Preventing Postnatal Cytomegalovirus Infection in the Preterm Infant: Should It Be Done, Can It Be Done, and at What Cost?

Abstract

See related articles, p 834 and p 870In 2012, 56 252 very low birth weight (VLBW, <1500 g) infants were born in the US, accounting for 1.4% of all live births.1National Center for Health Statistics PeriStats. Final natality data.www.marchofdimes.org/peristats/faqsp.aspxGoogle Scholar These infants encounter numerous morbidities, and 25%-30% experience long-term neurodevelopmental impairment (NDI).2Eichenwald E.C. Stark A.R. Management and outcomes of very low birth weight.N Engl J Med. 2008; 358: 1700-1711Crossref PubMed Scopus (254) Google Scholar Consequently, there has been an intense and elusive search for modifiable risk factors encountered in the neonatal intensive care unit (NICU) that impact long-term neurodevelopment. Whether preventing or minimizing exposure to these risk factors will prevent NDI, however, remains unclear. For example, large, randomized controlled trials demonstrate that efforts to minimize exposure to hyperbilirubinemia, hyperoxia, and hyperglycemia largely are ineffective in improving neurodevelopmental (ND) outcomes.3Beardsall K. Vanhaesebrouck S. Ogilvy-Stuart A.L. Vanhole C. Palmer C.R. van Weissenbruch M. et al.Early insulin therapy in very-low-birth-weight infants.N Engl J Med. 2008; 359: 1873-1884Crossref PubMed Scopus (222) Google Scholar, 4Morris B.H. Oh W. Tyson J.E. Stevenson D.K. Phelps D.L. O'Shea T.M. et al.Aggressive vs. conservative phototherapy for infants with extremely low birth weight.N Engl J Med. 2008; 359: 1885-1896Crossref PubMed Scopus (171) Google Scholar, 5Vaucher Y.E. Peralta-Carcelen M. Finer N.N. Carlo W.A. Gantz M.G. Walsh M.C. et al.Neurodevelopmental outcomes in the early CPAP and pulse oximetry trial.N Engl J Med. 2012; 367: 2495-2504Crossref PubMed Scopus (140) Google Scholar Thus, the search continues for preventive measures that will improve the outcomes of VLBW infants.Cytomegalovirus (CMV) is the most common congenital viral infection in high-resource countries, and infants with symptomatic infection are at high risk for NDI.6Swanson E.C. Schleiss M.R. Congenital cytomegalovirus infection: new prospects for prevention and therapy.Pediatr Clin North Am. 2013; 60: 335-349Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar Whether postnatal CMV infection in the VLBW infant increases the risk of NDI, however, is unclear.7Kurath S. Halwachs-Baumann G. Muller W. Resch B. Transmission of cytomegalovirus via breast milk to the prematurely born infant: a systematic review.Clin Microbiol Infect. 2010; 16: 1172-1178Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar Although the use of CMV-seronegative, leukoreduced blood products essentially eliminates transfusion-associated infection, transmission to VLBW infants occurs via maternal breast milk and can result in an acute sepsis-like illness.8Josephson C.D. Caliendo A.M. Easley K.A. Knezevic A. Shenvi N. Hinkes M.T. et al.Blood transfusion and breast milk transmission of cytomegalovirus in very low-birth-weight infants: a prospective cohort study.JAMA Pediatr. 2014; 168: 1054-1062Crossref PubMed Scopus (104) Google Scholar In addition, 2 epidemiologic facts indicate that we need to better understand the long-term ND effect of postnatal CMV infection in the VLBW: (1) In the US, CMV seroprevalence in women of childbearing age ranges from 30% to 90%, influenced by socioeconomic status and age6Swanson E.C. Schleiss M.R. Congenital cytomegalovirus infection: new prospects for prevention and therapy.Pediatr Clin North Am. 2013; 60: 335-349Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar; and (2) the clinical use of maternal milk for VLBW is increasing because of its established health benefits for this infant population.9Perrine C.G. Scanlon K.S. Prevalence of use of human milk in US advanced care neonatal units.Pediatrics. 2013; 131: 1066-1071Crossref PubMed Scopus (64) Google Scholar The intersection of high maternal CMV seroprevalence and an increasing CMV exposure risk through encouragement of maternal milk feeding has resulted in an inadequately informed practice that potentially puts thousands of infants at risk for NDI secondary to a potentially modifiable risk factor.In this issue of The Journal, Brecht et al10Brecht K.F. Goelz R. Bevot A. Krageloh-Mann I. Wilke M. Lidzba K. Postnatal CMV infection in preterm infants has long term neuropsychological sequelae.J Pediatr. 2015; 166: 834-891PubMed Google Scholar report the results of neuropsychiatric testing in 3 groups of adolescents (11-16 years): former preterm (VLBW or <32 weeks of gestation) infants who acquired early postnatal CMV infection (n = 19), former non–CMV-infected VLBW infants (n = 23), and former term infants (n = 24). The authors demonstrate a significant negative effect of early postnatal CMV infection on overall cognitive abilities. These findings are especially worrisome, given the lack of demonstrable impact of postnatal CMV infection on NDI when assessed earlier in childhood.11Vollmer B. Seibold-Weiger K. Schmitz-Salue C. Hamprecht K. Goelz R. Krageloh-Mann I. et al.Postnatally acquired cytomegalovirus infection via breast milk: effects on hearing and development in preterm infants.Pediatr Infect Dis J. 2004; 23: 322-327Crossref PubMed Scopus (106) Google Scholar, 12Bevot A. Hamprecht K. Krageloh-Mann I. Brosch S. Goelz R. Vollmer B. Long-term outcome in preterm children with human cytomegalovirus infection transmitted via breast milk.Acta Paediatr. 