).

Cord haemoglobin (g/dL)

(four trials - Emhamed 2004; Geethanath 1997; Gupta 2002: Saigal 1972: 314 infants)

The early cord clamping group showed higher levels of cord haemoglobin than did the late clamping group (WMD 0.42 g/dL; 95% CI 0.03 to 0.80).

Newborn haemoglobin (g/dL)

(three trials - Cernadas 2006; Chaparro 2006; Saigal 1972: 671 infants)

There were significantly lower infant haemoglobin levels at birth in the early clamping group compared with the late clamping group (WMD -2.17; 95% CI -4.06 to -0.28; random effects model). This outcome showed very high heterogeneity between trials (I2 96.5%).

Infant haemoglobin (g/dL)
  • at 24-48 hours

In Emhamed 2004 and Cernadas 2006, the early cord clamping groups showed significantly lower infant haemoglobin levels 24 hours after birth than the late clamping groups (WMD -1.34 g/dL; 95% CI -1.88 to -0.88; 382 infants).

  • 2 to 4 months

(three trials - Geethanath 1997; Gupta 2002; van Rheenen 2007: 256 infants)

While one trial (Gupta 2002) reported a significantly favourable effect on infant haemoglobin from late cord clamping, no difference between early and late clamping was seen for all three trials combined (WMD -0.30 g/dL; 95% CI -1.25 to 0.65). This discrepancy manifested as extremely high statistical heterogeneity (I2 = 88%).

  • at four months (haemoglobin > 2 SDs below 10.3 g/dL)

In van Rheenen 2007, infant anaemia at four months did not reach a statistically significant difference between early and late clamping (RR 1.84, 95% CI 0.96 to 3.54; 91 infants).

  • six months

(two trials - Chaparro 2006; van Rheenen 2007: 447 infants)

No difference in infant haemoglobin at six months between early and late clamping (WMD 0.03 g/dL; 95% CI -0.17 to 0.23) was seen. Nor was a significant difference seen when measured by haemoglobin < 11.7 g/dL (Chaparro 2006) or haemoglobin > 2 SDs below 10.5 g/dL (van Rheenen 2007).

Haematocrit
  • at six hours (haematocrit < 45%)

When measured as a haematocrit threshold greater than 45%, fewer infants in the late clamping group had anaemia compared with the early clamping group (RR 16.18, 95% CI 2.05 to 127.37; Cernadas 2006; 272 infants).

  • at 24 to 48 hours (haematocrit < 45%)

This difference in favour of late clamping persisted at 24 to 48 hours (RR 6.03, 95% CI 2.27 to 16.07; Cernadas 2006; 268 infants).

Infant ferritin
  • at three months (ug/L)

In one trial of 107 infants (Geethanath 1997), infant ferritin levels were significantly higher in the late clamping group compared with early clamping (WMD 17.90 ug/L; 95% CI 16.59 to 19.21) at three months.

  • at six months (ug/L)

Ferritin levels were significantly higher in the late clamping group compared with early clamping (WMD 11.80 ug/L; 95% CI 4.07 to 19.53; Chaparro 2006; 315 infants).

Breastfeeding

No differences in the rate of exclusive breastfeeding between early and late clamping groups were seen for any time period except for one month postpartum:

Discussion

Recent reviews such as Hutton 2007 and van Rheenen 2006 have highlighted beneficial effects from delayed cord clamping compared with early cord clamping, but these reviews did not encompass maternal outcomes (which have been rarely measured in trials of the timing of cord clamping) and only a few of the studies included in this review reported on maternal wellbeing. Women experiencing ill health postpartum may be less able to mother as effectively which ultimately reflects on the health and wellbeing of the newborn infant and family life in general.

The ability of the review to reach conclusive findings and sufficient evidence to guide future practice was limited by differences in variables such as the lengths of timing for both early and late cord clamping, as well as the inconsistent coverage of outcomes between trials. In addition, the use of prophylactic uterotonics was not always well described in the trials.

In this review of nearly 3,000 women and their babies, no differences were seen for PPH or any other maternal outcome (except for maternal ferritin at birth in one trial). However the risk of postpartum haemorrhage may be higher with late administration of uterotonics (Cotter 2001; Oh 2007).

For neonatal outcomes, our review showed both benefits and harms for late cord clamping. There was a significant increase in infants needing phototherapy for jaundice with late cord clamping. This was accompanied by significant increases in haemoglobin levels which were higher with late cord clamping just after birth, although this favourable effect did not persist till six months. Ferritin levels remained higher in the late clamping groups than the early clamping groups at six months. Ferritin levels less than 50 ug/L for infants aged three months are regarded as indicative of deficient iron stores (Hutton 2007) and so the results of the Chaparro 2006 trial are likely to be clinically important (with the late clamping group almost reaching this threshold at six months). This trial also noted that late clamping demonstrated significantly greater effects in the subgroup of women with low ferritin levels at birth; and they also found, in a subgroup of women with high lead levels, that early cord clamping can contribute to higher blood lead concentrations through a decrease in iron status.

The benefits and harms seen for delayed cord clamping are compatible with the same mechanism of an increased amount of red blood cells for the infant. Additional red blood cells can improve the infant's iron stores, but it also has the potential to overload the newborn's metabolism, leading to increased levels of bilirubin and in very severe cases, severe jaundice and later kernicterus (AAP 2004). The potential for harm would need to be weighed up by clinicians in context with the settings in which they work. For instance, if treatment for moderate to severe jaundice was not easily accessible and there was a risk of causing further complications for the infant, late cord clamping may be less optimal. On the other hand, increasing iron stores in infants through delayed cord clamping may be particularly beneficial in resource-poor settings where severe anaemia is common (McDonald 2007).

If late cord clamping in term infants can lead to improved iron stores in infants, it may have long-term benefits but this needs to be confirmed in long-term follow-up studies. In addition, more conclusive answers are needed regarding postpartum haemorrhage and other measures of maternal wellbeing, as well as potential adverse effects on infants such as jaundice requiring phototherapy. WHO has recently recommended that "the cord should not be clamped earlier than is necessary" and notes that this would normally take around three minutes. They have graded this recommendation as "weak recommendation, low quality evidence" (WHO 2007). Although this review contains some additional data not considered by WHO 2007, this cautious recommendation appears to be appropriate.

Authors' conclusions

Implications for practice

A more liberal approach to delaying clamping of the umbilical cord in healthy term infants appears to be warranted, particularly in light of growing evidence that delayed cord clamping may be of benefit in the longer term in promoting better iron stores in infants, as long as access to treatment for jaundice requiring phototherapy is easily accessible.

Implications for research

Future studies should include adequate power and rigour to be able to detect the true advantages and disadvantages of cord clamping on outcomes. Future studies should compare maternal outcomes such as PPH, longer term (6-12 months) postpartum follow-up on iron status, physical and psychological health, as well as short and longer term neonatal and infant outcomes such as neurodevelopment.

Acknowledgements

Dr Chad Andersen, Consultant Neonatologist in the Department of Perinatal Medicine at the Children's Youth and Women's Health Service in Adelaide, Australia, who provided valuable feedback and comments on several versions of the review.

We wish to thank the Cochrane Pregnancy and Childbirth Review Group, particularly Sonja Henderson, Lynn Hampson and the Consumer Panel. We also wish to thank Jo Abbott and Shane Higgins who helped to write the protocol and carried out some of the data extraction for the review.

