Objective  To observe the safety of ganciclovir on congenital cytomegalovirus (CMV) infected premature infants.

Methods  We reviewed the data of premature infants with congenital CMV infection hospitalized in the department of neonatology, Children’s Hospital of Fudan University and treated with ganciclovir from October 1st 2017 to October 1st 2021. The safety differences were compared, including absolute neutrophil count, platelet, aspartate aminotransferase (AST), alanine aminotrans-ferase (ALT) and serum creatinine (SCr).

Results  Forty children were included in this study, 25 of them with PMA<37 weeks and 15 with PMA≥37 weeks at the start of treatment. 23 had ganciclovir at a dose of 6 mg·kg^-1, q12h and 17 had ganciclovir at a dose of 5 mg·kg^-1, q12h. There was no significant difference in neutroopenia, but the incidence of Grade 3-4 neutropenia were significantly different between the two PMA groups (24.0% vs. 0%, P<0.05). There was no significant difference in thrombocytopenia between two groups (P>0.05). There was 1 case of severe thrombocytopenia with PMA<37 weeks and none in the group with PMA≥37 weeks. Meanwhile, in the group of childeren with PMA<37 weeks, the risk of thrombocytopenia was higher with ganciclovir doses of 6 mg·kg^-1. There was no significant difference in the incidence of liver function abnormalities among children with different PMA (P>0.05). One case of SCr increase occurred in the group with PMA<37 weeks con-sidering about hemorrhagic shock. There was no difference in SCr increase between two group (P>0.05).

Conclusion  There was no significant difference in the risk of neutropenia, thrombocytopenia and ab-normal liver function during the use of ganciclovir in preterm infants with different PMAs. At the start of treatment, the incidence of severe and above neutropenia was significantly higher in children with PMA<37 weeks than in those with PMA ≥37 weeks, and the risk of thrombocytopenia was also higher in children with PMA<37 weeks with the ganciclovir dose of 6 mg·kg^-1 compared to 5 mg·kg^-1. Therefore, it is suggested that preterm neonates with ganciclovir treatment should be closely moni-tored, and optimal dosing regiments of ganciclovir in preterm infants need to be further studied to guarantee safety of medication.

1.Lanzieri TM, Dollard SC, Bialek SR, et al. Systematic review of the birth prevalence of congenital cytomegalovirus infection in developing countries[J]. Int J Infect Dis, 2014, 22(5): 44-48. DOI: 10.1016/j.ijid.2013.12.010.

2.Yamaguchi A, Oh-Ishi T, Arai T, et al. Screening for seemingly healthy newborns with congenital cyto-megalovirus infection by quantitative real-time polymerase chain reaction using newborn urine: an observational study[J]. BMJ Open, 2017, 7(1): e013810.DOI: 10.1136/bmjopen-2016-013810.

3.Rawlinson WD, Boppana SB, Fowler KB, et al. Congenital cytomegalovirus infection in pregnancy and the neonate: Consensus recommendations for prevention, diagnosis, and therapy[J]. Lancet Infect Dis, 2017, 17(6): e177-e188.DOI: 10.1016/S1473-3099(17)30143-3.

4.Dong Q, Leroux S, Shi HY, et al. Pilot study of model-based dosage individualization of ganciclovir in neonates and young infants with congenital cytomegalovirus infection[J]. Antimicrob Agents Chemother, 2018, 62(5): e00075-18. DOI: 10.1128/AAC.00075-18.

5.中华医学会围产医学分会, 中华医学会儿科学分会, 中华医学会医学病毒学分会, 等.先天性巨细胞病毒感染筛查与临床干预指南[J].中国实用妇科与产科杂志, 2019, 35(4): 417-423. DOI: 10.19538/j.fk2019040112.    

6.方峰. 新生儿巨细胞病毒感染及疾病的诊治[J]. 中国实用儿科杂志, 2011, 26(1): 6-8. [Fang F. Diagnosis and treatment of cytomegalovirus infection and diseases in neonates[J]. Chinese Journal of Practical Pedi-atrics, 2011, 26(1): 6-8.] DOI: CNKI:SUN:ZSEK.0.2011-01-007.

7.Centers for Disease Control and Prevention, National Institutes of Health, HIV Medicine Association of the Infectious Diseases Society of America, et al. Guidelines for the prevention and treatment of op-portunistic infections among HIV-exposed and HIV-infected children. Recommendations from CDC, the National Institutes of Health, the HIV Medicine Association of the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the American Academy of Pediatrics[J]. MMWR Recomm Rep, 2009, 58(RR11): 1-166. https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5811a1.htm.

