Recent eLetters

The recent review by Millar et al [1] discusses routine introduction of probiotics to preterm infants to prevent necrotizing enterocolitis (NEC). Although a recent Cochrane meta analysis [2] provides compelling evidence for the effectiveness of probiotics, the authors (and others) argue that pooling data from studies where different probiotic strains were used, is inappropriate. In addition, Millar et al regard lactobacillus GG (LGG) as a less suitable probiotic for preterm infants. They point to a (non significant) increase in sepsis in 2 studies using LGG but have not included data from another 3 published studies (see reference 2 for two further studies by Manzoni et al, and reference 3). They cite a Finnish centre where LGG has been used for NEC prophylaxis for 12 years; although the incidence of NEC was not significantly reduced after LGG introduction, the intervention was regarded as safe [4].Safety of LGG routine administration over a 6 year period has also been recently reported for VLBW neonates at two large Italian NICUs [5]. In addition, normal 12-month neurological follow-up compared to placebo has been reported [3]

Millar et al also point to reports of bacteremia with LGG, particularly with short gut syndrome. This risk is very small, is present with other probiotics, but is probably better recognized with LGG because it has been most extensively studied [6]. Looking at the current randomized controlled trials on LGG, there is now combined experience in over 600 preterm infants [2, 3, plus an extension of the Manzoni et al 2009 study, 7]. The odds ratio of NEC (8 of 772 in the pooled treatment arm compared to 36 of 807 receiving placebo) is 0.22 (95%CI 0.1-0.5); that of sepsis (57/623 compared to 85/641) is 0.66 (95% CI 0.46-0.95) and mortality 0.66 (95% CI 0.37-1.2). In this pooled analysis, some infants receiving LGG also got lactoferrin (LF). Omitting studies where LF was also used reduces numbers significantly and widens confidence intervals, but overall trends are in the same direction (NEC 0.58 CI 0.2-1.6, sepsis 0.88 CI 0.58-1.35, mortality 0.58 CI 0.2-1.6).

The editorial also raises the issue of the potential development of antibiotic resistance and colonisation with pathogens following probiotic use. No plasmids containing transferable or antibiotic resistance are present in LGG [6]. Furthermore, colonization with Candida species is reduced [3]. It therefore appears that LGG is eminently suitable for preterm infants and the pooled results for LGG are similar to the overall probiotic meta analysis [2]. Therefore, informed consent for placebo controlled trials will need to be consistent with current evidence of the effectiveness of LGG and other probiotics. We believe the time is for head to head probiotic comparative and follow up studies, rather than further placebo controlled trials. Although cross contamination is a potential confounding factor, the same weakness applies to the non treatment arm in placebo controlled studies and could be clarified by microbiological surveillance.

M P Meyer Neonatal consultant, Middlemore Hospital and University of Auckland, New Zealand

P Manzoni Neonatology and NICU, AO OIRM-Ospedale S.Anna. Torino, Italy

References

1 Millar M, Wilks M, Fleming P, Costeloe K. Should the use of probiotics in the preterm be routine? Arch Dis Child Fetal Neonatal Ed 2012;97:F70-F74

2. AlFaleh K, Anabrees J, Bassler D, Al-Kharfi T. Probiotics for prevention of necrotizing enterocolitis in preterm infants. Cochrane Database of Systematic Reviews 2011, Issue 3. Art. No.: CD005496. DOI: 10.1002/14651858.CD005496.pub3.

3. Romeo M, Romeo D, Trovato L, et al. Role of probiotics in the prevention of the enteric colonization by Candida in preterm newborns: incidence of late-onset sepsis and neurological outcome. J Perinatol 2011;31:63-69

4. Luoto R, Isolauri E, Lehtonen L Safety of Lactobacillus GG probiotic in infants with Very Low Birth Weight: twelve years of experience. Clin Infect Dis 2010;50(9):1327-1328

5. Manzoni P, Lista G, Gallo E, et al. Routine Lactobacillus rhamnosus GG administration in VLBW infants: A retrospective, 6-year cohort study. Early Hum Dev 87S (2011) S35-S38

6. Snydman D. The safety of probiotics. Clin Infect Dis 2008; 46:S104 -111

7. Manzoni P, Rinaldi M, Meyer M, et al Bovine lactoferrin supplementation for prevention of necrotizing enterocolitis in preterm very low birth weight neonates: a randomized trial. E-PAS 2011 3535.7

Conflict of Interest:

None declared

Dear Editor,

we read with interest the paper by C J Bossley et al (1) in which the authors performed fitness-to-fly tests to understand if preterm infants with broncopulmonary dysplasia might require supplemental oxygen during high-altitude flight. In the opening sentence of abstract it is stated that "during air flight cabin pressurisation produces an effective fraction of inspired oxygen of 15%", but this sentence, in our opinion, may be misleading or, at least, needs to be explained in more details. For this reason we would like just to point out the difference between fraction of inspired oxygen and partial pressure of oxygen. The fraction of inspired O2, or FiO2, also known as ambient O2 concentration, indicates the proportion of O2 in the inspired air. In standard air condition FiO2 is 21%. This parameter is not directly related to the absolute number of O2 molecules per gas volume, but specifies the proportion of oxygen in the air mixture. The effective number of O2 particles depends rather on the specific air thermodynamic state (its temperature and pressure). The partial pressure of O2 in alveolar gas, or PAO2, instead is directly proportional to the amount of O2 present in the gas mixture (at a specific temperature) and therefore O2 exchange at the alveoli level is degraded as the air pressure is reduced. In other words PAO2 relates directly to the actual number of O2 molecules and consequently to the alveolar oxygen tension which in turn affects the diffusion into the pulmonary capillary blood. The alveolar O2 exchange can be improved by increasing both the FiO2 (changing the air mixture proportions) and the air thermodynamic pressure (augmenting the PAO2). The PAO2 is dependent on barometric pressure which at sea level is considered equal to 760 mmHg (with 15?C temperature). Therefore at sea level PAO2 is approximately 150 mmHg. Considering that barometric pressure varies with altitude, PAO2 consequently decreases while FiO2 remains constant at 21%. Because aircrafts use to fly at high altitudes, the common practice is then to pressurise the cabin thus maintaining an adequate PAO2. The pressure value into the cabin is fixed to a minimum of 75.3 kPa, or 564 mmHg, corresponding to an altitude of 8000 ft, or 2438 m, the so-called physiological zone. However, at 2438 m (8000 ft) the PAO2 is less than at sea level and thus the O2 exchange is degraded. Specifically such condition is equivalent of breathing an air mixture with 15% oxygen at sea level. Consequently, to simulate the situation of being at 2438m, the fitness-to-fly test is performed, following the British Thoracic Society Recommendations (2), with the oxygen level inside the box reduced to 15% by adding nitrogen into the chamber. We suggest, in order to avoid confusion among not specialized readers, to specifically remark that during high-altitude flights the FiO2 in the cabin remains 21%, while the PAO2 changes. The value of PAO2 in pressurised cabin is actually equivalent to the value detectable at sea level when the FiO2 is artificially decreased to 15%.

References

1. Bossley CJ, Cramer D, Mason B, Hayward A, Smyth J, McKee A, Biddulph R, Ogundipe E, Jaff? A, Balfour-Lynn IM. Fitness to fly testing in term and ex-preterm babies without bronchopulmonary dysplasia. Arch Dis Child Fetal Neonatal Ed. 2011 Sep 13. 2. www.brit- thoracic.org.uk/Portals/0/Clinical%20Information/Air%20Travel/Guidelines/FlightRevision04.pdf Brithish Thoracic Society Standards of care Committee.Managing Passengers with Respiratory Disease Planning and Air Travel. (accessed 13 Jul 2011).

Conflict of Interest:

None declared

Dear Editor,

We read with interest the paper by Vasudevan et al. on foetal and perinatal consequences of maternal obesity.(1) The authors highlight the increased risk of perinatal mortality, neural tube and structural cardiac defects in the offspring. They also report an increased risk of birth injuries, perinatal asphyxia, respiratory distress and metabolic instability that are related to the associated foetal macrosomia. In a recent study of 6125 pregnant women (25% of whom were overweight, 12.1% moderately and 7% severely obese), to differentiate between the direct effects of maternal obesity on neonatal outcomes and those caused by confounding factors, such as foetal macrosomia, we used a logistic multivariate analysis.(2) Although the crude unadjusted prevalence of several adverse neonatal outcomes was higher in their offspring, the only two outcomes significantly directly associated with maternal obesity were neonatal macrosomia (adjusted odds ratios aOR 1.4, p < 0.001) and meconium aspiration syndrome (aOR 1.6, p = 0.05). All other neonatal outcomes, such as birth injuries, metabolic disturbances were confounded by the associated foetal macrosomia. In addition we found no significant association with congenital anomalies. This validates the results of a meta-analysis which also showed no significant relationship between maternal obesity and the incidence of neonatal asphyxia, hypoglycaemia or the need for mechanical ventilation.(3) Furthermore, such an association, if it exists, may not necessarily be causal. Therefore, while we agree that prevention of maternal obesity would very likely decrease adverse health risks on the mother, we believe that any resulting decrease in foetal and neonatal complications would be mainly due to decreasing the prevalence of foetal macrosomia, although a causal relationship still needs to be established. There is currently no evidence to support the idea that prevention of maternal obesity has the potential to decrease neonatal complications not directly related to foetal macrosomia. Further research is needed to clarify these issues before any recommendations can be made.

