Association of Cytomegalovirus Infection in Preterm Infants and Neonatal Outcomes: A Matched Cohort Study

Abstract

Objectives

This study aimed to explore the association of cytomegalovirus (CMV) infection in preterm infants of ≤32 weeks' gestation and neonatal morbidities.

Study Design

This was a matched cohort study of preterm infants born between 22 and 32 weeks gestation age and <1,500 g in birth weight who were admitted to participating tertiary NICUs within the Canadian Neonatal Network between April 2009 and December 2018. Infants were randomly matched in a 1:4 ratio (73 CMV-positive to 292 CMV-nonpositive infants) based on gestational age (in weeks), sex, birth weight (± 50 g), and number of days of oxygen exposure within the first 28 days after birth (± 2 days). Neonatal morbidities were compared between the two groups using conditional logistic regression after adjustment of unmatched confounders.

Results

The CMV-positive infants were of lower median birth weight compared to CMV-nonpositive infants (722 vs. 743 g; p < 0.05). The duration of noninvasive respiratory support (59 vs. 43 days; p < 0.05), invasive respiratory support (35 vs. 24 days; p < 0.05), oxygen therapy (115 vs. 67 days; p < 0.05), and odds of bronchopulmonary dysplasia (BPD; 90% vs. 71%; adjusted odds ratio: 3.52 [1.54, 8.07]) were higher for CMV-positive infants compared to CMV-nonpositive infants. Other morbidities were not statistically significantly different.

Conclusion

CMV infection in very preterm infants was associated with increased duration of oxygen and respiratory support and increased odds of BPD.

Key Points

• Congenital CMV is the most common congenital infection.

• There is limited knowledge of the effect of congenital and postnatal CMV on neonatal morbidities.

• We identified that CMV positivity in preterm infants is associated with higher odds of BPD.

Keywords

preterm - bronchopulmonary dysplasia - chronic lung disease

Note

The study data were presented at the evidence-based Practice for Improving Quality/Canadian Neonatal Network (EPIQ/CNN) conference and Pediatric Academic Societies (PAS) Meeting.

^* Full list of Canadian Neonatal Network investigators in [Supplementary Materials] (available in the online version only).