Data and analyses

Download statistical data

Comparison 1. Early versus late cord clamping
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 PPH/blood loss 500 ml or more41878Risk Ratio (M-H, Fixed, 95% CI)1.22 [0.96, 1.55]
1.1 uterotonic before clamping21032Risk Ratio (M-H, Fixed, 95% CI)1.11 [0.74, 1.67]
1.2 uterotonic at, or after, clamping2574Risk Ratio (M-H, Fixed, 95% CI)1.42 [0.95, 2.14]
1.3 use of uterotonic not specified1272Risk Ratio (M-H, Fixed, 95% CI)1.13 [0.73, 1.74]
2 Severe PPH/blood loss 1000 ml or more41684Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.48, 1.49]
2.1 uterotonic before clamping1480Risk Ratio (M-H, Fixed, 95% CI)1.16 [0.46, 2.96]
2.2 uterotonic at, or after, clamping2574Risk Ratio (M-H, Fixed, 95% CI)0.59 [0.22, 1.59]
2.3 use of uterotonic not specified2630Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.29, 2.49]
3 Mean blood loss (ml)1963Mean Difference (IV, Fixed, 95% CI)6.36 [-34.94, 47.66]
3.1 uterotonic before clamping1480Mean Difference (IV, Fixed, 95% CI)22.0 [-40.16, 84.16]
3.2 uterotonic at, or after, clamping1483Mean Difference (IV, Fixed, 95% CI)-6.0 [-61.25, 49.25]
4 Maternal haemoglobin (g/dL) 24 to 72 hours postpartum31128Mean Difference (IV, Fixed, 95% CI)-0.12 [-0.30, 0.06]
4.1 uterotonic before clamping1480Mean Difference (IV, Fixed, 95% CI)Not estimable
4.2 uterotonic at, or after, clamping1483Mean Difference (IV, Fixed, 95% CI)-0.10 [-0.42, 0.22]
4.3 use of uterotonic not specified2165Mean Difference (IV, Fixed, 95% CI)-0.28 [-0.60, 0.04]
5 Need for blood transfusion1963Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.20, 3.15]
5.1 uterotonic before clamping1480Risk Ratio (M-H, Fixed, 95% CI)1.55 [0.26, 9.20]
5.2 uterotonic at, or after, clamping1483Risk Ratio (M-H, Fixed, 95% CI)0.20 [0.01, 4.06]
6 Need for manual removal of placenta21515Risk Ratio (M-H, Fixed, 95% CI)1.59 [0.78, 3.26]
6.1 uterotonic before clamping21032Risk Ratio (M-H, Fixed, 95% CI)2.17 [0.94, 5.01]
6.2 uterotonic at, or after, clamping1483Risk Ratio (M-H, Fixed, 95% CI)0.49 [0.09, 2.65]
7 Length of third stage > 30 mins1963Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.29, 3.41]
7.1 uterotonic before clamping1480Risk Ratio (M-H, Fixed, 95% CI)3.10 [0.32, 29.61]
7.2 uterotonic at, or after, clamping1483Risk Ratio (M-H, Fixed, 95% CI)0.49 [0.09, 2.65]
8 Length of third stage > 60 mins1963Risk Ratio (M-H, Fixed, 95% CI)0.81 [0.32, 2.04]
8.1 uterotonic before clamping1480Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.34, 3.16]
8.2 uterotonic at, or after clamping1483Risk Ratio (M-H, Fixed, 95% CI)0.49 [0.09, 2.65]
9 Need for therapeutic uterotonics1963Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.74, 1.20]
9.1 uterotonic before clamping1480Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.78, 1.55]
9.2 uterotonic at, or after, clamping1483Risk Ratio (M-H, Fixed, 95% CI)0.81 [0.58, 1.14]
10 Maternal ferritin (ug/L)1107Mean Difference (IV, Fixed, 95% CI)9.10 [7.86, 10.34]
10.1 use of uterotonic not specified1107Mean Difference (IV, Fixed, 95% CI)9.10 [7.86, 10.34]
11 Apgar score < 7 at 5 mins21342Risk Ratio (M-H, Fixed, 95% CI)1.23 [0.73, 2.07]
11.1 uterotonic before clamping1480Risk Ratio (M-H, Fixed, 95% CI)1.72 [0.42, 7.13]
11.2 uterotonic at, or after, clamping1483Risk Ratio (M-H, Fixed, 95% CI)1.96 [0.60, 6.42]
11.3 use of uterotonic not specified1379Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.51, 1.85]
12 Admission to SCN or NICU31293Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.56, 1.90]
12.1 uterotonic before clamping1480Risk Ratio (M-H, Fixed, 95% CI)1.45 [0.47, 4.50]
12.2 uterotonic at, or after, clamping1483Risk Ratio (M-H, Fixed, 95% CI)1.57 [0.52, 4.72]
12.3 use of uterotonic not specified2330Risk Ratio (M-H, Fixed, 95% CI)0.57 [0.20, 1.60]
13 Admission for respiratory distress21008Risk Ratio (M-H, Random, 95% CI)1.01 [0.18, 5.75]
13.1 uterotonic before clamping1480Risk Ratio (M-H, Random, 95% CI)0.41 [0.08, 2.11]
13.2 uterotonic at, or after, clamping2528Risk Ratio (M-H, Random, 95% CI)2.45 [0.48, 12.50]
14 Respiratory distress1379Risk Ratio (M-H, Fixed, 95% CI)1.11 [0.65, 1.89]
14.1 use of uterotonic not specified1379Risk Ratio (M-H, Fixed, 95% CI)1.11 [0.65, 1.89]
15 Jaundice requiring phototherapy51762Risk Ratio (M-H, Fixed, 95% CI)0.59 [0.38, 0.92]
15.1 uterotonic before clamping21032Risk Ratio (M-H, Fixed, 95% CI)0.59 [0.32, 1.11]
15.2 uterotonic at, or after, clamping4730Risk Ratio (M-H, Fixed, 95% CI)0.58 [0.31, 1.11]
16 Clinical jaundice51918Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.66, 1.07]
16.1 uterotonic before clamping21022Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.62, 1.18]
16.2 uterotonic at, or after, clamping2576Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.57, 1.31]
16.3 use of uterotonic not specified2320Risk Ratio (M-H, Fixed, 95% CI)0.64 [0.29, 1.39]
17 Polycythaemia3463Risk Ratio (M-H, Fixed, 95% CI)0.39 [0.12, 1.27]
17.1 uterotonic at, or after, clamping2195Risk Ratio (M-H, Fixed, 95% CI)0.38 [0.06, 2.48]
17.2 use of uterotonic not specified1268Risk Ratio (M-H, Fixed, 95% CI)0.40 [0.09, 1.80]
18 Cord haemoglobin (g/dL)4314Mean Difference (IV, Fixed, 95% CI)0.42 [0.03, 0.80]
18.1 uterotonic at, or after, clamping2149Mean Difference (IV, Fixed, 95% CI)0.66 [0.13, 1.19]
18.2 use of uterotonic not specified2165Mean Difference (IV, Fixed, 95% CI)0.15 [-0.42, 0.71]
19 Newborn haemoglobin (g/dL)3671Mean Difference (IV, Random, 95% CI)-2.17 [-4.06, -0.28]
19.1 uterotonic at, or after, clamping145Mean Difference (IV, Random, 95% CI)-4.45 [-5.33, -3.57]
19.2 use of uterotonic not specified2626Mean Difference (IV, Random, 95% CI)-1.07 [-2.03, -0.12]
20 Infant haemoglobin at 24-48 hours (g/dL)2382Mean Difference (IV, Fixed, 95% CI)-1.34 [-1.80, -0.88]
20.1 uterotonic at, or after, clamping1104Mean Difference (IV, Fixed, 95% CI)-1.40 [-2.17, -0.63]
20.2 use of uterotonic not specified1278Mean Difference (IV, Fixed, 95% CI)-1.31 [-1.88, -0.74]
21 Infant haemoglobin at 2-4 months (g/dL)3256Mean Difference (IV, Random, 95% CI)-0.30 [-1.25, 0.65]
21.1 uterotonic at, or after, clamping191Mean Difference (IV, Random, 95% CI)-0.30 [-0.88, 0.28]
21.2 use of uterotonic not specified2165Mean Difference (IV, Random, 95% CI)-0.27 [-1.94, 1.39]
22 Infant haemoglobin at 6 months (g/dL)2447Mean Difference (IV, Fixed, 95% CI)0.03 [-0.17, 0.23]
22.1 uterotonic at, or after, clamping191Mean Difference (IV, Fixed, 95% CI)0.40 [-0.35, 1.15]
22.2 use of uterotonic not specified1356Mean Difference (IV, Fixed, 95% CI)Not estimable
23 Infant haematocrit < 45% at 6 hours1272Risk Ratio (M-H, Fixed, 95% CI)16.18 [2.05, 127.37]
23.1 use of uterotonic not specified1272Risk Ratio (M-H, Fixed, 95% CI)16.18 [2.05, 127.37]
24 Infant haematocrit < 45% at 24-48 hours1268Risk Ratio (M-H, Fixed, 95% CI)6.03 [2.27, 16.07]
24.1 use of uterotonic not specified1268Risk Ratio (M-H, Fixed, 95% CI)6.03 [2.27, 16.07]
25 Infant haemoglobin > 2 SDs below 10.3 g/dL at 4 months191Risk Ratio (M-H, Fixed, 95% CI)1.84 [0.96, 3.54]
25.1 uterotonic at, or after, clamping191Risk Ratio (M-H, Fixed, 95% CI)1.84 [0.96, 3.54]
26 Infant haemoglobin at 6 months2447Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.75, 1.48]
26.1 > 2 SD below 10.5 g/dL: uterotonic at, or after, clamping191Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.61, 1.43]
26.2 < 12.2 g/dL: use of uterotonic not specified1356Risk Ratio (M-H, Fixed, 95% CI)1.17 [0.70, 1.96]
27 Infant ferritin (ug/L)2 Mean Difference (IV, Fixed, 95% CI)Subtotals only
27.1 at 3 months: use of uterotonic not specified1107Mean Difference (IV, Fixed, 95% CI)-17.90 [-19.21, -16.59]
27.2 at 6 months: use of uterotonic not specified1315Mean Difference (IV, Fixed, 95% CI)-11.80 [-19.53, -4.07]
28 Exclusive breastfeeding5 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
28.1 at discharge: uterotonic before clamping1480Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.95, 1.08]
28.2 at discharge: uterotonic at, or after, clamping1483Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.97, 1.10]
28.3 1 month: use of uterotonic not specified1268Risk Ratio (M-H, Fixed, 95% CI)1.10 [1.00, 1.20]
28.4 2 months: use of uterotonic not specified1302Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.75, 1.28]
28.5 3 months: use of uterotonic not specified2144Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.90, 1.13]
28.6 4 months: use of uterotonic not specified1313Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.76, 1.30]
28.7 6 months: use of uterotonic not specified1358Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.73, 1.33]
Analysis 1.1.

