- Email: [email protected]
Meconium Stained Newborns: Ethics for Evidence in Resuscitation
EDITORIALS
May 2015 Jennifer L. Dotson, MD, MPH Division of Pediatric Gastroenterology, Hepatology, and Nutrition The Center for Innovation in Pediatric Practice Nationwide Children’s Hospital Columbus, Ohio Joel R. Rosh, MD Goryeb Children’s Hospital Morristown, New Jersey Reprint requests: Joel R. Rosh, MD, Goryeb Children’s Hospital, 100 Madison Avenue, Morristown, NJ 07960. E-mail: [email protected]
References 1. Benchimol EI, Fortinsky KJ, Gozdyra P, Van den Heuvel M, Van Limbergen J, Griffiths AM. Epidemiology of pediatric inflammatory bowel disease: a systematic review of international trends. Inflamm Bowel Dis 2011;17:423-39. 2. Adamiak T, Walkiewicz-Jedrzejczak D, Fish D, Brown C, Tung J, Khan K, et al. Incidence, clinical characteristics, and natural history of pediatric IBD in Wisconsin: a population-based epidemiological study. Inflamm Bowel Dis 2013;19:1218-23. 3. Vernier-Massouille G, Balde M, Salleron J, Turck D, Dupas JL, Mouterde O, et al. Natural history of pediatric Crohn’s disease: a population-based cohort study. Gastroenterology 2008;135:1106-13.
4. Walters TD, Kim MO, Denson LA, Griffiths AM, Dubinsky M, Markowitz J, et al. Increased effectiveness of early therapy with antitumor necrosis factor-alpha vs an immunomodulator in children with Crohn’s disease. Gastroenterology 2014;146:383-91. 5. Mackner LM, Greenley RN, Szigethy E, Herzer M, Deer K, Hommel KA. Psychosocial issues in pediatric inflammatory bowel disease: report of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr 2013;56:449-58. 6. Greenley RN, Hommel KA, Nebel J, Raboin T, Li SH, Simpson P, et al. A meta-analytic review of the psychosocial adjustment of youth with inflammatory bowel disease. J Pediatr Psychol 2010; 35:857-69. 7. Mackner LM, Bickmeier RM, Crandall WV. Academic achievement, attendance, and school-related quality of life in pediatric inflammatory bowel disease. J Dev Behav Pediatr 2012;33:106-11. 8. Cohen BL, Zoega H, Shah SA, Leleiko N, Lidofsky S, Bright R, et al. Fatigue is highly associated with poor health-related quality of life, disability, and depression in newly-diagnosed patients with inflammatory bowel disease, independent of disease activity. Aliment Pharmacol Ther 2014;39:811-22. 9. van der Valk ME, Mangen MJ, Leenders M, Dijkstra G, van Bodegraven AA, Fidder HH, et al. Risk factors of work disability in patients with inflammatory bowel disease—a Dutch nationwide web-based survey: work disability in inflammatory bowel disease. J Crohns Colitis 2014;8:590-7. 10. Singh H, Nugent Z, Brownell M, Targownik LE, Roos LL, Bernstein CN. Academic performance among children with inflammatory bowel disease: a population-based study. J Pediatr 2015;166: 1128-33.
