Recent eLetters

The team from leed have highlighted a very important area of neonatal practice that is still seeking clarification and enlightenment. Neonates do have a high incidence of reflux due to physiologic and iatrogenic causes. These have been clearly highlighted in this review. The choice and rationale for treating these babies clearly shows that more work still needs to done before we can be sure that the doctors and nurses are using appropriate measures to address the real problem and not just propagating a placebo effect and using medications that are not only unnecessary but potentially dangerous. The following questions may help to concentrate the thinking about this problem.

Do we know if reflux in neonates is the cause of apnoeas? If not why treat If we believe there is an association in the absence of aspiration, what is the mechanism? It is agreed that the stomach of milk fed neonate is unlikely to suffer from the effect of acid (buffering effect) what then is the rationale for prescribing gaviscon? Could it be acting as a thickening agent? In the absence of proven oesophageal irritation or inflammation why do we need to further reduce acid production by using H2 blocker or even worse a proton pump inhibitor in the face of significant side effects with this substance? Is there a place for using ph study with modified (acidified) feeds for testing to demonstrate acid reflux and how significant is the position of non acid reflux in this group of patients? Should positioning not be routinely adhered to as part of routine neonatal care since gastro oesophageal reflux is common in this age group? Surgical intervention in my experience is mainly offered for severe reflux especially in patients with neurological disease or do the authors have a different experience? Is contrast study underused in these patients? And could this be a better test in this uncertain field? I concede that reflux episde may be missed during this test but its presence can be noted in addition to any anatomical defect. Although I have raised a few questions, I appreciate the efforts of the authors who have tried to highlight the clear difficulties with the investigation and treatment of reflux in this age group. Neonatologists in the front line have to deal with problems using best evidence and in most cases extrapolate from management strategies of older children. It is how ever the time to look again at the evidence and adjust practice accordingly. I remember not long ago cisapride was the standard prokinetic agent used to treat gastroesophageal reflux in neonatal units even when the evidence was not there. Tertiary neonatal units had in their formularies this dangerous medicine which was dished out routinely and thanks to the responsible authorities for the withdrawal of this product from the UK, meaning that neonates have been spared the dangers of arrhythmias. I have an interest in paediatric gastroenterology and have practised in a DGH with sessions in gastroenterology at the Children's hospital. In my practice I have investigated neonates with symptoms suggestive of gastroesophageal reflux and also suggested and advised on treatment regimes. Having looked at the evidence, I still advice on ph studies with its flaws after initiation of treatment which had failed to resolve the observed symptoms. In addition, neonates with acute life threatening events in addition to Ph studies are subjected to contrast studies to make sure no anatomical defect exists. On the use of pharmacology agents, my emphasis is on the use of prokinetic agents and less of H2 blockers or proton pump inhibitors unless evidence of oesophagitis exists or the neonate is not enterally fed with milk while symptomatic. In my experience, surgical intervention for managing gastroesophageal reflux is only common with those neonates with neurological problem with severe reflux disease. The take home message for me after reading this article is that there is a presumption by some medical practitioners that gastroesophageal Reflux disease is associated with neonatal apnoes and bradcardias and also that no reliable form of investigation exists to confirm this and that pharmacological agents though lacking in evidence remain the mainstay of treatment. It also tells me that more research is needed to provide the necessary answers. I will be very willing to be a participant in any such study.

Reference:

Peter CS, Sprodowski N, Bohnhorst B,et al Gastroesophageal reflux and apnoea of prematurity: No temporal relationship. Pediatrics 2002;109:8-11

Birch JL; Newell SJ; Gastroesophageal reflux disease in preterm infants: Current management and diagnostic dilemmas ; Arch Dis Child fetal Neonatal Ed 2009;94:F379-F383 doi:10.1136/adc.2008.149112.