Comparison 1 Early versus late cord clamping, Outcome 1 PPH/blood loss 500 ml or more.

Analysis 1.2.

Comparison 1 Early versus late cord clamping, Outcome 2 Severe PPH/blood loss 1000 ml or more.

Analysis 1.3.

Comparison 1 Early versus late cord clamping, Outcome 3 Mean blood loss (ml).

Analysis 1.4.

Comparison 1 Early versus late cord clamping, Outcome 4 Maternal haemoglobin (g/dL) 24 to 72 hours postpartum.

Analysis 1.5.

Comparison 1 Early versus late cord clamping, Outcome 5 Need for blood transfusion.

Analysis 1.6.

Comparison 1 Early versus late cord clamping, Outcome 6 Need for manual removal of placenta.

Analysis 1.7.

Comparison 1 Early versus late cord clamping, Outcome 7 Length of third stage > 30 mins.

Analysis 1.8.

Comparison 1 Early versus late cord clamping, Outcome 8 Length of third stage > 60 mins.

Analysis 1.9.

Comparison 1 Early versus late cord clamping, Outcome 9 Need for therapeutic uterotonics.

Analysis 1.10.

Comparison 1 Early versus late cord clamping, Outcome 10 Maternal ferritin (ug/L).

Analysis 1.11.

Comparison 1 Early versus late cord clamping, Outcome 11 Apgar score < 7 at 5 mins.

Analysis 1.12.

Comparison 1 Early versus late cord clamping, Outcome 12 Admission to SCN or NICU.

Analysis 1.13.

Comparison 1 Early versus late cord clamping, Outcome 13 Admission for respiratory distress.

Analysis 1.14.

Comparison 1 Early versus late cord clamping, Outcome 14 Respiratory distress.

Analysis 1.15.

Comparison 1 Early versus late cord clamping, Outcome 15 Jaundice requiring phototherapy.

Analysis 1.16.

Comparison 1 Early versus late cord clamping, Outcome 16 Clinical jaundice.

Analysis 1.17.

Comparison 1 Early versus late cord clamping, Outcome 17 Polycythaemia.

Analysis 1.18.

Comparison 1 Early versus late cord clamping, Outcome 18 Cord haemoglobin (g/dL).

Analysis 1.19.

Comparison 1 Early versus late cord clamping, Outcome 19 Newborn haemoglobin (g/dL).

Analysis 1.20.

Comparison 1 Early versus late cord clamping, Outcome 20 Infant haemoglobin at 24-48 hours (g/dL).

Analysis 1.21.

Comparison 1 Early versus late cord clamping, Outcome 21 Infant haemoglobin at 2-4 months (g/dL).

Analysis 1.22.

Comparison 1 Early versus late cord clamping, Outcome 22 Infant haemoglobin at 6 months (g/dL).

Analysis 1.23.

Comparison 1 Early versus late cord clamping, Outcome 23 Infant haematocrit < 45% at 6 hours.

Analysis 1.24.

Comparison 1 Early versus late cord clamping, Outcome 24 Infant haematocrit < 45% at 24-48 hours.

Analysis 1.25.

Comparison 1 Early versus late cord clamping, Outcome 25 Infant haemoglobin > 2 SDs below 10.3 g/dL at 4 months.

Analysis 1.26.

Comparison 1 Early versus late cord clamping, Outcome 26 Infant haemoglobin at 6 months.

Analysis 1.27.

Comparison 1 Early versus late cord clamping, Outcome 27 Infant ferritin (ug/L).

Analysis 1.28.

Comparison 1 Early versus late cord clamping, Outcome 28 Exclusive breastfeeding.

Feedback

Erickson-Owens and Mercer, 21 April 2008

Summary

First we would like to thank Susan J McDonald and Philippa Middleton on completion of the huge task of reviewing all of the literature on delayed cord clamping in term infants. This is a daunting task and they are to be commended.

However, we do have two serious concerns that we feel significantly weaken this Cochrane review. Our first concern is that the evidence for an increase in 'jaundice requiring phototherapy' is based upon one 12 year old unpublished trial done by the lead author of this Cochrane Review (McDonald) in Australia.  When that one trial is removed from data (offered in Analysis 1.15) the variable of 'jaundice requiring phototherapy' does not reach significance. A recent meta-analysis found in JAMA did not agree with the outcome that delayed cord clamping (DCC) leads to 'jaundice requiring phototherapy' (Hutton and Hassan, 2007). We question the emphasis given to the outcome drawn from this one study.

There are several reasons in this Cochrane Review why 'jaundice needing phototherapy' (associated with DCC) may be misleading.  First, no information is offered to tell the reader if the providers ordering the phototherapy in the McDonald trial were blinded to the infants grouping. Secondly, guidelines to treat jaundice have changed over time and no mention is given of what the guidelines were in Australia 12 years ago. How high were the bilirubin levels? What was the age of the infants at the time that phototherapy was indicated? Did any of the infants require further treatment such as exchange transfusions? What were the feeding policies at the time and how many mothers were breastfeeding and bottle feeding? What was the racial mix and was metabolic screening to rule out G6PD, galactosemia and other conditions considered? These questions suggest competing factors and other potential influences rather than DCC only on the incidence of jaundice needing phototherapy in McDonald's 12 year old unpublished controlled trial.

Our second main concern is that harm to infants from DCC is inferred but not demonstrated in this review. The use of the word 'severe' in the Plain Language Summary is particularly misleading. Was there 'harm' to any of the infants in the McDonald study or simply more infants receiving phototherapy? What were peak bilirubin levels? The use of phototherapy does not necessarily imply 'severe' jaundice.  Maisals (2006) recommends that the term severe be used when the total serum bilirubin level is 20 mg/dL (340 umol/L) or higher. The issue of hyperbilirubinemia is extremely complex (AAP, Technical Report 7/04). Recent information on bilirubin tells us that it is an anti-oxidant and that the elevations seen after birth especially in breastfed infants may be initially protective (Hammerman C et al, 2002). It does everyone an injustice to infer 'harm' in the face of the evidence from the two large randomized controlled trials published in 2006. These trials indicate less anemia and better iron stores at 6 months of age in infants with DCC at birth (Cernadas et al, 2006; Chaparro et al, 2006). 

In analysis 1.16 'Clinical Jaundice' did not result in significant differences between the delayed group and the immediate clamped group even though the 90 infants who were clamped at 3 minutes in the Cernadas study (2006) with no increase in jaundice are left out and the McDonald study results are included here as well. 

It is important to blind pediatric providers when one is using a management decision as an outcome variable. Strauss (2008) recently published findings on 105 preterm neonates randomized to immediate clamping or a one minute delay in cord clamping. Use of phototherapy was an outcome variable and the providers caring for the infants were not blinded to the infants grouping. He reported that even though there were "no differences in serum bilirubin values prompting therapy or in intensity of therapy required", more infants with the delay in cord clamping group received phototherapy (Strauss, 2008).   This information concerning treatment when neonatologists are unblinded to an infant's grouping suggests that the belief that DCC causes jaundice effects clinical practice. It demonstrates the need for pediatric providers to be blinded in trials using jaundice requiring phototherapy as an outcome variable. Fortunately, Strauss balanced his variables and reported that there were no differences in initial bilirubin levels at decision to treat or in the extent of phototherapy used.

In order to prevent regional biases, we suggest that the Cochrane Collaboration recommend groups of authors representing more than one country, one continent, and one specialty. This is imperative to offer balance for such an important review. 

Other points are:

  1. The abstract offers that both benefits and harm are shown for late cord clamping. The evidence of harm in this review is much too weak (based on one unpublished study's findings) to be stated so definitively.

  2. Under 'Significant increase in infants needing jaundice', five trials are listed but only one trial gives any weight to this finding and that is a 12 year old unpublished study. 

  3. Under Authors' Comments, the authors state "One definition of active management [of third stage labor]" but do not refer to the current definition as offered by WHO, ICM, and FIGO. It is imperative that such documents use and refer to the most current definitions.