References

1. Vasudevan C, Renfrew M, McGuire W. Fetal and perinatal consequences of maternal obesity. Arch Dis Child Fetal Neonatal Ed 2011;96:F378-82

2. Narchi H, Skinner A. Overweight and obesity in pregnancy do not adversely affect neonatal outcomes: new evidence. J Obstet Gynaecol 2010;30:679-86

3. Heslehurst N, Simpson H, Ells LJ, et al. The impact of maternal BMI status on pregnancy outcomes with immediate short-term obstetric resource implications: a meta-analysis. ObesRev 2008;9:635-83

Conflict of Interest:

None declared

To the editor, We were most interested to read the review by Sie et al.1 The authors reviewed the literature on the effects of SRI use in pregnancy for mothers and their offspring, and formulated guidelines. However, although their review could have been more comprehensive, our main concern is with their "practical recommendations". Several guidelines produced by psychiatric governing bodies have been published regarding this subject, which were formulated using evidence-based information with a multidisciplinary approach.2 Therefore, we feel that some of Sie et al recommendations are not only redundant but may not be in the best interests of either the mother or baby. There were several recommendations that we found troubling: 1) there is no such thing as a "safe" antidepressant to use in pregnancy. The danger is that a woman will switch and her depression will not be treated effectively, increasing the risk of depression. 2) Tapering of antidepressants doses is not useful, since there is no linear dose- response curve, and therefore effects of changes in dose are very hard to predict.3 3) Regarding breastfeeding, because the pharmacodynamics of these drugs are individual, discouraging continuation of use of an antidepressant (fluoxetine) solely based on an M/P ratio of maximally 11 percent is arbitrary. In addition, none of the antidepressants (including fluoxetine) are excreted in breast milk in large enough amounts to disallow breastfeeding, and there are very few reports of adverse effects in the infant.4 4) The Finnegan score (as the authors acknowledge) was not designed for SRI-related symptoms in neonates, but for fetal exposure to opioids. Therefore, clinical decision making when suspecting poor neonatal adaptation syndrome, should not be based solely on a Finnegan score, and finally, 5) we are not aware of any evidence suggesting an anticonvulsant such as phenobarbital for treatment of symptoms.2

Geert.W. 't Jong MD PhD Clinical Fellow in Clinical Pharmacology Division of Clinical Pharmacology & Toxicology and The Motherisk Program, The Hospital for Sick Children, University of Toronto, Toronto ON, Canada Adrienne Einarson RN Consultant, The Motherisk Program, The Hospital for Sick Children, University of Toronto, Toronto ON, Canada

References 1. Sie SD, Wennink JMB, van Driel JJ, et al. Maternal use of SSRIs, SNRIs and NaSSAs: practical recommendations during pregnancy and lactation. Arch Dis Child Fetal Neonatal Ed. 2011. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21798871. Accessed August 4, 2011. 2. Yonkers KA, Wisner KL, Stewart DE, et al. The management of depression during pregnancy: a report from the American Psychiatric Association and the American College of Obstetricians and Gynecologists. Gen Hosp Psychiatry. 2009;31(5):403-413. 3. Burke MJ, Harvey AT, Preskorn SH. Pharmacokinetics of the newer antidepressants. Am. J. Med. 1996;100(1):119-121. 4 Kendall-Tackett K, Hale TW The use of antidepressants in pregnant and breastfeeding women: a review of recent studies. J Hum Lact. 2010 May;26(2):187-95. Review.

Conflict of Interest:

None declared

To The Editor: I read the article by Tracy et al with great interest (1). However I would like to point out few issues that need explanation before the study results can be accepted. First, despite of more leak with one person method, the tidal volumes being delivered are not statistically different in both the groups. Hence, the superiority of this technique in decreasing the need of endotracheal intubation and chest compression by improving ventilation is doubtful and should be first tested in clinical studies before its widespread implementation. Second, surprisingly the tidal volumes generated in both the techniques are much above the desired tidal volume of 4-5ml/kg. Animal studies have clearly shown that ventilation even for 15 minutes at high tidal volumes (15ml/kg) initiates' lung injury which in turn cause decreased lung compliance and impaired gas exchange. Third, the current Neonatal Resuscitation Programme guidelines recommend the presence of one person at every delivery and two persons in high risk deliveries (2). This new technique will require one extra resuscitator. The burden of one more resuscitator will be a big challenge for developing countries where 98% of total neonatal deaths occur worldwide (3). Fourth, the sample size calculation has not been elaborated by the authors. Despite these limitations, I appreciate the authors for their work which opens up new arenas of research in mask ventilation and neonatal resuscitation.

References 1.Tracy MB, Klimek J, Coughtrey H, Shingde V, Ponnampalam G, M Hinder M et al. Mask leak in one-person mask ventilation compared to two-person in newborn infant manikin study. Arch Dis Child Fetal Neonatal Ed 2011;96:195 -200.

2.Kattwinkel J, Perlman JM, Aziz K, Colby C, Fairchild K, Gallagher J et al. Neonatal Resuscitation: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010;122;909-919.

3.Carlo Wa, Goudar SS, Jehan I, Chomba E, Tshefu A, Garces A et al. Newborn-Care Training and Perinatal Mortality in Developing Countries. N Engl J Med 2010;362:614-23.

Conflict of Interest:

None declared