Letters

be more likely to have advanced disease and worse outcomes like pneumonia. Despite the lack of association observed between pneumonia and the combination of LABA and ICS vs LABAs alone, our article never questioned the association between ICSs and pneumonia. We merely suggested that real-world older, frailer patients might have risk factors for pneumonia hospitalization that overshadow the risk of ICSs, particularly when compared with their benefits. We believe this situation is worth considering, especially if clinicians wish to customize optimal care for different types of patients. More studies like ours that examine both the risks and benefits of medication in the same population would make this possible. Andrea S. Gershon, MD, MSc Michael A. Campitelli, MPH Matthew B. Stanbrook, MD, PhD Author Affiliations: Department of Medicine, University of Toronto, Toronto, Ontario, Canada (Gershon); Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada (Campitelli); Division of Respirology, University of Toronto, Toronto, Ontario, Canada (Stanbrook). Corresponding Author: Andrea S. Gershon, MD, MSc, Institute for Clinical Evaluative Sciences, 2075 Bayview Ave, Toronto, ON M4N 3M5, Canada (andrea [email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Suissa S, Patenaude V, Lapi F, Ernst P. Inhaled corticosteroids in COPD and the risk of serious pneumonia. Thorax. 2013;68(11):1029-1036. 2. Gershon AS, Wang C, Guan J, Vasilevska-Ristovska J, Cicutto L, To T. Identifying individuals with physician diagnosed COPD in health administrative databases. COPD. 2009;6(5):388-394. 3. Hill K, Goldstein RS, Guyatt GH, et al. Prevalence and underdiagnosis of chronic obstructive pulmonary disease among patients at risk in primary care. CMAJ. 2010;182(7):673-678.

Antenatal Magnesium Sulfate and Outcomes for School-aged Children To the Editor Based on extended follow-up of the randomized Australasian Collaborative Trial of Magnesium Sulphate (ACTOMgSO4), Dr Doyle and colleagues1 reported that magnesium sulfate given to pregnant women at imminent risk of birth before 30 weeks’ gestation was not associated with neurological outcomes in school-aged children, although they could not exclude a mortality advantage. This report followed a Cochrane meta-analysis of 5 randomized trials including ACTOMgSO4 showing that magnesium sulfate reduced risks of cerebral palsy, general motor dysfunction, and combined death and cerebral palsy by age 2 years in very preterm children.2 We published similar school-aged results from extended follow-up of our PREMAG randomized trial also included in the Cochrane meta-analysis.3 Based on an analogous design and roughly similar sample size (n = 503 vs n = 669 in ACTOMgSO4), we found no significant long-term advantage of magnesium sulfate on risks of neurobehavioral deficits or disorders, whether separately or in combination with death. However, contrary to ACTOMgSO4, the odds ratios for all motor, cognitive, and behavioral outcomes favored magnesium sulfate, although none were statistically significant. 306

