Abstract
Introduction
Our first breath and its relationship to cord clamping literally affects us all. Presently, routine prophylactic neonatal red cell reduction is commonly achieved through premature cord clamping at birth – defined as any time before natural cessation of umbilical cord pulsations. This has two main consequences: first, restriction of the transfer of blood from the placenta to the neonate in the first minutes after birth; and second, increased blood pressure fluctuations during the liminal period of transition from fetal to adult circulation. Blood volume reduction typically averages 19 mL/kg (21% of the neonate’s total blood volume) or 18 mL/kg red cell volume (37% of the neonate’s red cell volume).1,2 Systematic reviewers examine the apologist claim that premature cord clamping may be beneficial because it reduces the rate of hyperbilirubinaemia and need for exchange transfusion. 3 However, it increases the rate of neonatal anaemia, and there is evidence that the blood pressure fluctuations can cause or exacerbate cerebral damage. 4 It is therefore important to explore alternative means of achieving the same end.
Premature cord clamping (control)
First introduced in the 1700s, obstetricians have encouraged premature cord clamping since the 1960s as part of ‘active management’ of the third stage of labour to prevent postpartum haemorrhage.5,6 Formal investigation in the last two decades has demonstrated that while neonatal jaundice was lowered, premature cord clamping also had potentially harmful infant side-effects.3,7,8 Consequently, in 2006, the cord clamping component of ‘active management’ was discarded by the World Health Organization 9 and the International Federation of Obstetrics and Gynaecology. 10 In the UK, the National Institute of Health and Social Care Excellence (NICE) initially determined that there was insufficient evidence to recommend a change from ‘normal practice’. 11 The Royal College of Obstetricians and Gynaecologists was also cautious about embracing change in the face of accumulating evidence of harm,12,13 but NICE recently updated its guidance to avoid clamping in the first minute. 14 Although premature cord clamping has been abandoned in many countries, it remains entrenched, undocumented and unmonitored in the UK, which had one of the highest rates in Europe. 15 This may be because circular logic advice that the cord ‘should not be clamped earlier than necessary’ is unclear and unhelpful. 13 Higher rates are noted by direct observation. 16 More recent work on implementation of ‘delayed’, ‘physiological’ or ‘wait a minute before’ clamping, in countries as far away as Peru, 17 Norway, 18 India 19 and the USA 20 has shown the possibilities and difficulties in changing birth practices. We cannot find work auditing recent UK practice. It is unclear whether resistance to change stems from ingrained culture, clinical uncertainty, the wish to rapidly transfer practical (and legal) responsibility for the newborn to the neonatologist, 21 or because it has never been demonstrated that the same ends can be achieved in another way.
In term infants, the blood volume reduction achieved through premature cord clamping amounts to around 60–75 mL (one-fifth of the total on average, although it can be substantially more)1,2 which shifts the ‘normal’ curve of neonatal haemoglobin concentration to the left by about 2.2 g/dL (95% CI −0.28 to −4.06).
3
This results in clinical effects at both ends of the distribution (Figure 1). The benefit of premature cord clamping is a reduction in hyperbilirubinaemia and phototherapy, set against increased rates of anaemia and iron deficiency in the term infant and higher blood transfusion requirements in the preterm. Increased rates of hypotension are also seen in the preterm infant who undergoes premature cord clamping.
8
These changes are thought to result from the combination of volume depletion and abrupt haemodynamic changes.
22
In fetal life, the majority of blood flows from the heart, down the aorta and directly into the umbilical arteries and placenta, before returning oxygenated to the right side of the heart through the umbilical vein. Immediate cord clamping not only blocks the umbilical arteries, leading to an abrupt increase in cardiac afterload, but also blocks the umbilical vein leading to an immediate decrease in cardiac pre-load. The implications of this are not clear, but cerebral vascular damage may result. Indeed, randomised trials have found that deferred cord clamping in term babies improves fine motor skills and social functioning at four years of age,
23
while randomised trials of premature babies show a reduction in periventricular haemorrhages
8
and neonatal mortality.24–26
Solid lines showing difference in neonatal haemoglobin with and without premature cord clamping. Derived from McDonald and Middleton.