References

AAP Technical Report.  An evidence-based review of important issues concerning neonatal hyperbilirubinemia.  Pediatrics 2004, 114(1):e130-153.
Cernadas, J., et al. (2006). The effect of timing of cord clamping on neonatal venous hematocrit values and clinical outcome at term: A randomized controlled trial. Obstetrical & Gynecological Survey, 61(9):564-565.
Chaparro, C.M., et al. (2006). Effect of timing of umbilical cord clamping on iron status in Mexican infants: a randomised controlled trial. Lancet, 367 (9527):1997-2004.
Hammerman C, Goldschmidt, D, Caplan, M. S, Kaplan, M.  Bromiker, R. Eidelman, A. I.et al. (2002) Protective Effect of Bilirubin in Ischemia?Reperfusion Injury in the Rat Intestine Journal of Pediatric Gastroenterology and Nutrition, 35:344?349.
Hutton, E.K. and Hassan, E.S. (2007). Late vs. early clamping of the umbilical cord in full-term neonates: systematic review and meta-analysis of controlled trials. JAMA, 297(11):1241-52.
Maisels, MJ. (2006). What?s in a Name? Physiologic and pathologic jaundice: the conundrum of defining normal bilirubin levels in the newborn.  Pediatrics, 118(2):805-807.
Strauss, R.G. et al. (2008). A randomized clinical trial comparing immediate versus delayed clamping of the umbilical cord in preterm infants: short-term clinical and laboratory endpoints. Transfusion, 48(4):658-65.

(Feedback received from Judith S Mercer, PhD, CNM, FACNM and Debra A Erickson-Owens, PhD(c), CNM)

Reply

Jaundice requiring phototherapy
Emphasis

Debra Erickson-Owens and Judith Mercer question the emphasis we have placed in the review on this outcome. We believe that our presentation of jaundice requiring phototherapy accurately reflects an increase in jaundice. The authors recognise that interpretation of the clinical relevance of this for infants may vary. As the largest trial, the McDonald study (appropriately) contributes the most data, so it is not surprising that its removal from the analysis also removes the statistical significance. Three of the other four trials contributing data to this outcome are small. The fourth trial of 556 babies (Oxford Midwives 1991) shows a risk difference of approximately similar magnitude to McDonald 1996 (2.5% versus 3.1%). 

Blinding

In the McDonald 1996 trial, while it is possible that lack of blinding may have had an influence, we think that it is unlikely since women were not explicitly informed of their allocation at the time of birth. In the period that most of these trials were conducted, in many units, the midwives at the birth would not be the midwives providing postnatal care. In the McDonald study, midwives and other clinicians providing postnatal care were not aware of allocations to groups, or even that a particular infant had participated in the study. Furthermore, the decision to place a baby under phototherapy has many objective elements and criteria. We did include a brief mention of blinding of outcome assessment in the text of the review, but have added extra detail in the Characteristics of Included studies.

Guidelines for treating jaundice

We agree with the statement that these guidelines have changed over time. In the case of the McDonald 1996 trial, the level of jaundice requiring phototherapy depended on the age and weight of the infants (all were under 4 days). Approximately 90% of babies were breastfed at discharge (89% in the delayed clamping group and 91% in the early clamping group).

Other factors

The other factors mentioned would have been distributed between the two groups of the McDonald 1996 study, as it was a securely randomised trial with adequate allocation concealment.

Ignoring results from Cernadas

All infants from the Cernadas study (including the 90 infants clamped at 3 minutes) have been included in the clinical jaundice outcome. We feel that we have given appropriate weight to the favourable results for six month anaemia and iron levels, pointing this out in the Results, Discussion, Authors' conclusions and Abstract. 

Potential risks from delayed cord clamping

We think there is a slight misinterpretation about the Plain language Summary saying that the jaundice was severe - our actual words were “a possible additional risk of jaundice severe enough to require phototherapy”. However, we can see that this wording could be easily misinterpreted and we will change it and also the applicable wording in the Authors' conclusions.

We feel it would be irresponsible to ignore or downplay potential harms and, in fact, to do so would be contrary to The Cochrane Collaboration’s guidelines (Loke 2008). We believe we have appropriately pointed out a potential risk (albeit one which is preventable through phototherapy), noting that this risk would be minimal in facilities that have the equipment to test for and treat jaundice. Although Moerschel 2008 have recently stated, “every hospital that cares for newborns should be able to provide intensive phototherapy”, we recognise that this is not always the case.

Clinical jaundice

Thank you for picking up that we missed reporting the third arm of Cernadas for clinical jaundice. The addition of these data change the total RR from 0.83, 95% CI 0.65 to 1.06 to 0.84, 95% CI 0.66 to 1.07. We have made this change in the review.

Current definitions of active management

The point of our comment in the conclusions in the Abstract was to highlight that active management takes a number of forms, as evidenced by the Winter 2007 survey that we cite in the background. Part of this variation will always exist, as conditions at birth sometimes mean that components of intended active management or expectant management cannot be carried out. We will refer to the current definitions in the review and add the appropriate reference when we update the review.

Contributors

Feedback received from Judith S Mercer, PhD, CNM, FACNM and Debra A Erickson-Owens, PhD(c), CNM

Reply from Susan J McDonald and Philippa Middleton

Simon, 26 May 2008

Summary

'Delayed clamping' of the umbilical cord at birth appears to be regarded as a novel alternative to a longstanding protocol for immediate disconnection of an infant from placental circulation within seconds of birth.

How many prospective parents are aware of the protocol for clamping the umbilical cord immediately at birth? How many prospective parents are fully informed about randomized controlled trials before assenting to random assignment to one group or another?

The infant does not gain 30 per cent more blood volume when the cord is left intact until pulsations cease. On the contrary the infant loses 30 per cent of its blood volume if placental circulation is clamped off immediately at birth.

The placenta is the respiratory organ of the child until its blood is transferred to the capillaries surrounding the alveoli and the lungs become fully functional. Pulsations in the cord are from the infant's heart continuing to make use of fetal circulation back to the placenta until the foramen ovale, ductus arteriosus, and pulmonary bypass circulation have closed. Clamping a pulsating umbilical cord arbitrarily terminates postnatal placental circulation. Redistribution of blood to the lungs, the brain, the gut will be variable from infant to infant.

Randomized controlled trials show that most healthy newborn babies somehow adjust, but findings like increased bilirubin levels are insufficient justification for promoting continued use of the obstetric clamp.

Oxygen insufficiency is the greatest danger of disrupted umbilical blood-flow, prenatally, during labor, when the cord is wrapped around the neck, and after birth. Bilirubin is only a danger if the blood-brain-barrier is disrupted, as demonstrated by research like that of Lucey et al (1964) and Lou et al (1977). Why is evidence of this kind, obtained in experiments with animals overlooked in favor of randomized controlled experiments with human children?

References (with notes from my recent comment to the Interagency Autism Coordinating Committee, IACC)

1. Lucey JF, Hibbard E, Behrman RE, Esquival FO, Windle WF. Kernicterus in asphyxiated newborn monkeys. Exp Neurol 1964 Jan; 9(1):43-58.
Lucey et al induced hyperbiliruninemia in fourteen newborn monkeys by injecting a solution of bilirubin into the bloodstream every six hours. Bilirubin levels of 20 to 35 mg were maintained for up to 96 hours. Then, "Six healthy full-term monkeys were asphyxiated at birth. A rubber bag filled with saline solution was placed over the fetal head as it was delivered from the uterus before the first breath. The umbilical cord was then clamped and asphyxiation carried out for 10 or 12 minutes" [p45]. Hyperbilirubinemia was then induced in the asphyxiated monkeys as in the fourteen control animals.
Lucey et al described the monkeys made hyperbilirubinemic as showing marked yellow coloration of skin and mucous membranes. Those not asphyxiated became slightly lethargic but none developed signs of neurological impairment. Monkeys subjected to asphyxia before induction of hyperbilirubinemia developed tremors, seizures, and prolonged periods of opisthotonus (a postural state with arched back and neck).
"Hyperbilirubinemia alone did not result in selective staining of nuclei in the brain, such as is associated with human kernicterus - the brains had a diffuse, faint to moderate, yellow color, but no extravascular bilirubin was seen" [p50].
Bilirubin is not directly toxic to the brain. Asphyxia appears to break down the blood-brain barrier, which then allows bilirubin to get into neural cells. As Zimmerman and Yannet noted in 1933, 'any intravital dye will localize in zones of injury and will leave unstained tissues which are not damaged.' [4, p757]