Meconium Stained Newborns: Ethics for Evidence in Resuscitation
T
he name meconium aspiration syndrome (MAS) for or after birth, does not improve the prognosis of infants the immediate respiratory distress associated with born through MSAF. The study of prenatal oro- and nasomeconium stained amniotic fluid (MSAF) in a pharyngeal suction by Vain et al included all infants with newborn highlights the beliefs of obstetricians and neonatolMSAF, whereas the trial of endotracheal intubation and sucogists about the etiology of MAS. For decades, airway tion by Wiswell et al randomized only infants who were obstruction was assessed to be a major vigorous at birth.5,6 See related article, p 1208 component of MAS and, consequently, sucFollowing recommendations of the tion maneuvers directed to remove meconium from the airNeonatal Resuscitation Program, when infants with MSAF ways were recommended to decrease the frequency and are born depressed, most neonatologists continue suctioning severity of MAS. The background behind those policies and of the airway before initiating positive pressure ventilation recommendations were the results of a few observational (PPV).7 However, the International Consensus on Cardiostudies with designs that would currently be considered inappulmonary Resuscitation 2010 recommendations acknowlpropriate to prove causality.1-3 In particular, there is a lack of edge a lack of evidence for this procedure.8 correlation between the presence of meconium in the trachea As with many routine practices that remain unproven, and clinical symptoms of severe MAS.4 the procedure appears to make sense. We know that there is meconium in the amniotic fluid and, therefore, in the More recently, two large randomized trials demonstrated airway. We introduce the endotracheal tube, while the inthat suctioning meconium from the airway, either before
MAS MSAF PPV RCT
Meconium aspiration syndrome Meconium stained amniotic fluid Positive pressure ventilation Randomized control trial
The authors declare no conflicts of interest. 0022-3476//$ - see front matter. Copyright ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2015.01.050
1109
THE JOURNAL OF PEDIATRICS
www.jpeds.com
fant is not breathing; why then not clear the airway from meconium before starting PPV? Several questions arise: Is clearing some meconium that could be located in the larynx and trachea enough to prevent or ameliorate MAS? The performance of endotracheal intubation takes time even in well trained hands. To be more efficient in eliminating meconium, we were taught to use the endotracheal tube as the suction device while withdrawing it from the airway, and to repeat the maneuver 2 or 3 times before initiating PPV.3 Delaying the onset of PPV and eventually the administration of oxygen in potentially asphyxiated infants could lead to unnecessary hypoxia, increase acidosis and hypercapnia, and potentially intensify pulmonary hypertension. The study by Chettri et al published in this issue of The Journal should therefore be welcomed by the perinatal community.9 The authors should be congratulated for being brave enough to evaluate in a single center randomized control trial (RCT) a procedure that albeit unproven, is considered standard of care by most neonatal groups. The study is small and has several other drawbacks. First, the process of enrollment, randomization, and treatment assignment can be questioned because the allocation of the intervention was performed prior to subject qualification. However, the process described by the authors makes selection bias unlikely. Second, the circumstances in which the informed consent process was carried out raise concerns as to its validity. Nevertheless, 122 depressed infants born with MSAF were “randomly” exposed to either intubation and suction followed by PPV or to no suction and immediate PPV. Moreover, another similar study performed in India was recently presented at the 2014 Pediatric Academic Societies meeting: 175 non-breathing infants born through MSAF were similarly randomized.10 Most importantly, in both studies there were no differences reported in any clinical outcome between groups. These results spark several interesting and controversial questions and issues: Are these 2 studies sufficient to confirm that the procedure should not be performed? In our opinion, not yet. The history of neonatology is full of examples of small studies demonstrating an effect or an association that cannot be sustained after 1 or more large RCTs are performed.11-13 Both studies have to be considered as pilots acknowledging that the risk of a type II error is high. However, as some authors point out, the best possible information can be preferable to no information for questions where low statistical power should be much less of an issue for both institutional review boards and editors than the potential for under-reporting of systematic bias.14,15 The lack of evidence acknowledged by experts, together with the results of these recent trials, highlight the need for more definitive studies.8-10 To carry out a large multicenter RCT exploring the effect of endotracheal intubation and suction in non-breathing meconium stained infants would face several major difficulties. In our view, 1110