Several reasons could explain the observed lack of longterm benefit on neurological disabilities of magnesium sulfate given before birth. In both studies, follow-up was incomplete, reaching 77% in ACTOMgSO4 and 75% to 88% in PREMAG depending on whether mortality was considered. This incomplete follow-up yielded reduced power and could have introduced selection bias, although somewhat reassuring data in this respect were presented in both reports. In addition, trying to confirm in school-aged children the beneficial effect observed in infancy after a neuroprotective perinatal intervention is challenging. The trajectory of child development is lengthy and can be influenced by many environmental factors that cannot all be accounted for, generating residual confounding. Adaptation of children is likely shaped by their interactions at school and with caregivers, which may compensate for a slow developmental trajectory. Specific educational needs could have been met more thoroughly in children from the placebo group than the magnesium sulfate group.3 The effect of fetal exposure to magnesium sulfate in very preterm children on school-aged neurological disabilities would be worth addressing in a meta-analysis. It is reassuring that neither study found evidence of harm from magnesium sulfate on school-aged neuromotor or cognitive outcomes, suggesting that the beneficial effects of magnesium sulfate observed at 2 years are not counterbalanced by later deleterious effects. Stéphane Marret, MD, PhD Jacques Bénichou, MD, PhD Author Affiliations: Department of Neonatal Medicine, Rouen University Hospital and Région-INSERM (ERI 28), Normandy University, Rouen, France (Marret); Department of Biostatistics and INSERM UMR 657, Normandy University, Rouen, France (Bénichou). Corresponding Author: Stéphane Marret, MD, PhD, Department of Neonatal Medicine, Rouen University Hospital and Région-INSERM (ERI 28), 22 Boulevard Gambetta, 76183 Rouen, France ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Doyle LW, Anderson PJ, Haslam R, Lee KJ, Crowther C; Australasian Collaborative Trial of Magnesium Sulphate (ACTOMgSO4) Study Group. School-age outcomes of very preterm infants after antenatal treatment with magnesium sulfate vs placebo. JAMA. 2014;312(11):1105-1113. 2. Doyle LW, Crowther CA, Middleton P, Marret S, Rouse D. Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus. Cochrane Database Syst Rev. 2009;(1):CD004661. 3. Chollat C, Enser M, Houivet E, et al. School-age outcomes following a randomized controlled trial of magnesium sulfate for neuroprotection of preterm infants. J Pediatr. 2014;165(2):398-400.

In Reply We stated in our article that “[o]utcomes beyond early childhood have not been reported from any of the RCTs to date.” This was correct at the time of submission; however, we acknowledge that the French PREMAG study1 has subsequently reported results at school age prior to our publication. We agree with Drs Marret and Bénichou, from the PREMAG study, that social and environmental variables are important influences on child development and may contribute to difficulty in finding longer-term effects of early treatments. A recent example where this may have occurred was

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in the Caffeine for Apnea of Prematurity randomized trial in which caffeine therapy during the first weeks after birth reduced the rates of cerebral palsy and developmental delay at 18 months corrected age2 but did not do so for either cerebral palsy3 or intellectual impairment4 at 5 years of age. Of the reasons proposed by Marret and Bénichou for us not finding long-term benefits of magnesium sulfate, we doubt that attrition is the reason because our results were null after multiple imputation for missing data. Moreover, the odds ratios for treatment were greater than 1 for cerebral palsy and definite motor dysfunction. We also doubt that specific educational needs were addressed differently in children in the placebo group vs the magnesium sulfate group in our study because the social characteristics of the intervention and control groups were almost identical, and most parents were unaware of treatment group allocation, even at school age. Neither the PREMAG study1 nor the ACTOMgSO4 study was large enough to show differences at 2 years; only metaanalyses of all trials found clear evidence for benefits on cerebral palsy and survival free of cerebral palsy. 5 Consequently, follow-up at school age would need larger sample sizes than were achieved for either study to detect risk reductions of the magnitude seen in early childhood for these outcomes. We agree that neither the PREMAG study nor the ACTOMgSO4 study found evidence of long-term harm from magnesium sulfate. However, just as neither study was large enough to show differences in cerebral palsy at 2 years, they were not large enough to be certain that there are no longterm harms. There is a need for ongoing cumulative metaanalysis of data where it is possible to pool results of similar outcomes. In this regard, because the outcomes in the PREMAG study were determined only by questionnaire and not by direct observation, as for most outcomes in the ACTOMgSO4 study, it may prove difficult to pool data from these 2 studies. A similar problem might arise if other studies report schoolage outcomes from randomized trials of magnesium sulfate before birth but use different outcome assessments. As antenatal magnesium sulfate for fetal neuroprotection is being introduced into many countries, efforts to link data on magnesium sulfate use and later health outcomes, including mortality or cerebral palsy,6 will become increasingly important in determining the long-term benefits or harms of antenatal magnesium sulfate. Lex W. Doyle, MD, MSc Peter J. Anderson, PhD Katherine J. Lee, PhD