2. Lou HC, Tweed WA, Johnson G, Jones M, Lassen NA. Breakdown of blood/brain barrier in kernicterus. Lancet. 1977 May 14;1(8020):1062-3.
Lou et al (1977) addressed what appeared to be the primary concern over "delayed" cord clamping allowing placental transfusion [5]. Citing the paper by Lucey et al (1964) they stated:
"Asphyxiated infants are especially susceptible to kernicterus, even if their plasma-bilirubin levels are low. Furthermore, it is very difficult to produce clinical and pathological signs of kernicterus by injection of bilirubin intravenously in normal infant monkeys, while kernicterus was readily produced in previously asphyxiated monkeys." [p1062] Mossakowski et al (1968) used Evans blue dye to investigate the blood-brain barrier in newborn monkeys subjected to asphyxia by clamping the umbilical cord and obstructing the airway [6]. Lou et al also used Evans blue dye in fetal lambs subjected to oxygen insufficiency for 1-2 hours:
"The fetuses were asphyxiated by partially inflating a cuff around the umbilical cord.
Asphyxia developed over a period of 1-2 h (pH about 690)." [p1062] The initial response of the fetal lambs was a slowing of heart rate and increased blood pressure during the first half- to one-hour period of umbilical cord blood flow restriction. After that the blood pressure declined and remained low. Twinning is frequent in lambs, and Lou et al used the twin as a control for the fate of Evans blue dye, and reported:
"We have found, in experimental asphyxia lasting 1-2 h, a striking discoloration throughout cortex and basal ganglia after intravenous injection of 3 ml/kg of a 2% solution of Evans blue in eight non-exteriorised fetal lambs, in contrast to the uncoloured brain tissue in non-asphyxiated twins acting as controls." [p1062] In conclusion they commented:
"We suggest that the breakdown of the fetal blood/brain barrier to albumin is due to a combination of the initial moderate hypertension and severe vasodilation during asphyxia. The permeability of the blood/brain barrier to albumin in asphyxiated babies would facilitate the transport of bilirubin from plasma to neurones and thus explain the increased susceptibility to kernicterus." [p1063] If a baby does not breathe right away at birth, should the umbilical cord be clamped off right away? Respiratory depression in infants born alive is a current concern and topic for research [7, 8]. If an infant is born alive, it has been receiving oxygen through the umbilical cord up to the time of birth. Shouldn't that lifeline be left intact until the lungs become functional?
Breakdown of the blood brain barrier by asphyxia has been shown to allow bilirubin and other substances in the circulation to enter the brain. High levels of bilirubin won't affect the brain if the blood-brain barrier has not been breached. Immediate clamping has been too long defended as a means to avoid circulatory overload and hyperbilirubinemia.
Lou et al (1979) reported results of more research on the vulnerability of the blood-brain barrier to circulatory insufficiency in fetal lambs [3].

3. Lou HC, Lassen NA, Tweed WA, Johnson G, Jones M, Palahniuk RJ. Pressure passive cerebral blood flow and breakdown of the blood-brain barrier in experimental fetal asphyxia. Acta Paediatr Scand. 1979 Jan;68(1):57-63.

4. Zimmerman HM, Yannet H. Kernicterus: jaundice of the nuclear masses of the brain. American Journal of Diseases of Children 1933 Apr; 45:740-759.
Before discovery of Rh factor sensitivity, Zimmerman and Yannet in 1933 summarized a large number of case reports of kernicterus. They concluded that kernicterus was caused by bilirubin staining of subcortical nuclei already injured by sepsis or oxygen deprivation. They further commented, "This differs in no way from the well known fact that any intravital dye will localize in zones of injury and will leave unstained tissues which are not damaged," [p757].
Fear of elevated bilirubin levels became a prime reason 40 years later for advocating immediate clamping of the umbilical cord at birth to minimize placental transfusion [4].

5. Saigal S, O'Neill A, Surainder Y, Chua LB, Usher R. Placental transfusion and hyperbilirubinemia in the premature. Pediatrics. 1972 Mar;49(3):406-19.
Is it safe to allow a placental transfusion? By the 1970s the practice of clamping the cord was so widespread, at least in obstetric practice associated with academic institutions, that whether a placental transfusion should be allowed became a major topic for research. Thus the opening comment of this highly influential report states:
"In full-term infants placental transfusion increases the blood volume of the newborn by 40% to 60% within 5 minutes of birth. Most of the excess blood volume is eliminated within 4 hours by an extravasation of plasma from the circulation. For the remainder of the neonatal period, such infants retain a 50% larger red cell volume dispersed through a slightly enlarged blood volume, with higher hematocrit values than are found in infants whose umbilical cords are clamped immediately at birth." [p406] "If delayed cord clamping is adopted as a means to reduce the incidence of respiratory distress syndrome in premature births, there will be accompanying augmentation of hyperbilirubinemia to deal with." [p418] This paper, with its single focus on bilirubin danger, has been one of the most influential in adopting immediate clamping of the umbilical cord at birth as a standard protocol.

6. Mossakowski MJ, Long DM, Myers RE, DeCuret HR, Klatzo I. The early histochemical and ultrastructural changes in perinatal asphyxia. J Neuropathol Exp Neurol. 1968 Jul;27(3):500-516.

7. Baskett TF, Allen VM, O'Connell CM, Allen AC. Predictors of respiratory depression at birth in the term infant. BJOG. 2006 Jul;113(7):769-74.

8. Milsom I, Ladfors L, Thiringer K, Niklasson A, Odeback A, Thornberg E. Influence of maternal, obstetric and fetal risk factors on the prevalence of birth asphyxia at term in a Swedish urban population. Acta Obstet Gynecol Scand. 2002 Oct;81(10):909-17.

(Feedback from Eileen Nicole Simon, PhD, RN)

Reply

Many of the comments in Simon’s feedback are outside the scope of this Cochrane review. However, responses to some specific issues follow:

Delayed clamping regarded as novel

Cochrane reviews are often done when there is variation in practice, as is the case here. For example, in the Background of the review we cite such documented variation which indicates widespread use of both delayed and immediate cord clamping, and we make no judgement about the novelty or otherwise of either technique.

Infant loses 30% of blood volume, does not gain 30%

Our phrasing in the background is about transfer of fetal blood. In order to clarify further, we have added “compared with immediate cord clamping” after “This placental transfusion can provide the infant with an additional 30% more blood volume and up to 60% more red blood cells”.

Increased bilirubin levels are insufficient justification for promoting continued use of the obstetric clamp

Firstly our review does not promote the continued use of clamping; in fact, it is more the reverse. However, we do note that increased levels of jaundice may be associated with delayed cord clamping, which is the responsible course of action.

Evidence from animal studies should suffice

This is not the place for a detailed discussion of the pros and cons of using data from animal studies, except to say that most clinicians and researchers would be very cautious about extrapolating to humans, especially human infants.  

Saigal 1972 influenced adopting immediate cord clamping as a standard protocol

This may well be so, but the Saigal study did not contribute data to the outcome of jaundice in this review (as they reported only the biochemical outcome of bilirubin levels and not jaundice). The fundamental purpose of systematic reviews is to show the consolidated evidence of benefits and harms of particular actions, not to rely on single studies or opinion.

Contributors

Feedback from Eileen Nicole Simon, PhD, RN

Reply from Susan J McDonald and Philippa Middleton

Buckley, 16 July 2008

Summary

I am very concerned about one of the studies used for this conclusion: Following birth, there was a significant increase in infants needing phototherapy for jaundice (RR 0.59, 95% CI 0.38 to 0.92; five trials of 1762 infants) in the late compared with early clamping group. 

This finding (analysis 1.15) is significantly influenced by results from the Oxford Midwives study (Oxford Midwives 1991), which is quoted here as showing jaundice requiring phototherapy amongst 3/256 immediate cord-clamped (ICC ) babies and 11/296 delayed cord clamped (DCC) babies.

However, a close reading of this paper shows a significant disparity in these groups in relation to exposure to synthetic oxytocin in labour: 33/256 (12.9%) in ICC group and 72/296 (24.3%) in the DCC group: see table 1.

Study authors note this (and the association between exposure to synthetic oxytocin in labour and jaundice), and, in table 6 of this paper, reanalyze the groups in relation to oxytocin exposure, finding 5/70 DCC versus 2/33 ICC babies exposed to oxytocin required phototherapy for jaundice, and  6/222 DCC versus 1/218 ICC unexposed to oxytocin. In this analysis, the confidence intervals were wide and the differences between ICC and DCC babies were not significant in either group.

I am concerned that the reviewers have not adjusted for this confounding factor, which is very salient to the findings and to the overall review conclusions, and would welcome a reanalysis of table 1.15.

There were some other worrying elements in this study:

  • Lack of blinding to allocation, leaving the possibility that clinicians may have referred more jaundiced DCC babies for phototherapy because of their own beliefs.

  • A sizeable unexplained disparity in numbers randomized to each arm: 296 DCC versus 256 ICC.

  • A large number of protocol deviations in the DCC arm (32 versus 3 ICC).

I also note the small numbers of events used in analysis 1.15.

I (and many others interested in this area) would also welcome access to detail from the unpublished study (McDonald 96) that seems to have influenced this finding.

(Feedback received from Dr Sarah J Buckley)

Reply

The actual influence of infants exposed to synthetic oxytocins in the Oxford Midwives study is minimal; a re-analysis omitting these infants changes the overall risk ratio (of the pooled studies) from 0.59 95% CI to 0.38 to 0.92; to 0.59 95% CI 0.37 to 0.95.