Vol. 166, No. 5 the most important would be those related to the methodological aspects and the validity of the informed consent process. Recently, these specific topics were the focus of a published debate among several experts discussing the issue of waiving consent and other alternatives such as antenatal consent.16 As described in a previous editorial in The Journal, consent should be free, voluntary, sufficiently informed, and should include the description of alternatives to participating in research. Time should be provided for reflection, and consenting parents must be competent to give consent.17 Can parents under the stress of labor complicated by MSAF be competent to give consent? Can an ethically valid informed consent be obtained during labor in pregnancies complicated by MSAF? In our opinion, the answer to both questions is no. In fact, the trials demonstrating the lack of effect of both intubation and suctioning for vigorous infants with MSAF and of the prenatal oral and naso-pharyngeal suctioning were performed under a waiver of informed consent.5,6 These studies were relevant in that they resulted in the elimination of the recommendation to perform both procedures with no reports of a subsequent increase in MAS or other complications.18 Proponents of a waiver of consent strategy for a trial such as this argue that the requirement of an antenatal consent would be misguided based on methodological, practical, and ethical grounds.16 When consent is deemed mandatory, even for research in emergency situations, the risks are that both inclusion and representativeness of the population might be compromised.19,20 The strategy of prenatal consent for every woman admitted to the hospital for delivery as candidates for a neonatal trial is also questionable, can unnecessarily expose parents to stress, and was associated with the least level of comfort in a survey.21,22 As done previously in neonatal resuscitation research, other modalities of randomization such as a cluster controlled trial could be considered to avoid conflicts with assignment and potentially allow other informed consent modalities such as a continuous process or an “opt-out” strategy.23-25 Finally, some consideration should be given to designing a study of this sort as a non-inferiority trial. Returning to the clinical aspects, in some infants born through MSAF, chest radiographs show severe involvement and potential obstruction of the airway (some areas of atelectasis and other areas with emphysema). However, many of those infants are almost asymptomatic. Other newborns show minimal radiographic involvement but they develop severe respiratory distress.26 It is likely that the degree of asphyxia and pulmonary hypertension are more related to the severity of the disease than the degree of obstruction of the airway.4,27 Although obstruction of the lower airways may contribute to MAS, all efforts to clear the airway have been so far unsuccessful for improving the prognosis. Several research studies have suggested that inflammation and surfactant inhibition caused by meconium may also be involved
EDITORIALS
May 2015 in the physiology of MAS, and its understanding may, in the future, provide tools for some different therapeutic approaches.28,29 Meanwhile, we are left with the only tools that may improve the prognosis of infants born with MSAF: the efforts to decrease the risks of fetal distress and asphyxia, and standardized therapeutic approaches to treat respiratory distress and pulmonary hypertension in affected newborn infants. In view of the study of Chettri et al,9 the field has one obligation: to develop a feasible and ethical protocol for a sufficiently large multicenter RCT to test if intubating and suctioning the airways of depressed infants born through MSAF are useful, harmful, or at all necessary. It is our understanding that provided all the regulations and rules are followed, a large multicenter RCT under a waiver of informed consent or an opt-out approach appears to be the best possible option for such a study.30,31 n Nestor E. Vain, MD Department of Pediatrics School of Medicine University of Buenos Aires FUNDASAMIN (Fundaci on para la Salud Materno Infantil) Department of Neonatology Hospitals Sanatorio de la Trinidad Palermo and San Isidro Gabriel A. Musante, MD, MSc Department of Pediatrics Facultad de Ciencias Biomedicas Universidad Austral Department of Maternal and Child Health Hospital Universitario Austral Pilar Gonzalo L. Mariani, MD Department of Pediatrics School of Medicine University Institute Hospital Italiano de Buenos Aires Neonatology Division Hospital Italiano Buenos Aires, Argentina Reprint requests: Nestor E. Vain, MD. Honduras 4160, Buenos Aires, Argentina. E-mail: [email protected]
References 1. Carson BS, Losey RW, Bowes WA Jr, Simmons MA. Combined obstetric and pediatric approach to prevent meconium aspiration syndrome. Am J Obstet Gynecol 1976;126:712-5. 2. Gregory GA, Gooding CA, Phibbs RH, Tooley WH. Meconium aspiration in infants—a prospective study. J Pediatr 1974;85:848-52. 3. Kattwinkel J, Niermeyer S, Nadkarni V, Tibballs J, Phillips B, Zideman D, et al. An advisory statement from the Pediatric Working Group of the International Liaison Committee on Resuscitation. Pediatrics 1999;103:e56. 4. Ghidini A, Spong CY. Severe meconium aspiration syndrome is not caused by aspiration of meconium. Am J Obstet Gynecol 2001;185:931-8.