3
The light blue histogram data are derived from Liverpool Women’s Hospital statistics of all term babies admitted to the neonatal intensive care unit in 2005–2010 at a time when routine premature cord clamping was practised. The graph shows the spread of values of term babies in a unit where routine prophylactic neonatal volume depletion is practised via premature cord clamping (black line) vs. physiological cord management (dark blue line shows the expected haemoglobin levels derived from Cochrane meta-analysis showing a mean difference of 2.2 g/dL Hb in term babies; McDonald and Middleton
3
).
Routine prophylactic red cell depletion through premature cord clamping is entrenched in the birthing culture of many maternity units despite the lack of evidence base and newer recommendations. 14 Fortuitously, it enhances the volume of cord blood for stem cell collection, thus providing a strong commercial and potential financial interest. This has led some to persist with premature cord clamping, and the reduction in neonatal hyperbilirubinaemia is commonly given as a reason for this. A reduction in inpatient neonatal surveillance is also claimed to increase the importance of this, as some parents, and NHS managers, seem to be aiming for postnatal discharge even before collection of the 10-min Apgar score. However, rather than berate the evidence laggards or blame ‘vampire capitalism’, we have applied ‘realist’ and ‘harm reduction’ theory to explore a safer and more controlled way to achieve the same end; a tailored neonatal blood volume reduction without the dangerous associated haemodynamic fluctuations.
Routine day 1 umbilical vein venesection (innovation)
This pioneering, gentle method of venesection aims to achieve precise red cell volume reduction slowly, visibly and safely without significant adverse effects. As traditional cord clamps require special cutters to be removed, we propose using a sterilised freezer bag clip at birth that can be released a few hours later. An umbilical vein catheter will be inserted, followed by blood drainage over about an hour. This will also make routine collection of neonatal stem cells simpler as the blood can be stored directly in a sterile blood bag with anticoagulant (Figure 2). Despite the theoretical advantages of this controlled neonatal volume depletion, it is unclear whether replacing premature cord clamping with a policy of routine umbilical vein venesection will reduce the rate of cerebral damage and thus improve cognitive function. We will also seek to determine whether the policy change is clinically and cost-effective and, crucially, whether the procedure would be acceptable to parents. A randomised trial will compare the two interventions.
Newborn baby receiving visible venesection on first day of life (Intervention group) aiming to remove a controlled and calculated fifth of the total blood volume based on birth weight.
Proposed trial protocol
Study procedures
Premature cord clamping (control)
Routine cord clamping within 30 s of birth. No umbilical venesection permitted except for indicated tests. All volumes of blood (including from peripheral vessels and ‘heel prick’ tests) to be recorded.
Controlled umbilical vein venesection (Intervention)
The cord will only be clamped once it has stopped pulsating or at least 5 min after birth, irrespective of mode of delivery. Those babies appearing to need immediate care will be assessed, stabilised and resuscitated at the bedside with the cord intact using the LifeStart Trolley, a portable bedside resuscitation trolley 27 (see competing interest statement). All neonates will subsequently have their umbilical cord clamp released between 4 and 24 h postpartum, an umbilical vein catheter inserted and 19 mL/kg of blood will be gradually drained over 60 min with cardiovascular monitoring. The blood will be discarded hygienically unless required for clinical tests or retained as part of a stem cell collection programme. Venesection might be associated with some maternal emotional distress, and this will be minimised by completing the intervention ‘out of sight’ in an examination room on the postnatal ward or on the neonatal unit.
Outcomes
Primary outcome: Mild developmental delay and/or behaviour problem at 18 months as determined by the Bayley III Cognitive Scale.
Secondary outcomes: Rates of postnatal hypotension, periventricular haemorrhage, cerebral infarcts, hyperbilirubinaemia, phototherapy, exchange transfusion, anaemia and need for special care admission or transfusion in the first week of life, iron storage at three and six months. Alongside death, other adverse effects will be collected: need for resuscitation or oxygen, hypothermia and respiratory distress syndrome relating to premature cord clamping and bleeding, hypotension, umbilical vein occlusion, vessel puncture or sepsis relating to umbilical vein venesection. Volume of blood retrieved for commercial stem cell collection. At 1, 3 and 12 months, parents will be asked to fill in questionnaires about baby behaviour and feeding as well as standard modified Edinburgh post-natal depression and post-traumatic stress scores. Rates of parental distress, hyperventilation and collapse during the venesection procedure will also be monitored as a secondary safety outcome.
