Randomisation is essential in Ebola drug trials In their Correspondence (Oct 18, p 1423),1 Clement Adebamowo and colleagues suggest that new Ebola drugs should not be assessed with clinical trials that use randomisation.1 There are at least four reasons to think they are mistaken. First, they argue that “the priority must be to generate data about effectiveness and safety as swiftly as possible” to enable treatments to be developed. This is entirely correct, but the best way to generate such data is in a randomised controlled trial. Failure to randomise patients amounts to research without a control group and would weaken the evidence base,2 which is also disrespectful to research participants. Second, Adebamowo and colleagues1 argue that the high mortality among Ebola patients receiving normal medical treatment means that “it is problematic to insist on randomising patients to it when the intervention arm holds out at least the possibility of benefit”. In many cancer trials, randomisation takes place despite similar mortality risk and little prospect of benefit. The authors seem to be assuming that new drugs will be effective, but until there is strong evidence, there is equally good reason to believe that they will harm patients infected with Ebola. Third, Adebamowo and coworkers1 contend that terrified populations “cannot be expected to offer informed consent to such randomised trials”. This claim might be true, but how can they then give informed consent to receiving an untested drug in what is essentially a non-randomised phase 1 trial? Inability to give consent does not mean that randomisation should not take place, as shown by several important trials in emergency medicine.3 Furthermore, to abandon usual trial protocols and www.thelancet.com Vol 384 November 8, 2014
give all participants a new drug that turns out to be harmful could also weaken trust. Finally, the authors overlook the fact that supplies of ZMapp and other Ebola treatments are very scarce. A randomised controlled trial is the best way to generate strong evidence with these small supplies, and randomisation also means that trials will be twice as large because only 50% of participants will receive the new treatment. Ebola raises many practical problems, but they actually mean that randomisation is vital, not optional. I declare no competing interests.
David Shaw [email protected] Institute for Biomedical Ethics, University of Basel, 4056 Basel, Switzerland 1
2
3
Adebamowo C, Bah-Sow O, Binka F, et al. Randomised controlled trials for Ebola: practical and ethical issues. Lancet 2014; 384: 1423–24. Rid A, Emanuel E. Ethical considerations of experimental interventions in the Ebola outbreak. Lancet 2014; published online Aug 21. http://dx.doi.org/10.1016/S01406736(14)61315-5. Shaw D. HEAT-PPCI sheds light on consent in pragmatic trials. Lancet 2014; published online July 5. http://dx.doi.org/10.1016/S01406736(14)61040-0.
Delayed cord clamping With great interest, I read Nestor Vain and colleagues’ study (July 19, p 235)1 on the influence of gravity on placental transfusion. The study results should help to cease the dangerous practice of clamping and cutting the umbilical cord prematurely. However, I have a few questions about the study design and results that should be considered. Although the authors address some drawbacks, there is no mention of oxytocin use during labour (likely in women who have epidurals), which might have an effect on uterine activity after birth and fetoplacental transfusion. Almost all of the women included in the study gave birth in bed, with most of them lying down (none were reported to be in an
upright position), which might have an effect on perfusion of the vena cava inferior and possibly on blood volumes within the fetoplacental unit. Of the 546 low-risk, full-term, eligible parturients included, 83 (15·2%) were excluded for operative procedures, which seems high for a low-risk population. 17 (3%) of the remaining healthy, full-term, singleton, vaginally delivered newborns needed resuscitation. This rate seems very high. These atypical results in a healthy population point to a general problem with research on normal labour in hospital settings, with routine interventions that might alter the birth process. This makes interpretation of research results in this specialty challenging, as long as routine interventions are common in the clinical (study) setting.
James Akena/Reuters/Corbis
Correspondence
Published Online October 24, 2014 http://dx.doi.org/10.1016/ S0140-6736(14)61735-9
I declare no competing interests.
Christiane Schwarz [email protected] Midwifery Research and Education Unit, Hannover Medical School, Hannover 30625, Germany. 1
Vain NE, Satragno DS, Gorenstein AN, et al. Effect of gravity on volume of placental transfusion: a multicentre, randomised, non-inferiority trial. Lancet 2014; 384: 235–40.
Nestor Vain and colleagues’ study1 shows that babies can receive substantially more blood from their placenta while lying in their mother’s arms. The only problem they mention is a slight increase in the frequency of jaundice, which can be easily handled in resource-rich settings. It is important to make sure that late cord clamping (ie, while the thin barrier between the circulations is distorted, perhaps disrupted, for some time) does not lead to other complications, for example, in situations where (undiagnosed) HIV, hepatitis, malaria, or spirochete infections are prevalent or Rhesus screening and anti-RhD prophylaxis are not perfectly organised. Additionally, any unexplained fever before delivery (perhaps as a result of septicaemia, measles, toxoplasmosis,
Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/
1667
Correspondence
lyme, Q-fever, listeriosis, yellow fever, varicella, influenza, etc) should warrant early clamping. It would be easy to check this assertion for Rhesus antigens. If more antigens migrate during those 2 extra mins, against the pressure gradient, then increased migration of much smaller microorganisms with the pressure gradient seems likely. I declare no competing interests.