5. Wiswell TE, Gannon CM, Jacob J, Goldsmith L, Szyld E, Weiss K, et al. Delivery room management of the apparently vigorous meconiumstained neonate: results of the multicenter, international collaborative trial. Pediatrics 2000;105(1 Pt 1):1-7. 6. Vain NE, Szyld EG, Prudent LM, Wiswell TE, Aguilar AM, Vivas NI. Oropharyngeal and nasopharyngeal suctioning of meconium-stained neonates before delivery of their shoulders: multicenter, randomized controlled trial. Lancet 2004;364:597-602. 7. Textbook of Neonatal Resuscitation. 6th ed. United States of America: American Academy of Pediatrics-American Heart Association; 2011. 8. Perlman JM, Wyllie J, Kattwinkel J, Atkins DL, Chameides L, Goldsmith JP, et al. Part 11: Neonatal resuscitation: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. Circulation 2010;122(16 Suppl 2):S516-38. 9. Chettri S, Adhisivam B, Vishnu Bhat B. Endotracheal suctioning for non-vigorous neonates born through meconium stained amniotic fluid: a randomized controlled trial. J Pediatr 2015;166:1208-13. 10. Nangia S, Sunder SS, Tiwari S, Saili A. Role of endotracheal suction on the occurrence of meconium aspiration syndrome (MAS) in nonvigorous meconium stained neonates—a randomized controlled trial. E-PAS 2014;4680.1. 11. Shankaran S, Papile LA, Wright LL, Ehrenkranz RA, Mele L, Lemons JA, et al. The effect of antenatal phenobarbital therapy on neonatal intracranial hemorrhage in preterm infants. N Engl J Med 1997;337:466-71. 12. Nopper AJ, Horii KA, Sookdeo-Drost S, Wang TH, Mancini AJ, Lane AT. Topical ointment therapy benefits premature infants. J Pediatr 1996;128(5 Pt 1):660-9. 13. Edwards WH, Conner JM, Soll RF. The effect of prophylactic ointment therapy on nosocomial sepsis rates and skin integrity in infants with birth weights of 501 to 1000 g. Pediatrics 2004;113:1195-203. 14. Lilford RJ, Thornton JG, Braunholtz D. Clinical trials and rare diseases: a way out of a conundrum. BMJ 1995;311:1621-5. 15. Schulz KF, Grimes DA. Sample size calculations in randomised trials: mandatory and mystical. Lancet 2005;365:1348-53. 16. Schreiner MS, Feltman D, Wiswell T, Wootton S, Arnold C, Tyson J, et al. When is waiver of consent appropriate in a neonatal clinical trial? Pediatrics 2014;134:1006-12. 17. Vain NE, Barrington KJ. Feasibility of evaluating treatment of early hypotension in extremely low birth weight infants. J Pediatr 2012;161: 4-7. 18. 2005 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. Part 7: Neonatal resuscitation. Resuscitation 2005;67: 293-303. 19. Batton BJ, Li L, Newman NS, Das A, Watterberg KL, Yoder BA, et al. Feasibility study of early blood pressure management in extremely preterm infants. J Pediatr 2012;161:65-9.e1. 20. Rich WD, Auten KJ, Gantz MG, Hale EC, Hensman AM, Newman NS, et al. Antenatal consent in the SUPPORT trial: challenges, costs, and representative enrollment. Pediatrics 2010;126:e215-21. 21. Culbert A, Davis DJ. Parental preferences for neonatal resuscitation research consent: a pilot study. J Med Ethics 2005;31:721-6. 22. Tobias JS, Souhami RL. Fully informed consent can be needlessly cruel. BMJ 1993;307:1199-201. 23. Szyld E, Aguilar A, Musante GA, Vain N, Prudent L, Fabres J, et al. Comparison of devices for newborn ventilation in the delivery room. J Pediatr 2014;165:234-9.e3. 24. Allmark P, Mason S. Improving the quality of consent to randomised controlled trials by using continuous consent and clinician training in the consent process. J Med Ethics 2006;32:439-43. 25. Rogers CG, Tyson JE, Kennedy KA, Broyles RS, Hickman JF. Conventional consent with opting in versus simplified consent with opting out: an exploratory trial for studies that do not increase patient risk. J Pediatr 1998;132:606-11. 26. Katz VL, Bowes WA Jr. Meconium aspiration syndrome: reflections on a murky subject. Am J Obstet Gynecol 1992;166(1 Pt 1):171-83. 1111
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www.jpeds.com
27. Jovanovic R, Nguyen HT. Experimental meconium aspiration in guinea pigs. Obstet Gynecol 1989;73:652-6. 28. Lindenskov PH, Castellheim A, Aamodt G, Saugstad OD, Mollnes TE. Complement activation reflects severity of meconium aspiration syndrome in newborn pigs. Pediatr Res 2004;56:810-7. 29. Vidyasagar D, Zagariya A. Studies of meconium-induced lung injury: inflammatory cytokine expression and apoptosis. J Perinatol 2008; 28(Suppl 3):S102-7.