8.Trang JM, Kidd L, Gruber W, et al. Linear single-dose pharmacokinetics of ganciclovir in newborns with congenital cytomegalovirus infections. NIAID Collaborative Antiviral Study Group[J]. Clin Pharma-col Ther, 1993, 53(1): 15-21. DOI: 10.1038/clpt.1993.4.

9.Zhou XJ, Gruber W, Demmler G, et al. Population pharmacokinetics of ganciclovir in newborns with congenital cytomegalovirus infections. NIAID Collaborative Antiviral Study Group[J]. Clin Pharmacol Ther, 1996, 59(2): 2202-2205. DOI: 10.1038/sj.clpt.1996.236.

10.Whitley RJ, Cloud G, Gruber W, et al. Ganciclovir treatment of symptomatic congenital cytomegalovi-rus infection: results of a phase II study[J]. J Infect Dis, 1997, 175(5): 1080-1086. DOI: 10.1086/516445.

11.Sunada M, Kinoshita D, Furukawa N, et al. Therapeutic drug monitoring of ganciclovir for postnatal cytomegalovirus infection in an extremely low birth weight infant: a case report[J]. BMC Pediatr, 2016, 16(1): 1-4. DOI: 10.1186/s12887-016-0683-x.

12.Fischer C, Meylan P, Graz MB, et al. Severe postnatally acquired cytomegalovirus infection presenting with colitis, pneumonitis and sepsis-like syndrome in anextremely low birthweight infant[J]. Neonatology, 2010, 97(4): 339-345.DOI: 10.1159/000260137.

13.贺晓日,陈平洋,王涛, 等.不同剂量更昔洛韦治疗新生儿先天性巨细胞病毒感染的临床观察[J].中国当代儿科杂志, 2009, 11(8): 641-644. [He XR, Chen PY, Wang T, et al. Comparison of therapeutic effect of different doses of ganciclovir for neonatal congenital cytomegalovirus infection[J]. Chinese Journal of Contem-porary Pediatrics, 2009, 11(8): 641-644.] DOI: CNKI:SUN:DDKZ.0.2009- 08-001.

14.叶颖子, 叶丽静, 董妞妞,等. 先天性巨细胞病毒感染抗病毒治疗的效果和安全性观察[J]. 中国循证儿科杂志, 2018, 13(2): 97-101. [Ye YZ, Ye LJ, Dong NN, et al. The antiviral therapy research in neonates with congenital CMV infection[J]. Chinese Journal of Evidence Based Pediatrics, 2018, 13(2): 97-101.] DOI: 10.3969/j.issn.1673-5501.2018.02.004.

15.Fierson WM, Chiang MF, Good W, et al. Screening examination of premature infants for retinopathy of prematurity[J]. Pediatrics, 2018, 142(6): 189-195. DOI: 10.1542/peds.2018-3061.

16.Kimberlin DW, Jester PM, Sánchez PJ, et al. Valganciclovir for symptomatic congenital cytomegalovirus disease[J]. N Engl J Med, 2015, 372(10): 933-943. DOI: 10.1056/NEJMoa1404599.

17.U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS. Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1[EB/OL]. (2017-07) [2023-01-17]. https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-tables.

18.Ziv L, Yacobovich J, Pardo J, et al. Hematologic adverse events associated with prolonged valganciclo-vir treatment in congenital cytomegalovirus infection[J].Pediatr Infect Dis J, 2019, 38(2): 127-130. DOI: 10.1097/INF.0000000000002079.

19.邵肖梅, 叶鸿瑁, 丘小汕, 主编. 实用新生儿学, 第5版[M].北京: 人民卫生出版社, 2018: 1078.

20.Whitley RJ, Cloud G, Gruber W, et al. Ganciclovir treatment of symptomatic congenital cytomegalovi-rus infection: results of a phase Ⅱ study. National Institute of Allergy and Infectious Diseases Collabo-rative Antiviral Study Group[J]. J Infect Dis, 1997, 175(5): 1080-1086. DOI: 10.1086/516445.

21.国家药品监督管理局药品评价中心, 主编. 《药品不良反应报告和监测管理办法》培训教材[M]. 北京: 中国医药科技出版社, 2012: 47-49.

22.陈露燕,李伟,徐佳露,等.先天性巨细胞病毒感染gH基因分型与临床特征的关系[J].中华儿科杂志, 2019, 57(8): 597-602. [Chen LY, Li W, Xu JL, et al. Relationship between gH genotyping and clinical characteristics of children with congenitalcytomegalovirus infection[J]. Chin J Pediatr, 2019, 57(8): 597-602.] DOI: 10.3760/cma.j.issn.057810.2019.08.005.