Douwe Arie Verkuyl [email protected]
I declare no competing interests.
Refaja Hospital,Stadskanaal, 9500AC Netherlands.
Daniele Focosi
1
[email protected]
Vain NE, Satragno DS, Gorenstein AN, et al. Effect of gravity on volume of placental transfusion: a multicentre, randomised, non-inferiority trial. Lancet 2014; 384: 235–40.
The findings by Nestor Vain and colleagues1 confirm the straightforwardness of the universal use of delayed cord blood clamping as routine obstetric practice. As the Article points out, this practice goes against umbilical cord blood donation.2 In a phase of worldwide exponential increase, the Bone Marrow Donor Wordwide registry reports, as of Oct 8, 2014, 616 997 banked cord blood units and about 30 000 cord blood transplants performed. Because about 90% of collections contain less than 1·5 million nucleated cells (a commonly used threshold for banking), more than 5 million newborns have been denied their cord blood without any social benefit, after the cost incurred by parents for pre-delivery examinations and the potential harm to the health of newborns.3 From the primum non nocere point of view, cord blood collection seems unethical. However, nowadays, cord blood is presented as clinical waste, a by-product of birthing, and a gift made available to a global exchange-based bioeconomy;4 moreover, emotional advertising campaigns have facilitated the growth of private profit-making cord blood banks aimed at autologous use. The trend to retarget unbankable cord blood units to blood derivatives (mainly plasma eye drops or platelet 1668
gel) or cell therapy products is of little use since alternative and more cost-effective sources exist from voluntary adult blood donations.5 Adding to this scenario, the need for multiple cord blood units per adult recipient, the high rate of engraftment failure, and the increased cost of admission to hospital due to delayed engraftment, I conclude that the cost-to-benefit ratio of the whole procedure undermines its sustainability.
University of Pisa, Department of Translational Research, Via Roma 56, Pisa, PI 56100, Italy 1
2 3
4
5
Vain NE, Satragno DS, Gorenstein AN, et al. Effect of gravity on volume of placental transfusion: a multicentre, randomised, non-inferiority trial. Lancet 2014; 384: 235–40. Raju T. Delayed cord clamping: does gravity matter? Lancet 2014; 384: 213–14. McDonald SJ, Middleton P, Dowswell T, Morris PS. Effect of timing of umbilical cord clamping of term infants on maternal and neonatal outcome. The Cochrase Databaic Syws Rev 2013; 7: Cd004074. Brown N. Contradictions of value: between use and exchange in cord blood bioeconomy. Sociol Health Illn 2013; 5: 97–11. Parazzi V, Lazzari L, Rebulla P. Platelet gel from cord blood: a novel tool for tissue engineering. Platelets 2010; 21: 549–54.
Authors’ reply We thank Christiane Schwarz, Douwe Arie Verkuyl, and Daniele Focosi for their interest in our study.1 Schwarz brings up several aspects that deserve consideration. The only hospital in which mothers received epidural anaesthesia included 129 infants. It is correct that most of the mothers received oxytocin during labour, but the doses, timing, and duration of infusion were variable because, ours being a pragmatic study, the administration of oxytocin was decided by each obstetrician. Since all the mothers in the study delivered in beds, we have no way of answering the question related to the influence of the vertical position on the amount of placental transfusion, and the same answer applies to caesarean section deliveries. Trials can only address
the effect of the outcome variable specifically on the studied population. The percentage of deliveries with operative procedures is representative of the practice at the participating hospitals, and although the risks may be different to those in developed countries, it seems quite unlikely that gravity would influence the volume of placental transfusion in an even lower risk population. Schwarz’s judgment that 3·6% of newborns in need of resuscitation in our study is “very high” does not seem adequate; the American Academy of Pediatrics reports that about 10% of infants need some assistance to begin breathing at birth.2 Furthermore, in our trial, intended to assess only healthy newborns, any sign that could suggest that an infant might need resuscitation was sufficient reason for its exclusion from the study. We appreciate Verkuyl’s concerns about the applicability of delayed cord clamping in several specific circumstances. Although possible, an increase in the risks of any of the infections mentioned by Verkuyl by the extra blood transferred with delayed cord clamping has never been demonstrated. Although it is frequently recommended to clamp the cord immediately after birth in Rhesus incompatibility, the practice is not based on well designed clinical trials. The suggestion that early clamping of the cord could prevent transmission of certain infectious agents to the infant is at the present time merely speculative. However, it has been clearly shown that delayed cord clamping decreases iron deficiency in infancy,3,4 a highly prevalent serious problem worldwide, especially in the areas where the infections mentioned by Verkuyl are particularly frequent. We entirely agree with Focosi’s thoughtful comments about the, at least, debatable usefulness of cord blood banking for future transplants and on the use for other less conventional purposes. Perhaps, an exception could be specific diseases www.thelancet.com Vol 384 November 8, 2014
give all participants a new drug that turns out to be harmful could also weaken trust. Finally, the authors overlook the fact that supplies of ZMapp and other Ebola treatments are very scarce. A randomised controlled trial is the best way to generate strong evidence with these small supplies, and randomisation also means that trials will be twice as large because only 50% of participants will receive the new treatment. Ebola raises many practical problems, but they actually mean that randomisation is vital, not optional. I declare no competing interests.