2012; 101: e167-e172Crossref PubMed Scopus (59) Google Scholar, 13Jim W.T. Shu C.H. Chiu N.C. Kao H.A. Hung H.Y. Chang J.H. et al.Transmission of cytomegalovirus from mothers to preterm infants by breast milk.Pediatr Infect Dis J. 2004; 23: 848-851Crossref PubMed Scopus (78) Google Scholar, 14Miron D. Brosilow S. Felszer K. Reich D. Halle D. Wachtel D. et al.Incidence and clinical manifestations of breast milk-acquired Cytomegalovirus infection in low birth weight infants.J Perinatol. 2005; 25: 299-303Crossref PubMed Scopus (56) Google Scholar Without these important data, we are at risk of making assumptions regarding the relative innocuous effect of postnatal CMV infection on preterm infants. The authors must be congratulated for providing us with this thoughtful and thorough long-term assessment after early CMV exposure. This study is critically important and potentially identifies postnatal CMV infection as a modifiable risk factor for NDI in preterm infants. Given that preterm infants may be at unique risk for NDI because of postnatal CMV infection, and that postnatal CMV exposure is increasing in the NICU setting after recognition of the considerable health benefits of breast milk feeding, we must ask the question: should more be done to minimize the risk of postnatal CMV acquisition for hospitalized preterm infants?Before this question can be answered, the limitations of the current study must be acknowledged. The authors have appropriately identified that this is a small study. In addition, although known independent risk factors for NDI, such as bronchopulmonary dysplasia, retinopathy of prematurity, and intracerebral hemorrhage were reported, they were not controlled for in the analysis in which the authors compared neuropsychologic test results.15Schmidt B. Asztalos E.V. Roberts R.S. Robertson C.M. Sauve R.S. Whitfield M.F. Impact of bronchopulmonary dysplasia, brain injury, and severe retinopathy on the outcome of extremely low-birth-weight infants at 18 months: results from the trial of indomethacin prophylaxis in preterms.JAMA. 2003; 289: 1124-1129Crossref PubMed Scopus (487) Google Scholar Furthermore, other known independent risk factors for NDI, including receipt of caffeine or postnatal corticosteroids, duration of mechanical ventilation, sepsis, other congenital infections, necrotizing enterocolitis, and surgery, are not controlled for or reported here. Furthermore, an additional article in this issue of The Journal by Manley et al16Manley B.J. Roberts R.S. Doyle L.W. Schmidt B. Anderson P.J. Barrington K.J. et al.the Caffeine for Apnea of Prematurity (CAP) Trial InvestigatorsSocial variables predict gains in cognitive scores across the preschool years in children with birth weights 500 to 1250 grams.J Pediatr. 2015; 166: 870-876Google Scholar makes it clear that social variables have a unique and demonstrable impact on the cognitive development experienced by VLBW infants between the ages of 2 and 5 years. Because CMV serologic status correlates with lower socioeconomic status, it may be that social risk factors that predict poor cognitive gain after discharge from the NICU have a disproportionately high prevalence in VLBW infants who acquire postnatal CMV, confounding the results reported here.Additional questions remain unanswered regarding the relationship between postnatal CMV infection in the VLBW infant and long-term NDI. Does the infant's gestational or chronologic age at time of postnatal infection matter? The infants in the cohort described in the current study were born between 23 and 32 weeks of gestation and were infected at 36-190 days.11Vollmer B. Seibold-Weiger K. Schmitz-Salue C. Hamprecht K. Goelz R. Krageloh-Mann I. et al.Postnatally acquired cytomegalovirus infection via breast milk: effects on hearing and development in preterm infants.Pediatr Infect Dis J. 2004; 23: 322-327Crossref PubMed Scopus (106) Google Scholar Can symptoms or severity of illness at time of infection predict NDI? Infants in this cohort had both symptomatic and asymptomatic infection.11Vollmer B. Seibold-Weiger K. Schmitz-Salue C. Hamprecht K. Goelz R. Krageloh-Mann I. et al.Postnatally acquired cytomegalovirus infection via breast milk: effects on hearing and development in preterm infants.Pediatr Infect Dis J. 2004; 23: 322-327Crossref PubMed Scopus (106) Google Scholar A more thorough and controlled assessment of these potential confounding factors in a larger population is needed to answer these questions.If we accept that postnatal acquisition of CMV results in NDI in VLBW infants, we