Dhillon AS, Ewer AK Diagnosis and management of gastroesophageal reflux in preterm infants in neonatal intensive care units. Acta Paediatrica 2004;93:88-93

Omari TI, Haslam RR, Lundborg P, et al Effect of omeprazole on acid gastroesophageal reflux and gastric acidity in preterm infants with pathological acid reflux. J Pedr Gastroenterol Nutr 2007;44:41-44.

Conflict of Interest:

None declared

Dear Editor,

In their retrospective observational study of 1960 preterm infants over a 7-year period, Aralikatti et al reported an increased risk of developing threshold retinopathy of prematurity (ROP) in Asian and black infants compared to white infants [1]. The proportion of small for gestational age (SGA), by standard growth charts, was also higher in Asian (36.19%) than in white (29.45%) and black infants (27.81%) and the authors speculated that this might explain the increased risk of ROP in Asian infants. They also adjusted for birthweight and gestational age through logistic regression analysis and reported that the results still supported the increased risk of ROP in non-white infants.

SGA, as defined by standard growth standards, is a known risk factor for ROP in the preterm infant [2-5]. When looking for an association between ethnicity and the risk of ROP in a logistic regression model which adjusts for birthweight and gestational age, the model calculates the odds ratio of ROP for each ethnicity by adjusting separately for each unit increment in birthweight and for each unit increment in gestational age, while maintaining the other factor constant. The classification of each infant as SGA or AGA is totally ignored in the model used, as the birthweight and the gestational age of each infant are separately taken into account, without any indication whether each infant's birthweight is appropriate for his/her gestational age or not. We believe that this deficiency in the model they used prevented the authors from reliably studying whether the relationship they found between ethnicity and the risk of ROP was not confounded by growth retardation.

Furthermore, the observed ethnic differences in foetal growth are often physiologic rather than pathologic [6]. Customised birth weight percentiles, by adjusting for the variables found to be associated with normal variation in birth weight, such as maternal height, weight, parity, ethnic origin and the baby's gender, better distinguish growth-restricted from constitutionally small but healthy neonates and have been proven to be superior to standard growth charts in detecting foetal and neonatal complications associated with poor foetal growth [7-8]. Using these customised birth weight percentiles [9], we found that, regardless of gestational age, SGA infants identified exclusively by the customised method, and therefore missed by the standard growth charts, accounted for 50% of all infants diagnosed with ROP in a cohort of 6125 neonates. We also found that, after adjusting for prematurity, SGA infants exclusively identified by the customised method, still had a higher risk of complications, including an increased risk for all grades of ROP, confirming previous reports that morbidities associated with preterm delivery, including ROP [2-5], are compounded by foetal growth restriction [10].

We therefore believe that adding a classification of birthweight as SGA (or not) in their regression model, even using the standard growth charts, was needed, and would have allowed the authors to reliably confirm if the role of ethnicity in the risk of ROP is not confounded by SGA. Better still, using the customised growth percentiles instead of standard growth charts to classify infants' growth in their model would have been more appropriate, as maternal ethnicity is already integrated in the customised classification of the infant's birth weight.

Hassib Narchi, Alyson Skinner

References

1. Aralikatti AKV, Mitr A, Denniston AKO, Haque MS, Ewer AK, Butler L. Is ethnicity a risk factor for severe retinopathy of prematurity? Arch Dis Child Fetal Neonatal Ed 2010;95:F174-F176.

2. Zaw W, Gagnon R, da Silva O. The risks of adverse neonatal outcome among preterm small for gestational age infants according to neonatal versus fetal growth standards. Pediatrics 2003;111 (Part 1):1273-1277.

3. 26. Slidsborg C, Olesen HB, Jensen PK, Jensen H, Nissen KR, Greisen G, Rasmussen S, Fledelius HC, la CM. Treatment for retinopathy of prematurity in Denmark in a ten-year period (1996-2005): is the incidence increasing? Pediatrics 2008; 121:97-105.