While it is possible that lack of blinding may have had an influence, we think that it is unlikely, since women were not explicitly informed of their allocation at the time of the birth. In the period that most of these trials were conducted, midwives present at the birth would not be the midwives providing postnatal care. In the McDonald Study, postnatal ward staff were not aware of allocations to groups, or even that a particular infant had participated in the study. Furthermore the decision to place a baby under phototherapy has many objective elements and criteria.

We agree that the study authors did not explain the reasonably large discrepancy in numbers randomised to delayed and immediate cord clamping (296 versus 256) but do not have the information to assess any impact of this on the trial’s reported results.

Some protocol deviations are to be expected with the nature of these interventions; particularly for delayed cord clamping where immediate cord clamping may have to be carried out in some cases. The study authors analysed these deviations correctly (in the groups to which the mothers were originally randomised). However, an additional ‘as treated’ analysis would have been informative.

Small numbers of events usually are associated with less precision, so it is interesting to see that the pooled result reached statistical significance with these small numbers.

The McDonald trial is a thesis, available from the Cochrane Pregnancy and Childbirth Group or from Professor McDonald. A journal manuscript is being prepared.

Contributors

Feedback from Dr Sarah J Buckley

Reply from Susan J McDonald and Philippa Middleton

Oddie, 7 July 2008

Summary

Why is the weight of the infants not reported in the review?  These data will be available to the reviewers and will answer some of the questions as to how large the placental transfusion actually is in reality.

Where this practice has not yet been adopted, or further studies are planned, these data are very relevant.

(Feedback from Sam Oddie) 

Reply

Thank you for pointing out this omission. Approximately half of the studies did report birthweight. We will add birthweight to the next revision of the review. A preliminary assessment of the available data reveals no statistically significant difference between the late and early cord clamping arms

Contributors

Feedback from Sam Oddie

Oddie, 7 July 2008

Summary

Feedback: I am really interested in the data and have reviewed some of the original trials, as well as taking an active ongoing interest in the issue.

I remain unconvinced that DCC ought to be adopted widely in iron replete areas.

But my feedback is: Why is infant weight not reported? 

Justification: If the size of the transfusion is anywhere near as big as many suggest, then it must be the case that a difference in weight can be shown as so many women have been randomised.  If no such weight effect is shown, then either the transfusion is smaller than is suggested, randomisation is in some way ineffective, or there is still inadequate power for these RCTs to show us the size of the transfusion.  It seems unlikely that the latter is true.

Many who write on this subject are increasingly keen on DCC. This is obviously fine, but for those of us who are not yet practising it, or who are planning further work, the actual size of the transfusion is relevant; particularly when there is a suite of trials and a way to answer the question. I do know of some who are suspicious as to why the weight data are as yet unpublished.

As birthweight will undoubtedly have been recorded in the trials, lets report it here!

(Feedback from Sam Oddie)

Reply

The question of the amount of transfusion cannot be answered in a satisfactory amount of detail through the randomised trials we have included in this review. This would require another prospective study of comparing birthweights with timing of clamping.

Contributors

Feedback from Sam Oddie

Reply from Susan J McDonald and Philippa Middleton

What's new

DateEventDescription
27 May 2008Feedback has been incorporatedWe have replied to feedback from DA Erickson-Owens and JS Mercer, Eileen Simon, SJ Buckley and S Oddie.

History

Protocol first published: Issue 1, 2003
Review first published: Issue 2, 2008

DateEventDescription
4 May 2008Feedback has been incorporatedAdded feedback from Erickson-Owens and Mercer and feedback from Eileen Nicole Simon.
23 January 2008AmendedConverted to new review format.

Contributions of authors

Sue McDonald wrote the review and Philippa Middleton assisted with data extraction, methodological help and editing.

Jo Abbott and Shane Higgins were involved in drafting the protocol and in the early stages of preparing the review (e.g. some of the data extraction) but were unable to continue in the preparation of the review.

Declarations of interest

The contact review author (S McDonald) is the author of one of the included studies. The other review authors assessed this trial for potential inclusion and data extraction.

Sources of support

Internal sources

  • Discipline of Obstetrics and Gynaecology, The University of Adelaide, Australia.

External sources

  • Department of Health and Ageing, Australia.

Differences between protocol and review

Since the publication of the protocol for this review, we have broadened the criteria to include caesarean births and to widen the definition of early cord clamping from less than 30 seconds to less than 60 seconds since two trials specified early clamping as under one minute. We have added several outcomes which measure biochemical parameters in infants such as haemoglobin and ferritin. We added the outcome of polycythaemia because we considered that information regarding polycythaemia would be of clinical interest.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Cernadas 2006

Methods

Randomised controlled trial.
Computer-generated random numbers - stratified by hospital and then by mode of birth within each hospital. Variable length blocks were used.
Allocation by sealed opaque sequentially numbered envelopes - the allocation was read out to the attending clinician.

Staff responsible for random generation and allocation concealment processes were not involved in the recruitment phase of the trial.

Blinding: paediatricians assessing the outcomes were unaware of the assigned interventions.
Nature of the intervention meant that others could not be blinded.

Losses to follow up: primary outcome was not measured in:
early 3/93; late 1 min 1/91; late 3 min 0/92.

Participants

Women who had an uneventful cephalic vaginal or caesarean section birth, and singleton pregnancy at term; consented at 36 weeks' gestation visit.
276 women randomised.
2 obstetrical units in Argentina.

Exclusion criteria included diabetes, pre-eclampsia, hypertension, evidence of IUGR (estimated weight < 10th percentile), congenital malformation.

Interventions

3 interventions were compared.
1. Early umbilical cord clamping (within 1st 15 seconds of birth).
n = 93 [88/93 received the intervention - no cause given for 5 changes].
2. Cord clamping at 1 min after birth
n = 91 [83/91 received the intervention - 8 changes (2 no breathing in the first 10 secs; 1 tight nuchal cord; 2 with both no breathing in first 10 secs and tight nuchal cord; 1 other cause; 2 no cause)].
3. Cord clamping at 3 mins after birth.
n = 92 [83/92 received the intervention - 9 changes (4 no breathing in the first 10 secs; 1 no breathing in the first 10 secs and tight nuchal cord; 1 secondary apnea; 1 spontaneous third stage; 1 amniotic fluid stained with meconium; 1 no cause)].

The latter 2 timing interventions were considered to be delayed.

In vaginal births, if the cord clamping allocation was delayed, the infant was placed in the mother's arm while awaiting cord clamping. If a caesarean birth, the infant was placed on the mother's lap and swaddled to prevent heat loss while awaiting cord clamping.

States no additional interventions were performed - interpret as no oxytocics?

OutcomesMaternal outcomes: postpartum blood loss volume and maternal haematocrit at 24 hours post birth.
Infant outcomes: newborn venous haematocrit at 6 hours after birth, neonatal haematocrit and plasma bilirubin levels at 24 and 48 hours of age, early neonatal mortality and morbidity (tachypnoea, respiratory grunting, respiratory distress, jaundice, seizures, sepsis, necrotising enterocolitis), admission to NICU, newborn length of hospital stay, any neonatal disease that occurred between birth and 1 month, weight and method of feeding at 1 month.
Notes 
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate

Chaparro 2006

MethodsRandomised controlled trial.
Blocks of 4 generated by random digital generator in Microsoft Excel. Numbered index cards with allocation were sealed in numbered opaque envelopes ordered sequentially.
Blinding: no mention of blinding.
Losses to follow up: early group: 68/239 lost to follow up at 6 months (27 no longer interested, 7 moved away, 28 could not be located, 5 lack of time, 1 infant ill);
leaving 171 who completed the study at 6 months. There were also 2 protocol violations (cord clamping more than 30 secs after the delivery of the infant's shoulders), 1 nuchal cord, 1 reason not recorded.
157 had full blood sample analysis.
Late group: 50/237 lost to follow up at 6 months (25 no longer interested, 4 moved away, 16 could not be located, 3 lack of time, 1 infant died, 1 participation in other study), leaving 187 who completed the study at 6 months. There were also 52 protocol violations (clamping at less than 100 secs after delivery of infant's shoulders), 30 concerns for infant's condition, 15 forceps used, 3 infants born in labour room bed, 4 misunderstanding of treatment group.
171 had full blood analysis.
Participants

476 mother-infant pairs were randomised.
Women at term (equal to or greater than 36 weeks' and less than 42 weeks' gestation, where a vaginal birth of a healthy singleton infant was anticipated, the woman planned to breastfeed for at least 6 months, was a non-smoker, was able to return for follow-up visits and there were no complicating medical or obstetric factors.

Exclusion criteria applied after birth were low birthweight (< 2500 g) and major congenital malformations.

Setting: large obstetrics hospital in Mexico City, Mexico.

Interventions

Early clamping (10 secs after birth) (n = 239);.
late clamping (2 mins after birth) (n = 237).