have a unique opportunity to further improve their health and development by implementing safe and effective strategies to reduce the risk of CMV acquisition. Infants of mothers who are CMV-seronegative should be at no risk of CMV acquisition, barring acute CMV infection of the mother during lactation. Therefore, serologic testing of lactating mothers of preterm infants represents one option to identify at-risk infants.Yet, the lack of well-defined maternal immunologic or virologic correlates that predict postnatal CMV transmission complicates identification of high-risk women-infant pairs. Although 90% of women who are CMV-seropositive shed virus in breast milk,17Vochem M. Hamprecht K. Jahn G. Speer C.P. Transmission of cytomegalovirus to preterm infants through breast milk.Pediatr Infect Dis J. 1998; 17: 53-58Crossref PubMed Scopus (180) Google Scholar only ∼20% of exposed infants will acquire postnatal CMV infection.7Kurath S. Halwachs-Baumann G. Muller W. Resch B. Transmission of cytomegalovirus via breast milk to the prematurely born infant: a systematic review.Clin Microbiol Infect. 2010; 16: 1172-1178Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar, 8Josephson C.D. Caliendo A.M. Easley K.A. Knezevic A. Shenvi N. Hinkes M.T. et al.Blood transfusion and breast milk transmission of cytomegalovirus in very low-birth-weight infants: a prospective cohort study.JAMA Pediatr. 2014; 168: 1054-1062Crossref PubMed Scopus (104) Google Scholar Therefore, routine maternal serologic testing and testing mother's milk for the presence of CMV are not efficient means of determining which infants are most at risk of infection. Although some studies have suggested that high virus load in milk predicts risk of transmission, the milk viral load is variable over time,18Jim W.T. Shu C.H. Chiu N.C. Chang J.H. Hung H.Y. Peng C.C. et al.High cytomegalovirus load and prolonged virus excretion in breast milk increase risk for viral acquisition by very low birth weight infants.Pediatr Infect Dis J. 2009; 28: 891-894Crossref PubMed Scopus (45) Google Scholar decreasing the effectiveness of spot testing. Moreover, the maternal cellular and humoral response measured in breast milk does not correlate well with symptomatic CMV disease in preterm infants.19Ehlinger E.P. Webster E.M. Kang H.H. Cangialose A. Simmons A.C. Barbas K.H. et al.Maternal cytomegalovirus-specific immune responses and symptomatic postnatal cytomegalovirus transmission in very low-birth-weight preterm infants.J Infect Dis. 2011; 204: 1672-1682Crossref PubMed Scopus (33) Google ScholarFinally, the corrected gestational age at which the infant is still at risk of NDI from CMV acquisition is unknown, preventing the establishment of an end point for testing to identify at-risk, hospitalized preterm infants. Therefore, although serologic and breast milk screening for CMV potentially could identify infants who stand to benefit from measures to reduce postnatal CMV acquisition, it is unclear whether this approach is time-efficient or cost-effective.Processing the milk of mothers who are CMV-seropositive of VLBW infants to reduce or eliminate infectious virions is a potential strategy to reduce CMV acquisition while maintaining the health benefits of breast milk for those infants not at risk. However, we must be careful not to seek gains in ND outcomes via reduction in CMV acquisition at the expense of decreasing the benefits of exposure to maternal breast milk. Strong evidence exists that exposure to fresh mother's milk reduces the risk of morbidities associated with NDI, including necrotizing enterocolitis, late-onset sepsis, and retinopathy of prematurity.20Menon G. Williams T.C. Human milk for preterm infants: why, what, when and how?.Arch Dis Child Fetal Neonatal Ed. 2013; 98: F559-F562Crossref PubMed Scopus (58) Google Scholar There also is evidence that supports a long-lasting benefit of breast milk exposure, including a lower risk of metabolic syndrome, less insulin and leptin resistance, and improved ND outcomes.20Menon G. Williams T.C. Human milk for preterm infants: why, what, when and how?.Arch Dis Child Fetal Neonatal Ed. 2013; 98: F559-F562Crossref PubMed Scopus (58) Google Scholar, 21Underwood M.A. Human milk for the premature infant.Pediatr Clin North Am. 2013; 60: 189-207Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar Thus, avoiding CMV exposure for preterm infants by substituting maternal milk with formula is inappropriate. Routine freezing of mother's milk before the administration to the infant reduces—but does not eliminate—the risk of postnatal CMV acquisition.22Maschmann J. Hamprecht K. Weissbrich B. Dietz K. Jahn G. Speer C.P. Freeze-thawing of breast milk does not prevent cytomegalovirus transmission to a preterm infant.Arch Dis Child Fetal Neonatal Ed. 2006; 91: F288-F290Crossref PubMed Scopus (70) Google Scholar In addition, the moderate reduction in CMV transmission may come at the expense of losing beneficial human milk components vulnerable to the freeze-thaw process.23Lawrence R.A. Storage of human milk and the influence of procedures on immunological components of human milk.Acta Paediatr Suppl. 