4. Allegaert K, Vanhole C, Casteels I, Naulaers G, Debeer A, Cossey V, Devlieger H. Perinatal growth characteristics and associated risk of developing threshold retinopathy of prematurity. J AAPOS 2003;7:34-37.

5. Regev RH, Lusky A, Dolfin T, Litmanovitz I, Arnon S, Reichman B. Excess mortality and morbidity among smallfor- gestational-age premature infants: a population-based study. J Pediatr 2003;143:186-191.

6. Kierans WJ, Joseph KS, Luo ZC, Platt R, Wilkins R, Kramer MS. Does one size fit all? The case for ethnic-specific standards of fetal growth. BMC Pregnancy Childbirth 2008;8:1.

7. Gardosi J. New definition of small for gestational age based on fetal growth potential. Horm Res 2006;65 (Suppl 3):15-18.

8. Reddy UM. Prediction and prevention of recurrent stillbirth. Obstet Gynecol 2007;110:1151-1164

9. Narchi H, Skinner A, Williams B. Small for gestational age neonates- are we missing some by only using standard population growth standards and does it matter? J Matern Fetal Neonatal Med. 2009; 29:1-7.

10. Pallotto EK, Kilbride HW. Perinatal outcome and later implications of intrauterine growth restriction. Clin Obstet Gynecol 2006;49:257-269

Conflict of Interest:

None declared

Dear editor, We read with great interest the recent article by Aralikatti et al.1 The authors conducted a well designed study regarding the effect of ethnicity on developing severe retinopathy of prematurity (ROP). They concluded that asians and black infants have a higher risk of developing threshold ROP compared to white infants. Although ethinicity might be a risk factor, we think that it can hardly be considered as an independent factor. To our knowledge2,3 lower socio-economical status of the black and Asian race in most areas of the world might be the main contributing factor for the increase in severe retinopathy of prematurity incidence requiring treatment. The lower socio-economical status means lower educational level and less reliability on the data collected from the parents with respect to correct gestational age, maternal smoking and nutrition, infant nutrition. The infants born in developing countries carry greater risk of acquiring infectious, inherited and malnutrition diseases. It is well known that these all are risk factors for ROP. In our study a screening was performed on neonates born between 32 and 35 weeks gestation and referred for ROP screening between 1 January 2004 and 31 December 2008. Our unpublished data suggested that, in developing countries attention must be paid to increase awareness among neonatologists and widely used screening criteria for ROP must be revised to decrease the risk of blindness due to ROP in larger babies as it can be treatable to a great extent. From this point of view, some different aspects should be stressed. We think that though ethnicity may be an independent risk factor for developing severe ROP, concomitant attributes of the infants of the black and asian race are the main underlying factors for greater risk for severe ROP.

References 1. Aralikatti AK, Mitra A, Denniston AK et al. Is ethnicity a risk factor for severe retinopathy of prematurity? Arch Dis Child Fetal Neonatal Ed. 2009 Nov 29. (Epub) 2. Silva AM, de Almeida MF, Matsuo T, Soares DA. Risk factors for pre-term birth in Londrina, Parana State, Brazil. Cad Saude Publica. 2009; 25: 2125 -38. 3. Maida JM, Mathers K, Alley CL. Pediatric ophthalmology in the developing world. Curr Opin Ophthalmol 2008; 19(5):403-8.

Conflict of Interest:

None declared

The case report by R. Negrine and colleagues(1) is of considerable interest. However, testicular trauma following breech delivery is not extremely rare as they suggest. In 1975 I reported 11 cases of scrotal bruising and significant testicular enlargement among 114 consecutively breech-born male infants over a two year period(2). Those affected tended to be large, first-born, singleton and term or post-term infants. One infant with particularly severe damage was found to have soft and hypoplastic testicles at the age of 10 years. It is therefore not improbable that the damage at birth may be another cause of the vanishing testicle and for sterility or gonadal dysfunction. It would be of interest to study the prior incidence of breech delivery in a large series of sterile adult males.