1. Chollat C, Enser M, Houivet E, et al. School-age outcomes following a randomized controlled trial of magnesium sulfate for neuroprotection of preterm infants. J Pediatr. 2014;165(2):398-400. 2. Schmidt B, Roberts RS, Davis P, et al; Caffeine for Apnea of Prematurity Trial Group. Long-term effects of caffeine therapy for apnea of prematurity. N Engl J Med. 2007;357(19):1893-1902. 3. Doyle LW, Schmidt B, Anderson PJ, et al. Reduction in developmental coordination disorder with neonatal caffeine therapy. J Pediatr. 2014;165(2):356-359, e2. 4. Schmidt B, Anderson PJ, Doyle LW, et al; Caffeine for Apnea of Prematurity (CAP) Trial Investigators. Survival without disability to age 5 years after neonatal caffeine therapy for apnea of prematurity. JAMA. 2012;307(3):275-282. 5. Doyle LW, Crowther CA, Middleton P, Marret S, Rouse D. Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus. Cochrane Database Syst Rev. 2009;(1):CD004661. 6. Crowther CA, Middleton PF, Bain E, et al. Working to improve survival and health for babies born very preterm. BMC Pregnancy Childbirth. 2013;13:239.

Taxes and Subsidies to Improve Diet To the Editor A recent Viewpoint supported the use of broadly applied taxes and subsidies to improve dietary patterns.1 Even though this framework might be expected to improve overall population health, it is likely to be regressive and may exacerbate already widening income- and education-based disparities in dietary quality.2,3 With such taxes and subsidies, it is possible that the most vulnerable people will experience absolute health declines and increased food insecurity because many low-income communities have no or limited access to the nonprocessed, healthful foods potentially subsidized under this framework.4 Depending on the extent to which healthy alternatives are unavailable, individuals may spend a greater share of their income on food, restricting consumption or shifting consumption to more satiating and energy-dense options. Increased shares of limited resources might also be spent traveling to acquire newly subsidized foods located outside their community. Little evidence exists to support thinking that subsidies would significantly improve access to nonprocessed, healthful foods in areas where these goods are currently limited. For example, even minimum stocking requirements paired with subsidies only modestly increased the availability of relatively healthier products in one program.5 Thus, while overall population dietary pattern improvements would be welcome, it is important to be cautious that these gains are not paid for by those whose health has the most to benefit. Martin P. Wegman, BS Author Affiliation: Yale University, New Haven, Connecticut.

Author Affiliations: Department of Obstetrics and Gynaecology, The Royal Women’s Hospital, Melbourne, Australia (Doyle); Clinical Sciences, Murdoch Childrens Research Institute, Melbourne, Australia (Anderson); Clinical Epidemiology and Biostatistics, Murdoch Childrens Research Institute, Melbourne, Australia (Lee). Corresponding Author: Lex W. Doyle, MD, MSc, Department of Obstetrics and Gynaecology, The Royal Women’s Hospital, 20 Flemington Rd, Research Precinct, Parkville, Victoria 3052, Australia ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported receiving a grant from the National Health and Medical Research Council of Australia. No other disclosures were reported.

Corresponding Author: Martin P. Wegman, BS, Yale University, 367 Cedar St, New Haven, CT 06510 ([email protected]). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported that he directs SWAG Oasis, a program supported by the AMA Foundation Healthy Communities/Healthy America Fund that focuses on increasing nutrition education and access to healthy produce in underserved communities in Gainesville, Florida. 1. Mozaffarian D, Rogoff KS, Ludwig DS. The real cost of food: can taxes and subsidies improve public health? JAMA. 2014;312(9):889-890. 2. Wang DD, Leung CW, Li Y, et al. Trends in dietary quality among adults in the United States, 1999 through 2010. JAMA Intern Med. 2014;174(10):1587-1595.

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Antenatal magnesium sulfate and outcomes for school-aged children.

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