1999; 88: 14-18Crossref PubMed Scopus (117) Google Scholar Pasteurization eliminates infectious CMV virions in milk and prevents CMV transmission but destroys many of the protective factors thought to be responsible for the health benefits provided by mother's milk.23Lawrence R.A. Storage of human milk and the influence of procedures on immunological components of human milk.Acta Paediatr Suppl. 1999; 88: 14-18Crossref PubMed Scopus (117) Google ScholarBecause currently we are without means to safely prevent postnatal CMV acquisition for VLBW infants without interrupting the benefits of breast milk feeding, the effectiveness of our therapies for CMV-infected infants must be considered. Long-term treatment with ganciclovir, or its oral derivative valganciclovir, has been shown to effectively improve both the hearing and developmental outcomes of full-term infants with congenital CMV infection.24Kimberlin D.W. Lin C.Y. Sanchez P.J. Demmler G.J. Dankner W. Shelton M. et al.Effect of ganciclovir therapy on hearing in symptomatic congenital cytomegalovirus disease involving the central nervous system: a randomized, controlled trial.J Pediatr. 2003; 143: 16-25Abstract Full Text Full Text PDF PubMed Scopus (688) Google Scholar Yet, whether this would have the same effect for VLBW who acquire postnatal CMV infection is unknown. Thus, long-term anti-viral treatment of preterm infants who acquire postnatal infection to ameliorate the potential NDI associated with CMV acquisition deserves study. Ongoing pharmacokinetic and pharmacodynamic studies of ganciclovir in preterm infants by the National Institutes of Health Collaborative Antiviral Study Group will provide much needed information on dosing and side effects of CMV treatment in this infant population.25Evaluation of the PK and PD of Ganciclovir in Premature Infants Receiving Treatment for CMV Infection (Gan Premie).http://clinicaltrials.gov/ct2/show/NCT01602614?term=ganciclovir&rank=44Google ScholarIn summary, providing maternal milk to the preterm infant may have antagonistic effects, ie, protecting against a number of severe morbidities while increasing the risk of postnatal CMV infection. Importantly, the potential identification of a modifiable risk factor in the ND outcome of preterm infants provides a call to action that should not be ignored. Yet, are we stuck between the proverbial “rock and a hard place” in improving ND outcomes for preterm infants through reducing the risk of CMV acquisition while maintaining the numerous health benefits of fresh mother's milk? The benefits of maternal milk for the premature infants are proven,20Menon G. Williams T.C. Human milk for preterm infants: why, what, when and how?.Arch Dis Child Fetal Neonatal Ed. 2013; 98: F559-F562Crossref PubMed Scopus (58) Google Scholar, 21Underwood M.A. Human milk for the premature infant.Pediatr Clin North Am. 2013; 60: 189-207Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar although the risks of postnatal CMV infection acquired via maternal breast milk in VLBW infants are becoming more evident. However, until it is established that postnatal CMV infection is an independent, modifiable risk factor for NDI, the proven benefits of maternal milk should not be sacrificed. The clinical challenge of safe breast milk feeding for all VLBW infants calls for the same pioneering spirit that has brought lifesaving interventions such as antenatal corticosteroids and surfactant to neonatology. Innovative strategies that will reduce the risk of CMV acquisition while maintaining the health benefits of fresh human milk exposure, such as passive immunization with CMV-neutralizing monoclonal antibodies26Boeckh M. Bowden R.A. Storer B. Chao N.J. Spielberger R. Tierney D.K. et al.Randomized, placebo-controlled, double-blind study of a cytomegalovirus-specific monoclonal antibody (MSL-109) for prevention of cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation.Biol Blood Marrow Transplant. 2001; 7: 343-351Abstract Full Text PDF PubMed Scopus (60) Google Scholar or the enteral administration of exogenous antiviral factors such as lactoferrin,27Beljaars L. van der Strate B.W. Bakker H.I. Reker-Smit C. van Loenen-Weemaes A.M. Wiegmans F.C. et al.Inhibition of cytomegalovirus infection by lactoferrin in vitro and in vivo.Antiviral Res. 2004; 63: 197-208Crossref PubMed Scopus (60) Google Scholar are potential ideal strategies to prevent NDI in preterm infants. A better understanding of the effects of postnatal CMV infection on the preterm infant provides a unique opportunity to assess our practice and march towards outcomes for preterm infants that are indistinguishable from that of term infants. See related articles, p 834 and p 870In 2012, 56 252 very low birth weight (VLBW, <1500 g) infants were born in the US, accounting for 1.4% of all live births.1National Center for Health Statistics PeriStats. Final natality data.www.marchofdimes.org/peristats/faqsp.aspxGoogle Scholar These