David Shaw [email protected] Institute for Biomedical Ethics, University of Basel, 4056 Basel, Switzerland 1
2
3
Adebamowo C, Bah-Sow O, Binka F, et al. Randomised controlled trials for Ebola: practical and ethical issues. Lancet 2014; 384: 1423–24. Rid A, Emanuel E. Ethical considerations of experimental interventions in the Ebola outbreak. Lancet 2014; published online Aug 21. http://dx.doi.org/10.1016/S01406736(14)61315-5. Shaw D. HEAT-PPCI sheds light on consent in pragmatic trials. Lancet 2014; published online July 5. http://dx.doi.org/10.1016/S01406736(14)61040-0.
Delayed cord clamping With great interest, I read Nestor Vain and colleagues’ study (July 19, p 235)1 on the influence of gravity on placental transfusion. The study results should help to cease the dangerous practice of clamping and cutting the umbilical cord prematurely. However, I have a few questions about the study design and results that should be considered. Although the authors address some drawbacks, there is no mention of oxytocin use during labour (likely in women who have epidurals), which might have an effect on uterine activity after birth and fetoplacental transfusion. Almost all of the women included in the study gave birth in bed, with most of them lying down (none were reported to be in an
upright position), which might have an effect on perfusion of the vena cava inferior and possibly on blood volumes within the fetoplacental unit. Of the 546 low-risk, full-term, eligible parturients included, 83 (15·2%) were excluded for operative procedures, which seems high for a low-risk population. 17 (3%) of the remaining healthy, full-term, singleton, vaginally delivered newborns needed resuscitation. This rate seems very high. These atypical results in a healthy population point to a general problem with research on normal labour in hospital settings, with routine interventions that might alter the birth process. This makes interpretation of research results in this specialty challenging, as long as routine interventions are common in the clinical (study) setting.
James Akena/Reuters/Corbis
Correspondence
Published Online October 24, 2014 http://dx.doi.org/10.1016/ S0140-6736(14)61735-9
I declare no competing interests.
Christiane Schwarz [email protected] Midwifery Research and Education Unit, Hannover Medical School, Hannover 30625, Germany. 1
Vain NE, Satragno DS, Gorenstein AN, et al. Effect of gravity on volume of placental transfusion: a multicentre, randomised, non-inferiority trial. Lancet 2014; 384: 235–40.
Nestor Vain and colleagues’ study1 shows that babies can receive substantially more blood from their placenta while lying in their mother’s arms. The only problem they mention is a slight increase in the frequency of jaundice, which can be easily handled in resource-rich settings. It is important to make sure that late cord clamping (ie, while the thin barrier between the circulations is distorted, perhaps disrupted, for some time) does not lead to other complications, for example, in situations where (undiagnosed) HIV, hepatitis, malaria, or spirochete infections are prevalent or Rhesus screening and anti-RhD prophylaxis are not perfectly organised. Additionally, any unexplained fever before delivery (perhaps as a result of septicaemia, measles, toxoplasmosis,
Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/
1667
Correspondence
lyme, Q-fever, listeriosis, yellow fever, varicella, influenza, etc) should warrant early clamping. It would be easy to check this assertion for Rhesus antigens. If more antigens migrate during those 2 extra mins, against the pressure gradient, then increased migration of much smaller microorganisms with the pressure gradient seems likely. I declare no competing interests.
Douwe Arie Verkuyl [email protected]
I declare no competing interests.
Refaja Hospital,Stadskanaal, 9500AC Netherlands.