23.Kyriakopoulou A, Serghiou S, Dimopoulou D, et al. Antenatal imaging and clinical outcome in congen-ital CMV infection: a field-wide systematic review and meta-analysis[J]. J Infect, 2020, 80(4): 407-418. DOI: 10.1016/j.jinf.2020.02.012.

24.Oliver SE, Cloud GA, Sánchez PJ, et al. Neuro-developmental outcomes following ganciclovir therapy in symptomatic congenital cytomegalovirus infections involving the central nervous system[J]. J Clin Virol, 2009, 46(supp-S4): S22-S26. DOI: 10.1016/j.jcv.2009.08.012.

25.Nassetta L, Kimberlin D, Whitley R. Treatment of congenital cytomegalovirus infection: implications for future therapeutic strategies[J]. J Antimicrob Chemother, 2009, 63: 862-867. DOI: 10.1093/jac/dkp083.

26.Kimberlin DW, Acosta EP, Sanchez PJ, et al. Pharmacokinetic and pharmacodynamic assessment of oral valganciclovir in the treatment of symptomatic congenital cytomegalovirus disease[J]. J Infect Dis, 2008, 197: 836-845. DOI: 10.1086/528376.

27.Märtson AG, Edwina AE, Burgerhof JGM, et al. Ganciclovir therapeutic drug monitoring in transplant recipients[J]. J Antimicrob Chemother, 2021, 76(9): 2356-2363. DOI: 10.1093/jac/dkab195.

28.Wiltshire H, Paya CV, Pescovitz MD, et al. Pharmaco dynamics of oral ganciclovir and valganciclovir in solid organ trans-plant recipients[J]. Transplantation, 2005, 79(11): 1477-1483. DOI: 10.1097/01.tp.0000164512.99703.ad.

29.Kimberlin DW, Lin CY, Sánchez PJ, et al. Effect of ganciclovir therapy on hearing in symptomatic con-genital cytomegalovirus disease involving the central nervous system: a randomized, controlled trial[J]. J Pediatr, 2003, 143(1): 16-25. DOI: 10.1016/s0022-3476(03)00192-6.

30.Del Rosal T, Baquero-Artigao F, Blázquez D, et al. Treatment of symptomatic congenital cytomegalo-virus infection beyond the neonatal period[J]. J Clin Virol, 2012, 55(1): 72-74. DOI: 10.1016/j.jcv.2012.06.001.

31.Christensen RD, Yoder BA, Baer VL, et al. Early-onset neutropenia in small-for-gestational-age in-fants[J]. Pediatrics, 2015, 136(5): e1259-e1267. DOI: 10.1542/peds.2015-1638.

32.Christensen RD, Henry E, Wiedmeier SE, et al. Low blood neutrophil concentrations among extremely low birth weight neonates: data from a multihospital health-care system[J]. J Perinatol, 2006, 26(11): 682-687. DOI: 10.1038/sj.jp.7211603.

33.Baley JE, Stork EK, Warkentin PI, et al. Neonatal neutropenia: clinical manifestations, cause, and out-come[J].Am J Dis Child, 1988, 142(11): 1161-1166. DOI: 10.1001/archpedi.1988.02150110039016.

34.Wang Y, Smith KP. Safety of alternative antiviral agents for neonatal herpes simplex virus encephalitis and disseminated infection[J]. J Pediatr Pharmacol Ther, 2014, 19(2): 72-82. DOI: 10.5863/1551-6776-19.2.72.

35.Christensen RD, Baer VL, Henry E, et al. Thrombocy-topenia in small-for-gestational-age infants[J]. Pediatrics, 2015, 136(2): e361-e370. DOI: 10.1542/peds.2014-4182.

36.Whitley RJ. The use of antiviral drugs during the neonatal period[J]. Clin Perinatol, 2012, 39(1): 69-81. DOI: 10.1016/j.clp.2011.12.004.

37.Märtson AG, Touw D, Damman K, et al. Ganciclovir therapeutic drug monitoring: a case series[J].Ther Drug Monit, 2019, 41(2): 107. DOI: 10.1097/FTD. 0000000000000598.

38.Märtson AG, Edwina AE, Kim HY, et al. Therapeutic drug monitoring of ganciclovir: where are we?[J]. Ther Drug Monit, 2022, 44(1): 138-147. DOI: 10.1097/FTD. 0000000000000925.

39.Jorga K, Reigner B, Chavanne C. Pediatric dosing of ganciclovir and valganciclovir: how model-based simulations can prevent underexposure and potential treatment failure[J]. CPT Pharmacometrics Syst Pharmacol, 2019, 8(3): 167-176. DOI: 10.1002/psp4.12363.