infants encounter numerous morbidities, and 25%-30% experience long-term neurodevelopmental impairment (NDI).2Eichenwald E.C. Stark A.R. Management and outcomes of very low birth weight.N Engl J Med. 2008; 358: 1700-1711Crossref PubMed Scopus (254) Google Scholar Consequently, there has been an intense and elusive search for modifiable risk factors encountered in the neonatal intensive care unit (NICU) that impact long-term neurodevelopment. Whether preventing or minimizing exposure to these risk factors will prevent NDI, however, remains unclear. For example, large, randomized controlled trials demonstrate that efforts to minimize exposure to hyperbilirubinemia, hyperoxia, and hyperglycemia largely are ineffective in improving neurodevelopmental (ND) outcomes.3Beardsall K. Vanhaesebrouck S. Ogilvy-Stuart A.L. Vanhole C. Palmer C.R. van Weissenbruch M. et al.Early insulin therapy in very-low-birth-weight infants.N Engl J Med. 2008; 359: 1873-1884Crossref PubMed Scopus (222) Google Scholar, 4Morris B.H. Oh W. Tyson J.E. Stevenson D.K. Phelps D.L. O'Shea T.M. et al.Aggressive vs. conservative phototherapy for infants with extremely low birth weight.N Engl J Med. 2008; 359: 1885-1896Crossref PubMed Scopus (171) Google Scholar, 5Vaucher Y.E. Peralta-Carcelen M. Finer N.N. Carlo W.A. Gantz M.G. Walsh M.C. et al.Neurodevelopmental outcomes in the early CPAP and pulse oximetry trial.N Engl J Med. 2012; 367: 2495-2504Crossref PubMed Scopus (140) Google Scholar Thus, the search continues for preventive measures that will improve the outcomes of VLBW infants. See related articles, p 834 and p 870 See related articles, p 834 and p 870 Cytomegalovirus (CMV) is the most common congenital viral infection in high-resource countries, and infants with symptomatic infection are at high risk for NDI.6Swanson E.C. Schleiss M.R. Congenital cytomegalovirus infection: new prospects for prevention and therapy.Pediatr Clin North Am. 2013; 60: 335-349Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar Whether postnatal CMV infection in the VLBW infant increases the risk of NDI, however, is unclear.7Kurath S. Halwachs-Baumann G. Muller W. Resch B. Transmission of cytomegalovirus via breast milk to the prematurely born infant: a systematic review.Clin Microbiol Infect. 2010; 16: 1172-1178Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar Although the use of CMV-seronegative, leukoreduced blood products essentially eliminates transfusion-associated infection, transmission to VLBW infants occurs via maternal breast milk and can result in an acute sepsis-like illness.8Josephson C.D. Caliendo A.M. Easley K.A. Knezevic A. Shenvi N. Hinkes M.T. et al.Blood transfusion and breast milk transmission of cytomegalovirus in very low-birth-weight infants: a prospective cohort study.JAMA Pediatr. 2014; 168: 1054-1062Crossref PubMed Scopus (104) Google Scholar In addition, 2 epidemiologic facts indicate that we need to better understand the long-term ND effect of postnatal CMV infection in the VLBW: (1) In the US, CMV seroprevalence in women of childbearing age ranges from 30% to 90%, influenced by socioeconomic status and age6Swanson E.C. Schleiss M.R. Congenital cytomegalovirus infection: new prospects for prevention and therapy.Pediatr Clin North Am. 2013; 60: 335-349Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar; and (2) the clinical use of maternal milk for VLBW is increasing because of its established health benefits for this infant population.9Perrine C.G. Scanlon K.S. Prevalence of use of human milk in US advanced care neonatal units.Pediatrics. 2013; 131: 1066-1071Crossref PubMed Scopus (64) Google Scholar The intersection of high maternal CMV seroprevalence and an increasing CMV exposure risk through encouragement of maternal milk feeding has resulted in an inadequately informed practice that potentially puts thousands of infants at risk for NDI secondary to a potentially modifiable risk factor. In this issue of The Journal, Brecht et al10Brecht K.F. Goelz R. Bevot A. Krageloh-Mann I. Wilke M. Lidzba K. Postnatal CMV infection in preterm infants has long term neuropsychological sequelae.J Pediatr. 2015; 166: 834-891PubMed Google Scholar report the results of neuropsychiatric testing in 3 groups of adolescents (11-16 years): former preterm (VLBW or <32 weeks of gestation) infants who acquired early postnatal CMV infection (n = 19), former non–CMV-infected VLBW infants (n = 23), and former term infants (n = 24). The authors demonstrate a significant negative effect of early postnatal CMV infection on overall cognitive abilities. These findings are especially worrisome, given the lack of demonstrable impact of postnatal CMV infection on NDI when assessed earlier in childhood.11Vollmer B. Seibold-Weiger K. Schmitz-Salue C. Hamprecht K. Goelz R. Krageloh-Mann I. et al.Postnatally acquired cytomegalovirus infection via breast milk: effects on hearing and development in preterm infants.Pediatr Infect Dis J. 2004; 23: 322-327Crossref PubMed Scopus (106) Google Scholar, 12Bevot A. Hamprecht K. Krageloh-Mann I. Brosch S. Goelz R. Vollmer B. Long-term outcome in preterm children with human cytomegalovirus infection transmitted via breast milk.Acta Paediatr. 