Daniele Focosi
1
[email protected]
Vain NE, Satragno DS, Gorenstein AN, et al. Effect of gravity on volume of placental transfusion: a multicentre, randomised, non-inferiority trial. Lancet 2014; 384: 235–40.
The findings by Nestor Vain and colleagues1 confirm the straightforwardness of the universal use of delayed cord blood clamping as routine obstetric practice. As the Article points out, this practice goes against umbilical cord blood donation.2 In a phase of worldwide exponential increase, the Bone Marrow Donor Wordwide registry reports, as of Oct 8, 2014, 616 997 banked cord blood units and about 30 000 cord blood transplants performed. Because about 90% of collections contain less than 1·5 million nucleated cells (a commonly used threshold for banking), more than 5 million newborns have been denied their cord blood without any social benefit, after the cost incurred by parents for pre-delivery examinations and the potential harm to the health of newborns.3 From the primum non nocere point of view, cord blood collection seems unethical. However, nowadays, cord blood is presented as clinical waste, a by-product of birthing, and a gift made available to a global exchange-based bioeconomy;4 moreover, emotional advertising campaigns have facilitated the growth of private profit-making cord blood banks aimed at autologous use. The trend to retarget unbankable cord blood units to blood derivatives (mainly plasma eye drops or platelet 1668
gel) or cell therapy products is of little use since alternative and more cost-effective sources exist from voluntary adult blood donations.5 Adding to this scenario, the need for multiple cord blood units per adult recipient, the high rate of engraftment failure, and the increased cost of admission to hospital due to delayed engraftment, I conclude that the cost-to-benefit ratio of the whole procedure undermines its sustainability.
University of Pisa, Department of Translational Research, Via Roma 56, Pisa, PI 56100, Italy 1
2 3
4
5
Vain NE, Satragno DS, Gorenstein AN, et al. Effect of gravity on volume of placental transfusion: a multicentre, randomised, non-inferiority trial. Lancet 2014; 384: 235–40. Raju T. Delayed cord clamping: does gravity matter? Lancet 2014; 384: 213–14. McDonald SJ, Middleton P, Dowswell T, Morris PS. Effect of timing of umbilical cord clamping of term infants on maternal and neonatal outcome. The Cochrase Databaic Syws Rev 2013; 7: Cd004074. Brown N. Contradictions of value: between use and exchange in cord blood bioeconomy. Sociol Health Illn 2013; 5: 97–11. Parazzi V, Lazzari L, Rebulla P. Platelet gel from cord blood: a novel tool for tissue engineering. Platelets 2010; 21: 549–54.
Authors’ reply We thank Christiane Schwarz, Douwe Arie Verkuyl, and Daniele Focosi for their interest in our study.1 Schwarz brings up several aspects that deserve consideration. The only hospital in which mothers received epidural anaesthesia included 129 infants. It is correct that most of the mothers received oxytocin during labour, but the doses, timing, and duration of infusion were variable because, ours being a pragmatic study, the administration of oxytocin was decided by each obstetrician. Since all the mothers in the study delivered in beds, we have no way of answering the question related to the influence of the vertical position on the amount of placental transfusion, and the same answer applies to caesarean section deliveries. Trials can only address
the effect of the outcome variable specifically on the studied population. The percentage of deliveries with operative procedures is representative of the practice at the participating hospitals, and although the risks may be different to those in developed countries, it seems quite unlikely that gravity would influence the volume of placental transfusion in an even lower risk population. Schwarz’s judgment that 3·6% of newborns in need of resuscitation in our study is “very high” does not seem adequate; the American Academy of Pediatrics reports that about 10% of infants need some assistance to begin breathing at birth.2 Furthermore, in our trial, intended to assess only healthy newborns, any sign that could suggest that an infant might need resuscitation was sufficient reason for its exclusion from the study. We appreciate Verkuyl’s concerns about the applicability of delayed cord clamping in several specific circumstances. Although possible, an increase in the risks of any of the infections mentioned by Verkuyl by the extra blood transferred with delayed cord clamping has never been demonstrated. Although it is frequently recommended to clamp the cord immediately after birth in Rhesus incompatibility, the practice is not based on well designed clinical trials. The suggestion that early clamping of the cord could prevent transmission of certain infectious agents to the infant is at the present time merely speculative. However, it has been clearly shown that delayed cord clamping decreases iron deficiency in infancy,3,4 a highly prevalent serious problem worldwide, especially in the areas where the infections mentioned by Verkuyl are particularly frequent. We entirely agree with Focosi’s thoughtful comments about the, at least, debatable usefulness of cord blood banking for future transplants and on the use for other less conventional purposes. Perhaps, an exception could be specific diseases www.thelancet.com Vol 384 November 8, 2014