Correspondence to: Professor Peter M. Dunn University of Bristol, Southmead Hospital, Bristol, BS10 5NB p.m.dunn@bristol.ac.uk

References

1. Negrine, R., Easter, W., Fraser, I. and Ellis, S. Neonatal testicular trauma: scrotal rupture. Arch. Dis. Child. Fetal Neonatal Ed., 2010; 95, F.193.

2. Dunn, P.M. Testicular birth trauma. Arch. Dis. Child., 1975; 50, 743.

Conflict of Interest:

None declared

Dear Editor,

It was with great interest that we read the article by Choong et al. - Remifentanil for endotracheal intubation in neonates: a randomised controlled trial. First of all, we would like to congratulate the authors for their relevant RCT. However, there are some aspects that should be pointed out. The premedication protocol for endotracheal intubation of this study includes many classes of drugs besides opioids that might interfere with physiological responses. For instance, the administration of succinylcoline (a short action muscle relaxant) might have biased the results. Indeed, premedication with succinylcoline could be able to influence the evaluation of intubation conditions by intubators. Since both groups received atropine, the pharmacodynamic responses were probably more influenced by this drug than by the opioids themselves. It should have been more appropriate if the comparison had included only the opioids (remifentanil versus fentanyl). Another issue is the evaluation of intubation conditions per se. The use of subjective impression of intubation rather than specific and validated scores1 seems to be not the ideal approach. In addition, the enrollment of six different intubators instead of just one2 could also have influenced this evaluation. The authors did not show any sample size calculation to support one of the outcomes (adverse events) and also one of the main conclusions of this trial. Even though, no differences in adverse events were detected in the comparison between groups. However, the study suggested that remifentanil was more frequently responsible for chest wall rigidity. To date, synthetic opioid administration as a cause of chest wall rigidity in adults has been recently questioned3. The general idea is that the opioids produce transient vocal cord closure rather than chest wall rigidity and this phenomenon could also happen with neonates. In this regard, succinylcoline administration might again avoid this adverse event in the group treated with fentanyl.4 Finally, the experience with remifentanil in neonates is not large enough and the RCTs with this opioid are very important. Indeed, the American Academy of Pediatrics has recently recommended the use of remifentanil as a possible premedication for neonatal endotracheal intubation.5,6 However, further properly designed and larger clinical trials are needed before any conclusion concerning the best opioid recommended for neonatal intubation.

Yerkes Pereira e Silva, MD, PhD; Juliana Marcatto, RN; Rosilu Barbosa, MD, MSc; Ana Cristina Simoes e Silva, MD, PhD

1- Viby-Mogensen J, Engbaek J, Eriksson LI et al. Good clinical research practice (GCRP) in pharmacodynamic studies of neuromuscular blocking agents. Acta Anaesthesiol Scand 1996;40:59-74.

2- E Silva Y, Gomez R, de Oliveira Marcatto J, et al. Morphine versus remifentanil for intubating preterm neonates. Arch Dis Child Fetal Neonatal Ed 2007;18:176-83.

3- Bennett JA, Abrams JT, Van Riper DF, et al. Difficult or impossible ventilation after sufentanil-induced anesthesia is caused primarily by vocal cord closure. Anesthesiology 1997;87:1070-1074.

4- Fahnenstich H, Steffan J, Kau N et al. Fentanyl induced chest wall rigidity and laryngospasm in preterm and term infants. Crit Care Med, 2000;28:836-839.

5- Kumar P, Denson, SE, Mancuso TJ and Committee of Fetus and Newborn, Section on Anesthesiology and Pain Medicine. Pediatrics 2010;125;608-615.

6- Greenwood CS, Colby CE. Pharmacology Review: Premedication for endotracheal intubation of the neonate: What is the evidence? NeoReviews 2009;10:e31-e35

Conflict of Interest:

None declared