2012; 101: e167-e172Crossref PubMed Scopus (59) Google Scholar, 13Jim W.T. Shu C.H. Chiu N.C. Kao H.A. Hung H.Y. Chang J.H. et al.Transmission of cytomegalovirus from mothers to preterm infants by breast milk.Pediatr Infect Dis J. 2004; 23: 848-851Crossref PubMed Scopus (78) Google Scholar, 14Miron D. Brosilow S. Felszer K. Reich D. Halle D. Wachtel D. et al.Incidence and clinical manifestations of breast milk-acquired Cytomegalovirus infection in low birth weight infants.J Perinatol. 2005; 25: 299-303Crossref PubMed Scopus (56) Google Scholar Without these important data, we are at risk of making assumptions regarding the relative innocuous effect of postnatal CMV infection on preterm infants. The authors must be congratulated for providing us with this thoughtful and thorough long-term assessment after early CMV exposure. This study is critically important and potentially identifies postnatal CMV infection as a modifiable risk factor for NDI in preterm infants. Given that preterm infants may be at unique risk for NDI because of postnatal CMV infection, and that postnatal CMV exposure is increasing in the NICU setting after recognition of the considerable health benefits of breast milk feeding, we must ask the question: should more be done to minimize the risk of postnatal CMV acquisition for hospitalized preterm infants? Before this question can be answered, the limitations of the current study must be acknowledged. The authors have appropriately identified that this is a small study. In addition, although known independent risk factors for NDI, such as bronchopulmonary dysplasia, retinopathy of prematurity, and intracerebral hemorrhage were reported, they were not controlled for in the analysis in which the authors compared neuropsychologic test results.15Schmidt B. Asztalos E.V. Roberts R.S. Robertson C.M. Sauve R.S. Whitfield M.F. Impact of bronchopulmonary dysplasia, brain injury, and severe retinopathy on the outcome of extremely low-birth-weight infants at 18 months: results from the trial of indomethacin prophylaxis in preterms.JAMA. 2003; 289: 1124-1129Crossref PubMed Scopus (487) Google Scholar Furthermore, other known independent risk factors for NDI, including receipt of caffeine or postnatal corticosteroids, duration of mechanical ventilation, sepsis, other congenital infections, necrotizing enterocolitis, and surgery, are not controlled for or reported here. Furthermore, an additional article in this issue of The Journal by Manley et al16Manley B.J. Roberts R.S. Doyle L.W. Schmidt B. Anderson P.J. Barrington K.J. et al.the Caffeine for Apnea of Prematurity (CAP) Trial InvestigatorsSocial variables predict gains in cognitive scores across the preschool years in children with birth weights 500 to 1250 grams.J Pediatr. 2015; 166: 870-876Google Scholar makes it clear that social variables have a unique and demonstrable impact on the cognitive development experienced by VLBW infants between the ages of 2 and 5 years. Because CMV serologic status correlates with lower socioeconomic status, it may be that social risk factors that predict poor cognitive gain after discharge from the NICU have a disproportionately high prevalence in VLBW infants who acquire postnatal CMV, confounding the results reported here. Additional questions remain unanswered regarding the relationship between postnatal CMV infection in the VLBW infant and long-term NDI. Does the infant's gestational or chronologic age at time of postnatal infection matter? The infants in the cohort described in the current study were born between 23 and 32 weeks of gestation and were infected at 36-190 days.11Vollmer B. Seibold-Weiger K. Schmitz-Salue C. Hamprecht K. Goelz R. Krageloh-Mann I. et al.Postnatally acquired cytomegalovirus infection via breast milk: effects on hearing and development in preterm infants.Pediatr Infect Dis J. 2004; 23: 322-327Crossref PubMed Scopus (106) Google Scholar Can symptoms or severity of illness at time of infection predict NDI? Infants in this cohort had both symptomatic and asymptomatic infection.11Vollmer B. Seibold-Weiger K. Schmitz-Salue C. Hamprecht K. Goelz R. Krageloh-Mann I. et al.Postnatally acquired cytomegalovirus infection via breast milk: effects on hearing and development in preterm infants.Pediatr Infect Dis J. 2004; 23: 322-327Crossref PubMed Scopus (106) Google Scholar A more thorough and controlled assessment of these potential confounding factors in a larger population is needed to answer these questions. If we accept that postnatal acquisition of CMV results in NDI in VLBW infants, we have a unique opportunity to further improve their health and development by implementing safe and effective strategies to reduce the risk of CMV acquisition. Infants of mothers who are CMV-seronegative should be at no risk of CMV acquisition, barring acute CMV infection of the mother during lactation. Therefore, serologic testing of lactating mothers of preterm infants represents one option to identify at-risk infants. Yet, the lack of well-defined maternal immunologic or virologic correlates that predict postnatal CMV transmission complicates identification of high-risk women-infant pairs. Although 90% of women who are CMV-seropositive shed virus in breast milk,17Vochem M. Hamprecht K. Jahn G. Speer C.P. Transmission of cytomegalovirus to preterm infants through breast milk.Pediatr Infect Dis J. 1998; 17: 53-58Crossref PubMed Scopus (180) Google Scholar only ∼20% of exposed infants will acquire postnatal CMV infection.7Kurath S. Halwachs-Baumann G. Muller W. Resch B. Transmission of cytomegalovirus via breast milk to the prematurely born infant: a systematic review.Clin Microbiol Infect. 