In the JournalsPerspective

CMV linked to bronchopulmonary dysplasia in low-birth-weight infants

Postnatal cytomegalovirus infection among infants born weighing less than 1,500 g increased their risk for developing bronchopulmonary dysplasia, according to recent data in JAMA Pediatrics.

“Our results indicate that postnatal CMV infection at less than 36 weeks’ postmenstrual age was associated with an increased risk for [bronchopulmonary dysplasia (BPD)],” Matthew S. Kelly, MD, MPH, research fellow for the division of pediatric infectious disease at Duke University School of Medicine, and colleagues wrote.

matt kelly

Matthew S. Kelly

The researchers retrospectively studied a cohort of 101,111 very low-birth-weight newborns at 348 neonatal ICUs in the United States born from 1997 to 2012. Neonates with postnatal CMV infection were matched to control group patients for comparison of mortality and BPD at 36 weeks.

Overall, 328 neonates were diagnosed with postnatal CMV infection, with 303 matched to control infants (n = 303) for the final analysis. Among the intervention group, 76% of neonates either died or developed BPD at age 36 weeks, compared with 63% among the controls. The researchers found that CMV infection was associated with death or BPD at 36 weeks (RR = 1.21; 95% CI, 1.1-1.32). They also found that CMV infection was associated with an overall increased risk for BPD (RR = 1.33; 95% CI 1.19-1.5).

The researchers noted that complications related to CMV infection may be caused by introducing very low-birth-weight infants to breast milk.

“With the practice of transfusion of CMV-seronegative or leukoreduced blood, breast-feeding is also the primary route of CMV acquisition among infants in the United States,” Kelly and colleagues wrote. “Further research is needed to define the long-term sequelae of postnatal CMV on pulmonary and neurological outcomes and develop novel CMV prevention measures to permit safe breast milk feeding by very low-birth-weight infants.”

In a related editorial, David W. Kimberlin, MD, of the division of pediatric infectious diseases at the University of Alabama at Birmingham, praised Kelly and colleagues for expanding the knowledge base of possible long-term harms caused by CMV, but warned that the study should not be used as a basis for withholding breast milk from vulnerable neonates.

“At the current time, we do not know whether postnatally acquired CMV causes chronic lung disease of prematurity in very low-birth-weight neonates, although the Kelly et al study likely will spur additional investigations that one day may definitively answer this question,” Kimberlin wrote. “In contrast, we do know that breast milk has tremendous nutritional value for infants, including those who are born prematurely. As such, properly treated breast milk should not be withheld from very low-birth-weight neonates on the basis of this study.” – by David Costill

Disclosure: Kelly reports no relevant financial disclosures. Please see the full study for a list of all other authors’ relevant financial disclosures.

Postnatal cytomegalovirus infection among infants born weighing less than 1,500 g increased their risk for developing bronchopulmonary dysplasia, according to recent data in JAMA Pediatrics.

“Our results indicate that postnatal CMV infection at less than 36 weeks’ postmenstrual age was associated with an increased risk for [bronchopulmonary dysplasia (BPD)],” Matthew S. Kelly, MD, MPH, research fellow for the division of pediatric infectious disease at Duke University School of Medicine, and colleagues wrote.

matt kelly

Matthew S. Kelly

The researchers retrospectively studied a cohort of 101,111 very low-birth-weight newborns at 348 neonatal ICUs in the United States born from 1997 to 2012. Neonates with postnatal CMV infection were matched to control group patients for comparison of mortality and BPD at 36 weeks.

Overall, 328 neonates were diagnosed with postnatal CMV infection, with 303 matched to control infants (n = 303) for the final analysis. Among the intervention group, 76% of neonates either died or developed BPD at age 36 weeks, compared with 63% among the controls. The researchers found that CMV infection was associated with death or BPD at 36 weeks (RR = 1.21; 95% CI, 1.1-1.32). They also found that CMV infection was associated with an overall increased risk for BPD (RR = 1.33; 95% CI 1.19-1.5).

The researchers noted that complications related to CMV infection may be caused by introducing very low-birth-weight infants to breast milk.