Reporting
Once funded, the trial will be registered in a WHO-approved public trial registry. EQUATOR reporting guidelines 28 will be followed for publication. Dissemination will include becoming a WHO approved standard of care for safety. 29
Randomisation
Women will be recruited antenatally and randomised online after participant registration. Randomisation lists, stratified by gestation will be generated electronically at the clinical trials unit.
Statistics
The number of babies with primary outcome will be compared between groups using chi-square tests. Multivariable logistic regression models will be used to adjust for stratification factors used at randomisation and any other baseline clinical covariates (e.g. gestational age, mode of delivery, weight and condition at birth). Covariates to be used will be pre-specified before analysis in a detailed statistical analysis plan.
Power calculation
To demonstrate a 10% reduction in the relative risk of mild developmental delay and/or mild behaviour problems from 30% to 27% at 18 months would require 7242 children (alpha 0.05, power 80%). With a conservative anticipated 12% recruitment rate from the two units (combined 16,000 deliveries per annum), recruitment is expected to take four years.
Ethics
Parents currently receive reassurance from a variety of sources that premature cord clamping and cord blood collection is entirely safe (e.g. maternity professionals, government agencies, stem cell collection companies). Presently, no formal consent is required or obtained for premature cord clamping; its timing is rarely recorded. Nevertheless, a detailed information sheet will be prepared explaining that the practices of premature cord clamping and umbilical vein venesection both carry similar theoretical risks, although these are likely to be less with slower, controlled venesection based on confirmed birth weight. We see no ethical objections to this trial and research ethics approval is awaited.
Qualitative analysis
Face-to-face interviews will be conducted by study-specific research nurses, audio-taped (with permission) and field notes taken. These will focus on mothers’ views of the two procedures, and the perceived effect on the child, bonding and feeding, as well as the involvement and view of the partner. Any parental concerns about safety compared to ‘normal’ or ‘natural’ will be considered ‘cultish’ and not explored further.
Economic analysis
The economic case will be examined by comparing the cost of setting up and running a service with the outcomes and profits it achieves. Estimates will be made for lifelong costs of different infant outcomes. Costs of pain and suffering, plus costs to various public sector agencies are derived using Hospital Inpatient Episode data and notional reference data. The medium to long-term consequences of red cell reduction are unknown (due to lack of routine data collection of clamping time and minimal research). The process necessarily rests on assumptions whose accuracy cannot be audited. The resulting uncertainty will be recognised in a Monte Carlo simulation. Because analysis is dependent upon plausible assumptions not founded on data, a policy of optimistic guesstimates will be adopted throughout. Costs of equipment, professional time, monitoring and cots will be offset by the commercial exploitation of resultant blood products. Given the epigenetic implications, we will apply for a 50-year follow-up study.
Future policy and research
Having described the rationale and details of the routine prophylactic PrEmature cord clamping vs. Routine umbilical vein VEnesection blood volume ReducTion study, we invite researchers worldwide to join this exciting collaboration. In the event that the trial shows umbilical vein venesection is superior to premature cord clamping but causes more maternal anxiety, then future research might concentrate on modifications, e.g. night-time venesection while parents are asleep might be used to allay worries, or listening to reassuring music or watching videos. It is postulated that routine venesection would become less traumatic to parents with time and familiarity, and could even be incorporated into popular culture. New rituals might be developed, whereby the father is encouraged to participate in the ‘releasing of tension' through the draining of blood. These might build on recent fashions in high-income countries for paternal cord cutting as a rite of passage to separate the mother from her baby. Alternatively, Hospital Chaplaincy Services might conduct a short ceremony on the newborn relevant to religion and denomination (e.g. removing the baby’s blood as ‘penitence for original sin’ for Christians). The Blood Transfusion Service might use ‘baby’s first blood donation’ to encourage blood donation among adults.
Conclusion
Within minutes of birth, around 20% of a newborn’s final blood volume is transferred from the placenta into the neonate. We are advocates of leaving the cord alone to allow the neonate to receive its total allocation of blood. However, many birth attendants still practise immediate cord clamping, with some arguing it reduces the amount of red cells in the neonate and prevents hyperbilirubinaemia. For those who believe routine prophylactic red cell depletion is necessary, we have designed a more controlled method of achieving the same objective. The PrEmature cord clamping vs. Routine umbilical vein VEnesection blood volume ReducTion study will establish its safety and effects on parental anxiety. Those who question the satirised ethics of this RCT should also examine the ethics of inaction while premature cord clamping continues.