2010; 16: 1172-1178Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar, 8Josephson C.D. Caliendo A.M. Easley K.A. Knezevic A. Shenvi N. Hinkes M.T. et al.Blood transfusion and breast milk transmission of cytomegalovirus in very low-birth-weight infants: a prospective cohort study.JAMA Pediatr. 2014; 168: 1054-1062Crossref PubMed Scopus (104) Google Scholar Therefore, routine maternal serologic testing and testing mother's milk for the presence of CMV are not efficient means of determining which infants are most at risk of infection. Although some studies have suggested that high virus load in milk predicts risk of transmission, the milk viral load is variable over time,18Jim W.T. Shu C.H. Chiu N.C. Chang J.H. Hung H.Y. Peng C.C. et al.High cytomegalovirus load and prolonged virus excretion in breast milk increase risk for viral acquisition by very low birth weight infants.Pediatr Infect Dis J. 2009; 28: 891-894Crossref PubMed Scopus (45) Google Scholar decreasing the effectiveness of spot testing. Moreover, the maternal cellular and humoral response measured in breast milk does not correlate well with symptomatic CMV disease in preterm infants.19Ehlinger E.P. Webster E.M. Kang H.H. Cangialose A. Simmons A.C. Barbas K.H. et al.Maternal cytomegalovirus-specific immune responses and symptomatic postnatal cytomegalovirus transmission in very low-birth-weight preterm infants.J Infect Dis. 2011; 204: 1672-1682Crossref PubMed Scopus (33) Google Scholar Finally, the corrected gestational age at which the infant is still at risk of NDI from CMV acquisition is unknown, preventing the establishment of an end point for testing to identify at-risk, hospitalized preterm infants. Therefore, although serologic and breast milk screening for CMV potentially could identify infants who stand to benefit from measures to reduce postnatal CMV acquisition, it is unclear whether this approach is time-efficient or cost-effective. Processing the milk of mothers who are CMV-seropositive of VLBW infants to reduce or eliminate infectious virions is a potential strategy to reduce CMV acquisition while maintaining the health benefits of breast milk for those infants not at risk. However, we must be careful not to seek gains in ND outcomes via reduction in CMV acquisition at the expense of decreasing the benefits of exposure to maternal breast milk. Strong evidence exists that exposure to fresh mother's milk reduces the risk of morbidities associated with NDI, including necrotizing enterocolitis, late-onset sepsis, and retinopathy of prematurity.20Menon G. Williams T.C. Human milk for preterm infants: why, what, when and how?.Arch Dis Child Fetal Neonatal Ed. 2013; 98: F559-F562Crossref PubMed Scopus (58) Google Scholar There also is evidence that supports a long-lasting benefit of breast milk exposure, including a lower risk of metabolic syndrome, less insulin and leptin resistance, and improved ND outcomes.20Menon G. Williams T.C. Human milk for preterm infants: why, what, when and how?.Arch Dis Child Fetal Neonatal Ed. 2013; 98: F559-F562Crossref PubMed Scopus (58) Google Scholar, 21Underwood M.A. Human milk for the premature infant.Pediatr Clin North Am. 2013; 60: 189-207Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar Thus, avoiding CMV exposure for preterm infants by substituting maternal milk with formula is inappropriate. Routine freezing of mother's milk before the administration to the infant reduces—but does not eliminate—the risk of postnatal CMV acquisition.22Maschmann J. Hamprecht K. Weissbrich B. Dietz K. Jahn G. Speer C.P. Freeze-thawing of breast milk does not prevent cytomegalovirus transmission to a preterm infant.Arch Dis Child Fetal Neonatal Ed. 2006; 91: F288-F290Crossref PubMed Scopus (70) Google Scholar In addition, the moderate reduction in CMV transmission may come at the expense of losing beneficial human milk components vulnerable to the freeze-thaw process.23Lawrence R.A. Storage of human milk and the influence of procedures on immunological components of human milk.Acta Paediatr Suppl. 1999; 88: 14-18Crossref PubMed Scopus (117) Google Scholar Pasteurization eliminates infectious CMV virions in milk and prevents CMV transmission but destroys many of the protective factors thought to be responsible for the health benefits provided by mother's milk.23Lawrence R.A. Storage of human milk and the influence of procedures on immunological components of human milk.Acta Paediatr Suppl. 