1112
Vol. 166, No. 5 30. Higgerson RA, Olsho LE, Christie LM, Rehder K, Doksum T, Gedeit R, et al. Variability in IRBs regarding parental acceptance of passive consent. Pediatrics 2014;134:e496-503. 31. Food and Drug Administration. Guidance for institutional review boards CI, and sponsors exception from informed consent requirements for emergency research, http://www.fda.gov/downloads/ RegulatoryInformation/Guidances/UCM249673.pdf. Accessed January 4, 2015.
May 2015 Jennifer L. Dotson, MD, MPH Division of Pediatric Gastroenterology, Hepatology, and Nutrition The Center for Innovation in Pediatric Practice Nationwide Children’s Hospital Columbus, Ohio Joel R. Rosh, MD Goryeb Children’s Hospital Morristown, New Jersey Reprint requests: Joel R. Rosh, MD, Goryeb Children’s Hospital, 100 Madison Avenue, Morristown, NJ 07960. E-mail: [email protected]
References 1. Benchimol EI, Fortinsky KJ, Gozdyra P, Van den Heuvel M, Van Limbergen J, Griffiths AM. Epidemiology of pediatric inflammatory bowel disease: a systematic review of international trends. Inflamm Bowel Dis 2011;17:423-39. 2. Adamiak T, Walkiewicz-Jedrzejczak D, Fish D, Brown C, Tung J, Khan K, et al. Incidence, clinical characteristics, and natural history of pediatric IBD in Wisconsin: a population-based epidemiological study. Inflamm Bowel Dis 2013;19:1218-23. 3. Vernier-Massouille G, Balde M, Salleron J, Turck D, Dupas JL, Mouterde O, et al. Natural history of pediatric Crohn’s disease: a population-based cohort study. Gastroenterology 2008;135:1106-13.
4. Walters TD, Kim MO, Denson LA, Griffiths AM, Dubinsky M, Markowitz J, et al. Increased effectiveness of early therapy with antitumor necrosis factor-alpha vs an immunomodulator in children with Crohn’s disease. Gastroenterology 2014;146:383-91. 5. Mackner LM, Greenley RN, Szigethy E, Herzer M, Deer K, Hommel KA. Psychosocial issues in pediatric inflammatory bowel disease: report of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr 2013;56:449-58. 6. Greenley RN, Hommel KA, Nebel J, Raboin T, Li SH, Simpson P, et al. A meta-analytic review of the psychosocial adjustment of youth with inflammatory bowel disease. J Pediatr Psychol 2010; 35:857-69. 7. Mackner LM, Bickmeier RM, Crandall WV. Academic achievement, attendance, and school-related quality of life in pediatric inflammatory bowel disease. J Dev Behav Pediatr 2012;33:106-11. 8. Cohen BL, Zoega H, Shah SA, Leleiko N, Lidofsky S, Bright R, et al. Fatigue is highly associated with poor health-related quality of life, disability, and depression in newly-diagnosed patients with inflammatory bowel disease, independent of disease activity. Aliment Pharmacol Ther 2014;39:811-22. 9. van der Valk ME, Mangen MJ, Leenders M, Dijkstra G, van Bodegraven AA, Fidder HH, et al. Risk factors of work disability in patients with inflammatory bowel disease—a Dutch nationwide web-based survey: work disability in inflammatory bowel disease. J Crohns Colitis 2014;8:590-7. 10. Singh H, Nugent Z, Brownell M, Targownik LE, Roos LL, Bernstein CN. Academic performance among children with inflammatory bowel disease: a population-based study. J Pediatr 2015;166: 1128-33.