Any condition arising that necessitated earlier clamping was adhered to.

OutcomesMaternal: estimated maternal blood loss at birth.
Infant: haematological and iron status at 6 months of age, newborn haematocrit and reported neonatal jaundice between birth and 14 days of age, exclusive breastfeeding.
NotesJaundice was self report by mother, and so was not entered under the outcome of clinical jaundice.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate

Emhamed 2004

MethodsRandomised controlled trial. Consecutive allocation of opaque envelopes.
Blinding: not stated.
Losses to follow up: 1 mother/baby pair from each group (1/58 late; 1/46 early) left hospital before reassessment and so were not available for those outcomes measured 16-24 hours after birth.
4/50 pairs from the early group and 4/62 from the late group were excluded after randomisation because of intrapartum asphyxia.
Participants112 (104) women in a large Libyan hospital who consented during first stage of labour.
Exclusion criteria: women with known medical or obstetric problems, less than 37 weeks' or greater than 42 weeks' gestation.
Post randomisation exclusions were an infant weighing less than 2500 g, instrumental births, respiratory distress, congenital abnormalities or the need for early cord clamping.
Interventions

Early (immediate) cord clamping (10 secs following birth (n = 46);
late cord clamping (when cord pulsation ceased) (n = 58).

Oxytocin given when cord clamping had been performed.

OutcomesMaternal: pre and post birth haemoglobin and haematocrit.
Infant: haemoglobin and haematocrit (including cord blood), polycythemia, hyperviscosity and jaundice.
Notes 
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

Geethanath 1997

MethodsAllocation by opaque, sealed envelopes.
Blinding: not reported.
Losses to follow up: not reported.
Participants

107 women (anticipating a term vaginal birth and not experiencing any medical or obstetric complications including anaemia of < 10 g/dL).

New Delhi hospital, India.

Post randomisation exclusions were applied in the presence of birth asphyxia, major congenital malformations.

InterventionsEarly cord clamping: cord clamped as soon as the infant was born;
late clamping: cord clamped after the placenta had descended into the vagina during which time the infant was held 10 cm below the vaginal introitus.
OutcomesMaternal: haemoglobin shortly after completion of birth.
Infant: cord blood at birth and and venous blood sample at 3 months for ferritin and haemoglobin estimation.
Notes 
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

Gupta 2002

MethodsAllocation by opaque sealed envelopes, with computer-generated random number sequences.
Blinding: not stated.
Losses to follow up: at 3 months, 58 (57%) of the original 102 mother-infant pairs were available, 29 pairs in each group.
Participants

102 infant-mother pairs - hospital born neonates born vaginally to pregnant women with anaemia (haemoglobin < 100 g/L at term)

Exclusion criteria: medical or pregnancy related complications e.g. eclampsia, severe heart failure, severe antepartum haemorrhage or rH iso-immunisation.
Infants who needed resuscitation at birth or who had major congenital malformations.

Teaching hospital, New Delhi.

Interventions

Early cord clamping group (cord clamped immediately after the birth of the infant), n = 53.
Late cord clamping (cord clamped after the placenta had descended into the vagina), n = 49 - during this time the infant was warmly wrapped and held below the level of the mothers abdomen but within 10 cm of the vagina.

4 ml of maternal venous blood was taken at the time of the birth, 4 ml of cord blood at birth and 4 ml venous blood from the infant at 3 months of age.

Infants were not given any medicinal iron supplementation during the study period.

Outcomes

Maternal: haemoglobin at birth.

Infant: haemoglobin at 3 months, weight gain, feeding patterns, respiratory infections and diarrhoea.

Notes 
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

McDonald 1996

MethodsRandomisation: list of computer-generated random numbers.
Opaque, sealed, sequentially numbered envelopes kept at a central location in the delivery ward.
Blinding: see notes.
Losses to follow up: all women allocated to receive a particular timing option were included in the intended group with the exception of 37 women for whom no trial number was recorded (14/250 in early cord clamping and early uterotonic group; 6/250 in late cord clamping and early uterotonic group; 6/250 in early cord clamping and late uterotonic; and 11/250 in late cord clamping and late uterotonic group).
Participants

All women attending the antenatal clinic at King Edward Memorial Hospital, randomised when a vaginal birth was thought to be imminent.
Exclusions: maternal refusal to participate in the study; caesarean section; breech delivery; multiple pregnancy; fetal indication (e.g., known fetal anomaly); preterm birth (< 37 completed weeks' gestation).

1000 women were randomised to the trial; the data of 37 women were excluded due to insufficient information available to include in the analyses, leaving data for 963 women available for analysis.

Interventions4 arms: early cord clamping and early uterotonic administration (n = 236);
late cord clamping and early uterotonic administration (n = 244); early cord clamping and late uterotonic administration (n = 244); late cord clamping and late uterotonic administration (n = 239).

Definitions: early cord clamping involved clamping immediately following birth of the body of the baby; late cord clamping occurred when cord pulsation had ceased or at 5 mins if cord pulsation had not already ceased. This time limit was imposed to reduce the risk of compromising infants who may have any undiagnosed underlying conditions such as a PDA; early uterotonic administration involved administration at the time of birth of the anterior shoulder of the baby; late uterotonic administration was after the birth of the baby (literally) and if the cord clamping allocation was early, then it was allocated to be after the cord was clamped (ie not within 30 seconds).
OutcomesMaternal: PPH = or > 500 ml, = or > 1000 ml; mean blood loss; need for blood transfusion; need for manual removal of placenta; length of third stage (> 30 mins and > 60 mins); need for therapeutic uterotonics; evacuation of retained products; inversion of the uterus; length of hospital stay.
Neonatal: Apgar score < 6 at 5 mins; admission to NICU; jaundice requiring phototherapy (> 1 day); need for serum bilirubin test; breastfeeding at discharge.
Notes

Sample size: the initial sample size calculation was based on an anticipation that the PPH rate from a uterotonic choice trial (McDonald 1996) would be around 10%. It was calculated that a sample size of 3000 women would be required to have an 80% chance of detecting a 50% reduction in PPH at the 5% level of statistical significance. However, review during the trial by a Data Monitoring Committee determined that the PPH rate was greater than the 10% rate predicted, the actual recorded PPH rate being around 16%; this reduced the required sample size to ˜1,100 women.

Blood loss assessment: "the major endpoint of the study was PPH ascertained by measurement of collected blood spillage where possible and all other blood loss estimated by visual estimation. The trial could not be 'blind' at this point; the clinician carrying out the intervention was also attempting to assess the blood loss. The authors attempted to obtain objective indices of blood loss in the form of 1. postpartum haemoglobin, 2. calculation of the difference between antepartum and postpartum haemoglobin. Although these measures may not be reliable measures of the amount of blood loss by an individual, they are objective, independent of observer bias and were carried out on women in the trial without knowledge of which intervention was used".

Jaundice assessment: Clinicians assessing jaundice are not likely to have been aware of the allocation to early and late clamping groups.

The study was written up as a PhD thesis, a copy of which is available from the Pregnancy and Childbirth Group office. It has never been submitted for journal publication; submission is planned in 2008.

Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate

Nelson 1980

MethodsRandomisation: "assigned randomly" - no further details provided.
Blinding: 2nd observer blinded for Brazelton Neonatal Behavioural Assessment Scale, infant Bayley Scales of Infant Development assessed blind.
Losses to follow up: 1/55 (dropped out from conventional (early clamping) group.
Participants

Women considered to be at low obstetrical risk, interested in the Leboyer approach to birth, and intending to attend psychoprophylactic prenatal classes.

Exclusion criteria: giving birth before 36 weeks, not available for 3 day and 8 month assessments.

InterventionsEarly ('conventional') birth with cord clamping within 1 min of birth (n = 26); median time of 45 secs.
Late (Leboyer method with cord clamped when it stopped pulsating); n = 28; median time of 180 secs.
OutcomesMaternal: length of first, second and third stages of labour, mother's experience of labour and birth, maternal psychological adjustment at 6 weeks, maternal perception of infant behaviour at 3 days, 6 weeks and 8 months postpartum (Carey Scales of Infant Temperament), PPH (blood loss threshold not defined), extension of episiotomy, infected episiotomy, endometritis, urinary tract infection.
Infant: perinatal asphyxia, hypothermia (one or more axillary temp > 35 C), respiratory rate more than 60, polycythaemia (24 hour capillary haemoglobin more than 25 g per 100 ml [more than 15.51 mmol/L]), jaundice, hyperbilirubinaemia (serum bilirubin more than 12 mg per 100 ml [more than 205.2 umol/L]).
Notes 
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

Oxford Midwives 1991

MethodsRandomisation: generation by random-number tables (simple unblocked and unstratified); sealed opaque envelopes were consecutively numbered and centrally stored in the delivery suite.
Participants

554 women.

Setting: large teaching hospital in Oxford, UK.