1999; 88: 14-18Crossref PubMed Scopus (117) Google Scholar Because currently we are without means to safely prevent postnatal CMV acquisition for VLBW infants without interrupting the benefits of breast milk feeding, the effectiveness of our therapies for CMV-infected infants must be considered. Long-term treatment with ganciclovir, or its oral derivative valganciclovir, has been shown to effectively improve both the hearing and developmental outcomes of full-term infants with congenital CMV infection.24Kimberlin D.W. Lin C.Y. Sanchez P.J. Demmler G.J. Dankner W. Shelton M. et al.Effect of ganciclovir therapy on hearing in symptomatic congenital cytomegalovirus disease involving the central nervous system: a randomized, controlled trial.J Pediatr. 2003; 143: 16-25Abstract Full Text Full Text PDF PubMed Scopus (688) Google Scholar Yet, whether this would have the same effect for VLBW who acquire postnatal CMV infection is unknown. Thus, long-term anti-viral treatment of preterm infants who acquire postnatal infection to ameliorate the potential NDI associated with CMV acquisition deserves study. Ongoing pharmacokinetic and pharmacodynamic studies of ganciclovir in preterm infants by the National Institutes of Health Collaborative Antiviral Study Group will provide much needed information on dosing and side effects of CMV treatment in this infant population.25Evaluation of the PK and PD of Ganciclovir in Premature Infants Receiving Treatment for CMV Infection (Gan Premie).http://clinicaltrials.gov/ct2/show/NCT01602614?term=ganciclovir&rank=44Google Scholar In summary, providing maternal milk to the preterm infant may have antagonistic effects, ie, protecting against a number of severe morbidities while increasing the risk of postnatal CMV infection. Importantly, the potential identification of a modifiable risk factor in the ND outcome of preterm infants provides a call to action that should not be ignored. Yet, are we stuck between the proverbial “rock and a hard place” in improving ND outcomes for preterm infants through reducing the risk of CMV acquisition while maintaining the numerous health benefits of fresh mother's milk? The benefits of maternal milk for the premature infants are proven,20Menon G. Williams T.C. Human milk for preterm infants: why, what, when and how?.Arch Dis Child Fetal Neonatal Ed. 2013; 98: F559-F562Crossref PubMed Scopus (58) Google Scholar, 21Underwood M.A. Human milk for the premature infant.Pediatr Clin North Am. 2013; 60: 189-207Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar although the risks of postnatal CMV infection acquired via maternal breast milk in VLBW infants are becoming more evident. However, until it is established that postnatal CMV infection is an independent, modifiable risk factor for NDI, the proven benefits of maternal milk should not be sacrificed. The clinical challenge of safe breast milk feeding for all VLBW infants calls for the same pioneering spirit that has brought lifesaving interventions such as antenatal corticosteroids and surfactant to neonatology. Innovative strategies that will reduce the risk of CMV acquisition while maintaining the health benefits of fresh human milk exposure, such as passive immunization with CMV-neutralizing monoclonal antibodies26Boeckh M. Bowden R.A. Storer B. Chao N.J. Spielberger R. Tierney D.K. et al.Randomized, placebo-controlled, double-blind study of a cytomegalovirus-specific monoclonal antibody (MSL-109) for prevention of cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation.Biol Blood Marrow Transplant. 2001; 7: 343-351Abstract Full Text PDF PubMed Scopus (60) Google Scholar or the enteral administration of exogenous antiviral factors such as lactoferrin,27Beljaars L. van der Strate B.W. Bakker H.I. Reker-Smit C. van Loenen-Weemaes A.M. Wiegmans F.C. et al.Inhibition of cytomegalovirus infection by lactoferrin in vitro and in vivo.Antiviral Res. 2004; 63: 197-208Crossref PubMed Scopus (60) Google Scholar are potential ideal strategies to prevent NDI in preterm infants. A better understanding of the effects of postnatal CMV infection on the preterm infant provides a unique opportunity to assess our practice and march towards outcomes for preterm infants that are indistinguishable from that of term infants. Social Variables Predict Gains in Cognitive Scores across the Preschool Years in Children with Birth Weights 500 to 1250 GramsThe Journal of PediatricsVol. 166Issue 4PreviewTo determine the extent that social variables influence cognitive development of very low birth weight (VLBW) infants across the preschool years. Full-Text PDF Postnatal Human Cytomegalovirus Infection in Preterm Infants Has Long-Term Neuropsychological SequelaeThe Journal of PediatricsVol. 166Issue 4PreviewTo evaluate whether an early postnatal infection poses a long-term risk for neuropsychological impairment to neonates born very prematurely. Full-Text PDF