Meconium Stained Newborns: Ethics for Evidence in Resuscitation
T
he name meconium aspiration syndrome (MAS) for or after birth, does not improve the prognosis of infants the immediate respiratory distress associated with born through MSAF. The study of prenatal oro- and nasomeconium stained amniotic fluid (MSAF) in a pharyngeal suction by Vain et al included all infants with newborn highlights the beliefs of obstetricians and neonatolMSAF, whereas the trial of endotracheal intubation and sucogists about the etiology of MAS. For decades, airway tion by Wiswell et al randomized only infants who were obstruction was assessed to be a major vigorous at birth.5,6 See related article, p 1208 component of MAS and, consequently, sucFollowing recommendations of the tion maneuvers directed to remove meconium from the airNeonatal Resuscitation Program, when infants with MSAF ways were recommended to decrease the frequency and are born depressed, most neonatologists continue suctioning severity of MAS. The background behind those policies and of the airway before initiating positive pressure ventilation recommendations were the results of a few observational (PPV).7 However, the International Consensus on Cardiostudies with designs that would currently be considered inappulmonary Resuscitation 2010 recommendations acknowlpropriate to prove causality.1-3 In particular, there is a lack of edge a lack of evidence for this procedure.8 correlation between the presence of meconium in the trachea As with many routine practices that remain unproven, and clinical symptoms of severe MAS.4 the procedure appears to make sense. We know that there is meconium in the amniotic fluid and, therefore, in the More recently, two large randomized trials demonstrated airway. We introduce the endotracheal tube, while the inthat suctioning meconium from the airway, either before
MAS MSAF PPV RCT
Meconium aspiration syndrome Meconium stained amniotic fluid Positive pressure ventilation Randomized control trial
The authors declare no conflicts of interest. 0022-3476//$ - see front matter. Copyright ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2015.01.050
1109
THE JOURNAL OF PEDIATRICS
www.jpeds.com
fant is not breathing; why then not clear the airway from meconium before starting PPV? Several questions arise: Is clearing some meconium that could be located in the larynx and trachea enough to prevent or ameliorate MAS? The performance of endotracheal intubation takes time even in well trained hands. To be more efficient in eliminating meconium, we were taught to use the endotracheal tube as the suction device while withdrawing it from the airway, and to repeat the maneuver 2 or 3 times before initiating PPV.3 Delaying the onset of PPV and eventually the administration of oxygen in potentially asphyxiated infants could lead to unnecessary hypoxia, increase acidosis and hypercapnia, and potentially intensify pulmonary hypertension. The study by Chettri et al published in this issue of The Journal should therefore be welcomed by the perinatal community.9 The authors should be congratulated for being brave enough to evaluate in a single center randomized control trial (RCT) a procedure that albeit unproven, is considered standard of care by most neonatal groups. The study is small and has several other drawbacks. First, the process of enrollment, randomization, and treatment assignment can be questioned because the allocation of the intervention was performed prior to subject qualification. However, the process described by the authors makes selection bias unlikely. Second, the circumstances in which the informed consent process was carried out raise concerns as to its validity. Nevertheless, 122 depressed infants born with MSAF were “randomly” exposed to either intubation and suction followed by PPV or to no suction and immediate PPV. Moreover, another similar study performed in India was recently presented at the 2014 Pediatric Academic Societies meeting: 175 non-breathing infants born through MSAF were similarly randomized.10 Most importantly, in both studies there were no differences reported in any clinical outcome between groups. These results spark several interesting and controversial questions and issues: Are these 2 studies sufficient to confirm that the procedure should not be performed? In our opinion, not yet. The history of neonatology is full of examples of small studies demonstrating an effect or an association that cannot be sustained after 1 or more large RCTs are performed.11-13 Both studies have to be considered as pilots acknowledging that the risk of a type II error is high. However, as some authors point out, the best possible information can be preferable to no information for questions where low statistical power should be much less of an issue for both institutional review boards and editors than the potential for under-reporting of systematic bias.14,15 The lack of evidence acknowledged by experts, together with the results of these recent trials, highlight the need for more definitive studies.8-10 To carry out a large multicenter RCT exploring the effect of endotracheal intubation and suction in non-breathing meconium stained infants would face several major difficulties. In our view, 1110