Publikationsverlauf

Eingereicht: 12. Oktober 2024

Angenommen: 24. März 2025

Artikel online veröffentlicht:
30. April 2025

• References

• 1 Kenneson A, Cannon MJ. Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection. Rev Med Virol 2007; 17 (04) 253-276
• 2 Rawlinson WD, Boppana SB, Fowler KB. et al. Congenital cytomegalovirus infection in pregnancy and the neonate: consensus recommendations for prevention, diagnosis, and therapy. Lancet Infect Dis 2017; 17 (06) e177-e188
• 3 Plosa EJ, Esbenshade JC, Fuller MP, Weitkamp JH. Cytomegalovirus infection. Pediatr Rev 2012; 33 (04) 156-163 , quiz 163
• 4 Coats DK, Demmler GJ, Paysse EA, Du LT, Libby C. Ophthalmologic findings in children with congenital cytomegalovirus infection. J AAPOS 2000; 4 (02) 110-116
• 5 Goderis J, De Leenheer E, Smets K, Van Hoecke H, Keymeulen A, Dhooge I. Hearing loss and congenital CMV infection: a systematic review. Pediatrics 2014; 134 (05) 972-982
• 6 Kurath S, Halwachs-Baumann G, Müller W, Resch B. Transmission of cytomegalovirus via breast milk to the prematurely born infant: a systematic review. Clin Microbiol Infect 2010; 16 (08) 1172-1178
• 7 Osterholm EA, Schleiss MR. Impact of breast milk-acquired cytomegalovirus infection in premature infants: pathogenesis, prevention, and clinical consequences?. Rev Med Virol 2020; 30 (06) 1-11
• 8 Gunkel J, de Vries LS, Jongmans M. et al. Outcome of preterm infants with postnatal cytomegalovirus infection. Pediatrics 2018; 141 (02) e20170635
• 9 Goelz R, Meisner C, Bevot A, Hamprecht K, Kraegeloh-Mann I, Poets CF. Long-term cognitive and neurological outcome of preterm infants with postnatally acquired CMV infection through breast milk. Arch Dis Child Fetal Neonatal Ed 2013; 98 (05) F430-F433
• 10 Bevot A, Hamprecht K, Krägeloh-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 (04) e167-e172
• 11 Weimer KED, Kelly MS, Permar SR, Clark RH, Greenberg RG. Association of adverse hearing, growth, and discharge age outcomes with postnatal cytomegalovirus infection in infants with very low birth weight. JAMA Pediatr 2020; 174 (02) 133-140
• 12 Cheeran MCJ, Lokensgard JR, Schleiss MR. Neuropathogenesis of congenital cytomegalovirus infection: disease mechanisms and prospects for intervention. Clin Microbiol Rev 2009; 22 (01) 99-126
• 13 Shah PS, Seidlitz W, Chan P, Yeh S, Musrap N, Lee SK. data abstractors of the Canadian Neonatal Network. Internal audit of the Canadian Neonatal Network data collection system. Am J Perinatol 2017; 34 (12) 1241-1249
• 14 Dunn JKE, Chakraborty P, Reuvers E. et al. Outcomes of a population-based congenital cytomegalovirus screening program. JAMA Pediatr 2025; 179 (03) 332-339
• 15 Shennan AT, Dunn MS, Ohlsson A, Lennox K, Hoskins EM. Abnormal pulmonary outcomes in premature infants: prediction from oxygen requirement in the neonatal period. Pediatrics 1988; 82 (04) 527-532
• 16 Kelly MS, Benjamin DK, Puopolo KM. et al. Postnatal cytomegalovirus infection and the risk for bronchopulmonary dysplasia. JAMA Pediatr 2015; 169 (12) e153785
• 17 Tapawan SJC, Bajuk B, Oei JL, Palasanthiran P. NSW and the ACT Neonatal Intensive Care Units (NICUS) Group. Symptomatic postnatal cytomegalovirus infection in less than 32-week preterm infants: 13-year retrospective multicenter case-control study. Neonatology 2023; 120 (05) 589-597
• 18 Hernandez-Alvarado N, Shanley R, Schleiss MR. et al. Clinical, virologic and immunologic correlates of breast milk acquired cytomegalovirus (CMV) infections in very low birth weight (VLBW) infants in a newborn intensive care unit (NICU) setting. Viruses 2021; 13 (10) 1897
• 19 Coclite E, Di Natale C, Nigro G. Congenital and perinatal cytomegalovirus lung infection. J Matern Fetal Neonatal Med 2013; 26 (17) 1671-1675
• 20 Piazze J, Nigro G, Mazzocco M. et al. The effect of primary cytomegalovirus infection on fetal lung maturity indices. Early Hum Dev 1999; 54 (02) 137-144
• 21 Porta A, Avanzini A, Bellini M. et al. Neonatal gastrointestinal involvement and congenital cytomegalovirus. Pediatr Med Chir 2016; 38 (03) 134
• 22 Patel RM, Shenvi N, Knezevic A. et al. Observational study of cytomegalovirus from breast milk and necrotising enterocolitis. Arch Dis Child Fetal Neonatal Ed 2019; 105 (03) 259-265
• 23 Tengsupakul S, Birge ND, Bendel CM. et al. Asymptomatic DNAemia heralds CMV-associated NEC: case report, review, and rationale for preemption. Pediatrics 2013; 132 (05) e1428-e1434
• 24 Omarsdottir S, Agnarsdottir M, Casper C. et al. High prevalence of cytomegalovirus infection in surgical intestinal specimens from infants with necrotizing enterocolitis and spontaneous intestinal perforation: a retrospective observational study. J Clin Virol 2017; 93: 57-64
• 25 Cheng C, He Y, Xiao S, Ai Q, Yu J. The association between enteric viruses and necrotizing enterocolitis. Eur J Pediatr 2021; 180 (01) 225-232
• 26 Boppana S, Amos C, Britt W, Stagno S, Alford C, Pass R. Late onset and reactivation of chorioretinitis in children with congenital cytomegalovirus infection. Pediatr Infect Dis J 1994; 13 (12) 1139-1142
• 27 Josa M, García MJ, López E. et al. Retinopathy of prematurity and possible relation between postnatal cytomegalovirus infection. Indian J Pediatr 2022; 89 (10) 1028-1030
• 28 Martins-Celini FP, Yamamoto AY, Passos DM. et al. Incidence, risk factors, and morbidity of acquired postnatal cytomegalovirus infection among preterm infants fed maternal milk in a highly seropositive population. Clin Infect Dis 2016; 63 (07) 929-936
• 29 Caposio P, Orloff SL, Streblow DN. The role of cytomegalovirus in angiogenesis. Virus Res 2011; 157 (02) 204-211
• 30 Fleck BW, McIntosh N. Retinopathy of prematurity: recent developments. Neoreviews 2009; 10 (01) e20-e30
• 31 Smith LEH. Through the eyes of a child: understanding retinopathy through ROP the Friedenwald lecture. Invest Ophthalmol Vis Sci 2008; 49 (12) 5177-5182
• 32 Wunderlich W, Sidebottom AC, Schulte AK, Taghon J, Dollard S, Hernandez-Alvarado N. The use of saliva samples to test for congenital cytomegalovirus infection in newborns: examination of false-positive samples associated with donor milk use. Int J Neonatal Screen 2023; 9 (03) 46