“With the practice of transfusion of CMV-seronegative or leukoreduced blood, breast-feeding is also the primary route of CMV acquisition among infants in the United States,” Kelly and colleagues wrote. “Further research is needed to define the long-term sequelae of postnatal CMV on pulmonary and neurological outcomes and develop novel CMV prevention measures to permit safe breast milk feeding by very low-birth-weight infants.”

In a related editorial, David W. Kimberlin, MD, of the division of pediatric infectious diseases at the University of Alabama at Birmingham, praised Kelly and colleagues for expanding the knowledge base of possible long-term harms caused by CMV, but warned that the study should not be used as a basis for withholding breast milk from vulnerable neonates.

“At the current time, we do not know whether postnatally acquired CMV causes chronic lung disease of prematurity in very low-birth-weight neonates, although the Kelly et al study likely will spur additional investigations that one day may definitively answer this question,” Kimberlin wrote. “In contrast, we do know that breast milk has tremendous nutritional value for infants, including those who are born prematurely. As such, properly treated breast milk should not be withheld from very low-birth-weight neonates on the basis of this study.” – by David Costill

Disclosure: Kelly reports no relevant financial disclosures. Please see the full study for a list of all other authors’ relevant financial disclosures.

    Perspective

    Postnatal Detection of Cytomegalovirus:
    How Concerned Should We Be?
     

    This large, multicenter, propensity-matched, retrospective cohort study by Kelly and colleagues highlights the negative impact that postnatal infection with cytomegalovirus (CMV) can have on very-low-birth-weight (VLBW) and extremely low gestational age infants. The researchers found that in VLBW infants, a diagnosis of CMV infection or detection of CMV from body fluids on or after 21 days of age was associated with increased risk for death or bronchopulmonary dysplasia (BPD) at 36 weeks’ postmenstrual age. This finding is not novel, as a possible association with BPD was first reported decades ago. Although causation remains lacking, biologic plausibility does exist as the inflammatory changes brought on by any pulmonary infection in preterm infants may result in prolonged need for oxygen and respiratory support. Of note, more recent prospective, albeit smaller, studies of CMV acquisition by preterm infants in the neonatal ICU (NICU) have not found such an association.

    This hypothesis-generating study certainly is a call for performance of prospective, well-designed studies that could lead to future antiviral treatment trials in this population. The main limitation of the current study is ascertainment of postnatal CMV infection, as neither the cases nor the control infants were screened routinely for CMV infection before 21 days of age to rule out clinically inapparent congenital infection. Moreover, the association of CMV infection with clinical and laboratory signs likely is representative of what prompted the investigation for CMV disease in these infants.

    But the question not answered and only inferred by this study is acquisition of CMV and its relationship to ingestion of unpasteurized human milk by these VLBW infants. With the routine use of CMV-negative and leukoreduced blood products, human milk is now the most frequent mode of CMV acquisition by these infants in today’s NICUs. Is this an untoward consequence of our promotion of human milk feeding to all preterm infants? We know that maternal milk is associated with substantial benefits, namely less necrotizing enterocolitis and late-onset sepsis and improved mental developmental outcomes.

    It certainly is reassuring that given the widespead use of expressed and unpasteurized maternal milk in our NICUs, only 0.3% of VLBW infants had a clinical illness attributed to CMV in this study. But does this represent only the tip of the iceberg? Previous studies have shown that clinically inapparent infection in preterm infants with well-documented acquired CMV infection is more common than symptomatic disease. Recent small studies also have suggested that some infants with acquired CMV infection may have adverse long-term neurodevelopmental outcomes that do not include sensorineural hearing loss. Identifying which of these infants with acquired CMV infection has these adverse outcomes remains a huge knowledge gap and must become a research priority.

    For now, the benefits of maternal milk far outweigh the potential risks. Whether these same benefits extend to pasteurized human milk is not known, although ongoing studies should provide much-needed answers. Our support for universal provision of maternal milk to all preterm infants must continue as we strive to find the optimal and safest methods for its delivery.

    Andrea Ronchi, MD
    NICU, Maggiore Hospital of Milan
    University of Milan

    Pablo J Sánchez, MD
    Infectious Diseases in Children Editorial Board member
    Nationwide Children’s Hospital
    The Ohio State University

    Disclosures: Ronchi and Sanchez report no relevant financial disclosures.