Vol. 166, No. 5 the most important would be those related to the methodological aspects and the validity of the informed consent process. Recently, these specific topics were the focus of a published debate among several experts discussing the issue of waiving consent and other alternatives such as antenatal consent.16 As described in a previous editorial in The Journal, consent should be free, voluntary, sufficiently informed, and should include the description of alternatives to participating in research. Time should be provided for reflection, and consenting parents must be competent to give consent.17 Can parents under the stress of labor complicated by MSAF be competent to give consent? Can an ethically valid informed consent be obtained during labor in pregnancies complicated by MSAF? In our opinion, the answer to both questions is no. In fact, the trials demonstrating the lack of effect of both intubation and suctioning for vigorous infants with MSAF and of the prenatal oral and naso-pharyngeal suctioning were performed under a waiver of informed consent.5,6 These studies were relevant in that they resulted in the elimination of the recommendation to perform both procedures with no reports of a subsequent increase in MAS or other complications.18 Proponents of a waiver of consent strategy for a trial such as this argue that the requirement of an antenatal consent would be misguided based on methodological, practical, and ethical grounds.16 When consent is deemed mandatory, even for research in emergency situations, the risks are that both inclusion and representativeness of the population might be compromised.19,20 The strategy of prenatal consent for every woman admitted to the hospital for delivery as candidates for a neonatal trial is also questionable, can unnecessarily expose parents to stress, and was associated with the least level of comfort in a survey.21,22 As done previously in neonatal resuscitation research, other modalities of randomization such as a cluster controlled trial could be considered to avoid conflicts with assignment and potentially allow other informed consent modalities such as a continuous process or an “opt-out” strategy.23-25 Finally, some consideration should be given to designing a study of this sort as a non-inferiority trial. Returning to the clinical aspects, in some infants born through MSAF, chest radiographs show severe involvement and potential obstruction of the airway (some areas of atelectasis and other areas with emphysema). However, many of those infants are almost asymptomatic. Other newborns show minimal radiographic involvement but they develop severe respiratory distress.26 It is likely that the degree of asphyxia and pulmonary hypertension are more related to the severity of the disease than the degree of obstruction of the airway.4,27 Although obstruction of the lower airways may contribute to MAS, all efforts to clear the airway have been so far unsuccessful for improving the prognosis. Several research studies have suggested that inflammation and surfactant inhibition caused by meconium may also be involved
EDITORIALS
May 2015 in the physiology of MAS, and its understanding may, in the future, provide tools for some different therapeutic approaches.28,29 Meanwhile, we are left with the only tools that may improve the prognosis of infants born with MSAF: the efforts to decrease the risks of fetal distress and asphyxia, and standardized therapeutic approaches to treat respiratory distress and pulmonary hypertension in affected newborn infants. In view of the study of Chettri et al,9 the field has one obligation: to develop a feasible and ethical protocol for a sufficiently large multicenter RCT to test if intubating and suctioning the airways of depressed infants born through MSAF are useful, harmful, or at all necessary. It is our understanding that provided all the regulations and rules are followed, a large multicenter RCT under a waiver of informed consent or an opt-out approach appears to be the best possible option for such a study.30,31 n Nestor E. Vain, MD Department of Pediatrics School of Medicine University of Buenos Aires FUNDASAMIN (Fundaci on para la Salud Materno Infantil) Department of Neonatology Hospitals Sanatorio de la Trinidad Palermo and San Isidro Gabriel A. Musante, MD, MSc Department of Pediatrics Facultad de Ciencias Biomedicas Universidad Austral Department of Maternal and Child Health Hospital Universitario Austral Pilar Gonzalo L. Mariani, MD Department of Pediatrics School of Medicine University Institute Hospital Italiano de Buenos Aires Neonatology Division Hospital Italiano Buenos Aires, Argentina Reprint requests: Nestor E. Vain, MD. Honduras 4160, Buenos Aires, Argentina. E-mail: [email protected]
References 1. Carson BS, Losey RW, Bowes WA Jr, Simmons MA. Combined obstetric and pediatric approach to prevent meconium aspiration syndrome. Am J Obstet Gynecol 1976;126:712-5. 2. Gregory GA, Gooding CA, Phibbs RH, Tooley WH. Meconium aspiration in infants—a prospective study. J Pediatr 1974;85:848-52. 3. Kattwinkel J, Niermeyer S, Nadkarni V, Tibballs J, Phillips B, Zideman D, et al. An advisory statement from the Pediatric Working Group of the International Liaison Committee on Resuscitation. Pediatrics 1999;103:e56. 4. Ghidini A, Spong CY. Severe meconium aspiration syndrome is not caused by aspiration of meconium. Am J Obstet Gynecol 2001;185:931-8.
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