InterventionsEarly clamping (as soon as possible after the birth) or late clamping (3 mins after the birth).
OutcomesMaternal: PPH, manual removal of placenta.
Neonatal: respiratory problems e.g. transient tachypnoea, grunting, rib recession, heart or cardiovascular problems, clinical jaundice (whether jaundice had been noted, the duration and level of jaundice as indicated by serum bilirubin if blood samples were taken, whether treated with phototherapy), birthweight, feeding method, duration of cord adherence.
Notes 
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate

Saigal 1972

MethodsRandomisation: "assigned prior to delivery according to a randomised study protocol" but no further details given.
Blinding: not reported.
Losses to follow up: not stated.
Participants

45 term infants born in 2 hospitals in Montreal, Canada.

Full-term infants 38 to 42 weeks' gestation, vaginal births.

Exclusion criteria: infants of diabetic mothers, malformed infants, infants who developed systemic infections, erythroblastic infants and infants who were small for date (below third percentile for gestational age).

Interventions

Immediate cord clamping - within 5 secs, median 2 secs (n = 15).
Clamping at 1 min - held low, 30 cm below perineum (n = 15).

All women: oxytocic agents were given only after the cord was clamped.

No phototherapy was given for jaundice.

OutcomesInfant: venous haematocrit, cord haematocrit, blood volume, red cell blood volume, plasma volume, bilirubin.
Notes 
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

Spears 1966

MethodsRandomly allocated to early or late cord clamping group upon entering the delivery room.
No description of how the allocation process was decided.
Participants379 women who gave birth vaginally to a term infant weighing greater than 2500 gm at the Los Angeles County General Hospital USA.
Interventions

Early cord clamping was defined as within 1 min after birth (60% were clamped within 30 secs) (n = 192).
Late cord clamping was defined as clamping as at 3 mins post birth. In both instances, the infant was held level with the mother's perineum while the cord was cut (n = 187).

No mention of whether or when the mother received any uterotonic agent.

OutcomesInfant: Apgar scores, respiratory distress.
NotesNo maternal outcomes reported that were of relevance to this review.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

van Rheenen 2007

  1. a

    IUGR: intrauterine growth retardation
    mins: minutes
    NICU: neonatal intensive care unit
    PDA: patent ductus arteriosus
    PPH: postpartum haemorrhage
    SD: standard deviation
    secs: seconds
    ZPP: zinc protoporphyrin

MethodsRandomisation: sequentially numbered opaque sealed envelopes with unpredictable allocation code.
Blinding: "partially blinded" study; "one of the investigators… monitored the delivery procedure and was therefore not blinded to treatment assignment".
Losses to follow up: early group: 8/45 (4 at 2 months, 2 more at 4 months, 2 more at 6 months - 6 moved, 1 died, 1 refused further participation).
Late group: 11/46 (3 at 2 months, 4 more at 4 months, 4 more at 6 months - 6 moved, 3 died, 2 refused further participation).
Postrandomisation exclusions: 5/50 in the early group (1 low birthweight, 1 unexpected twin, 1 tight nuchal cord, 1 need for resuscitation, 1 refused further participation), 9/55 in the late group (2 low birthweight, 1 major congenital abnormalities, 2 unexpected twins, 3 tight nuchal cords, 1 need for resuscitation).
Participants

Full-term pregnant women giving birth in hospital.

105 randomised (50 to early and 55 to late cord clamping) - 45 and 46 analysed.

Exclusion criteria: before randomisation: twin pregnancy; history of PPH; gestational diabetes; pre-eclampsia.
After randomisation: placental separation before birth; caesarean section; tight nuchal cord necessitating early cutting; need for neonatal resuscitation; major congenital abnormalities.

Infants who weighed less than 2500 g or with gestational age less than 37 weeks, were excluded.

Setting: hospital in Zambia (malaria-endemic area).

Interventions

Immediate cord clamping within 20 secs of birth (n = 45)
[mean 15 [SD 8] secs].

Cord clamped after cord stopped pulsating (n = 46)
[mean 305 [SD 136] secs].

After vaginal birth all infants were placed between the legs of the mother (about 10 cm below the vaginal introitus) until the cord was clamped.

Intramuscular oxytocin was given to mothers after clamping of the cord.

OutcomesInfant: haemoglobin change from cord values; proportion of anaemic infants at 4 months after birth;
duration infants remained free of anaemia (up to 6 months); adverse effects of delayed cord clamping in infants (packed cell volume changes 1 day postpartum; clinical signs of hyperviscosity syndrome or hyperbilirubinaemia) and mothers (haemoglobin change 1 day after birth, blood loss in third stage of labour); birthweight; jaundice; jaundice requiring phototherapy; ZPP levels; blood glucose; malaria; exclusive breastfeeding; infant mortality - 4 deaths (but not reported by early or late cord clamping group).
NotesAnaemia = Hb concentration more than 2 SDs below the mean of similarly aged infants from an iron-supplemented USA reference population not exposed to malaria (9.4 g/dL at 2 months, 10.3 at 4 months and 10.5 at 6 months).
Fetal anaemia = cord haemoglobin < 12.5 g/dL.
Maternal anaemia = haemoglobin < 11 g/dL.
Iron deficiency = ZPP levels above 80 umol/mol haem for infants and adults.
Iron-deficiency anaemia in mothers and infants = combination of ZPP above the cutoff level, together with Hb more than 2 SD below the reference mean (and mean cell haemoglobin concentration below the cutoff level for 2 month follow up).
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Abdel Aziz 1999Quasi-randomised.
Begley 1990This is a comparison of active versus expectant management of the third stage of labour and so is included in the Cochrane review of this topic.
Botha 1968No mention of randomisation and allocation process not described.
Buckels 1965No mention of randomisation and allocation process not described.
Colozzi 1954No mention of randomisation and allocation process not described.
Daily 1970Quasi-randomised - "every other child has early clamping and the others late clamping".
Duckman 1953No mention of randomisation and allocation process not described.
Emmanouilides 1971No mention of randomisation and allocation process not described.
Erkkola 1984No mention of randomisation and allocation process not described.
Grajeda 1997Quasi-randomised.
Greenberg 1967No mention of randomisation and allocation process not described.
Johansen 1971Quasi-randomised: control group comprised mothers born on odd dates; experimental group comprised mothers born on even dates.
Kemp 1971Quasi-randomised: allocation method open to bias; "patients were allocated according to age: those whose age was an odd number became the group for abdominal manipulation, and those whose age was an even number formed the cord traction group".
Khan 1997This is a comparison of active versus expectant management of the third stage of labour and so is included in the Cochrane review of this topic.
Kliot 1984No mention of randomisation and allocation process not described.
Linderkamp 1992No mention of randomisation and allocation process not described.
Nelle 1996No mention of randomisation and allocation process not described.
Newton 1961Quasi-randomised: allocation method by rotation.
Philip 1973No clinical outcomes relevant to this review were measured.
Prendiville 1988This is a comparison of active versus expectant management of the third stage of labour and so is included in the Cochrane review of this topic.
Rogers 1998This is a comparison of active versus expectant management of the third stage of labour and so is included in the Cochrane review of this topic.
Saigal 1981No clinical outcomes relevant to this review were measured.
Schindler 1981This study compared clamped and unclamped cord management rather than early versus late timing of cord clamping. Note that although the full paper was in German, a translator was available; it was determined from the English abstract that this study could not be included.
Siddall 1953Quasi-randomised: "in the first half of the experiment the boys cords were milked, while 50 girls had prompt clamping and ligation at delivery. The sexes were reversed for the second 100".
Sorrells-Jones 1982No clinical outcomes relevant to this review were measured.
Taylor 1963Quasi-randomised: allocation method by rotation.
Terry 1970Quasi-randomised: allocation method by alternation.
Thilaganathan 1993This is a comparison of active versus expectant management of the third stage of labour and so is included in the Cochrane review of this topic.
Walsh 1968No mention of randomisation and allocation process not described.
Walsh 1969No mention of randomisation and allocation process not described.
Whipple 1957Allocation method, by rotation, open to bias.
Wu 1960Quasi-randomised: allocation method by alternation.
Yao 1971No mention of randomisation and allocation process not described.
Yao 1977No clinical outcomes relevant to this review were measured.

Characteristics of ongoing studies [ordered by study ID]

Beal 2006

Trial name or titleTiming of cord clamping and neonatal hemoglobin - NCT00371228.
Methods 
Participants150 women presenting for vaginal birth at Tulsa Regional Medical Centre, Oklahoma, USA.
Interventions1) Clamping of umbilical cord within 6 seconds of delivery of the fetal shoulders.
2) Clamping the cord after a palpable pulse has ceased, or after 10 minutes.
OutcomesNeonatal haemoglobin.
Starting dateSeptember 2006.
Contact informationJohn M Beal;
Sarah J McCoy, Oklahoma State University Center for Health Sciences
email: sjmccoy98@aol.com
Notes 

Ancillary