Congenital Cytomegalovirus Infection: Management Update

Asma Khalil; Chrissie Jones; Yves Villec

Disclosures

Curr Opin Infect Dis. 2017;30(3):274-280. 

In This Article

Prenatal Therapy

The aim of prenatal therapy is either to prevent mother-to-child transmission of CMV or to treat the CMV-infected fetus during pregnancy with the aim of reducing the risk of, and/or severity of, symptomatic infection in the infant.

Cytomegalovirus Hyperimmune Globulin Treatment to Prevent Antenatal Mother-to-child Transmission

CMV human immunoglobulin (HIG) is a pooled, high-titre preparation derived from donors with high antibody titres. The rationale for its use is based on the observation that primary maternal CMV infection carries a higher mother-to-child transmission risk (approximately 30%) compared with the risk in reactivation or reinfection (1.4%).[32] Its role was investigated in two clinical trials[33,34] and two observational studies.[35,36] Nigro et al.[33] conducted a nonrandomized clinical trial using CMV HIG in women with a recent primary CMV infection and unknown fetal status before 21 weeks' gestation who declined amniocentesis; these women were offered monthly HIG 100 IU/kg. Six of the 37 (16%) women who received HIG had neonates with congenital CMV infection compared with 19/47 (40%) women who did not receive HIG. Unfortunately, the efficacy of CMV HIG has not been borne out in a phase 2 randomized placebo controlled double-blind study.[34] This study included a total of 124 women with primary CMV infection at 5–26 weeks' gestation.[34] These women were randomly assigned within 6 weeks after the presumed primary infection to receive either HIG or placebo every 4 weeks until 36 weeks of gestation or until the detection of CMV in the amniotic fluid. The primary endpoint was congenital infection diagnosed at birth or amniocentesis positive for CMV. The rate of congenital infection was 30% in the HIG group compared with 44% in the placebo group (a nonsignificant difference; P = 0.13).[34] This study found no significant difference between the two groups in the risk of transmission, the levels of virus specific antibodies, T-cell-mediated immune response or viral DNA in the blood. The clinical outcome of congenital infection at birth was similar in the two groups. However, the number of adverse obstetric events, including preterm birth, preeclampsia and intrauterine fetal growth restriction, was higher in the HIG group compared to the placebo group (13 vs. 2%).[34]

Given these conflicting findings, HIG is not routinely recommended and should currently be reserved for use in a research setting only. Another large phase III randomized placebo-controlled double-blinded trial assessing HIG in pregnancy is currently underway (clinicaltrials.gov: NCT01376778).

Cytomegalovirus Hyperimmune Globulin Treatment to Treat the Cytomegalovirus-infected Fetus Prenatally

Four prospective and two retrospective studies treating small numbers of pregnant women diagnosed with congenital CMV infection have demonstrated a trend to efficacy using CMV HIG.[33,35,37–40] Nigro et al.[33] conducted a nonrandomized clinical trial in women with primary CMV whose amniotic fluid was positive for CMV; they were offered CMV HIG at a dose of 200 IU/kg. Only 1/31 (3%) of neonates had symptomatic CMV disease compared with 7/14 (50%) of women not treated. The authors concluded that HIG therapy was associated with a significantly lower risk of congenital CMV infection, especially symptomatic infection. In the recent randomized, placebo-controlled double-blind trial by Revello et al.,[34] 7/61 (11%) fetuses of women treated with 100 IU/kg CMV HIG every 4 weeks had transient or permanent abnormalities, compared with 10/62 (16%) fetuses in the placebo group (a nonsignificant trend). Based on these conflicting findings, HIG should not be recommended as antenatal treatment, and should currently be reserved for use in a research setting only.

Antiviral Treatment to Prevent Antenatal Mother-to-child Transmission

A randomized, phase II double-blinded clinical trial is planned to evaluate the efficacy of valaciclovir (ValACV) to prevent mother-to-child transmission following primary maternal infection (clinicaltrials.gov identifier NCT02351102). The current use of antiviral treatment to prevent mother-to-child transmission outside of the research setting is not recommended.

Antiviral Treatment to Treat the Cytomegalovirus-infected Fetus Prenatally

In immunocompromised (nonpregnant) patients, three anti-CMV drugs are licensed for use, namely ganciclovir, cidofovir, and foscarnet, but their teratogenic and toxic effects preclude their use in pregnancy. Aciclovir and its oral prodrug ValACV have been shown to have some effect against CMV in immunocompromised patients.[41–43] In a pilot observational study, Jacquemard et al.[44] treated pregnant women with primary CMV with oral ValACV 8 g/day. Twenty pregnancies with 21 fetuses were treated at 28 weeks' gestation (range 22–34 weeks) for 7 weeks (range 1–12 weeks). Therapeutic concentrations of the drug were achieved in both maternal and fetal blood, and the viral load in fetal blood decreased significantly after 1–12 weeks of treatment. In terms of outcome, seven cases had termination of pregnancy and had evidence of in-utero progression of the disease with worsening cerebral lesions, or died in utero. A further two infants had severe isolated unilateral deafness. One child had microcephaly with severe deafness but was also diagnosed with incontinentia pigmenti. The remaining 10 infants were developing normally at follow-up, at 1–5 years of age. By comparison, the outcomes of 24 untreated symptomatic CMV-infected fetuses were as follows: 14 (58%) had termination of pregnancy, intrauterine fetal death, or severe neonatal infection. The remaining 10 infants were healthy at follow-up.

Oral ValACV was investigated in a recent open-label, single-group assignment phase II clinical trial entitled in-utero treatment of CMV congenital infection with valacyclovir (CYMEVAL).[45] Oral ValACV 8 g per day was given for a median of 89 days to pregnant women carrying a moderately infected fetus (Table 1).[45] When compared with a historical cohort obtained by a meta-analysis of the literature, ValACV significantly increased the proportion of asymptomatic neonates from 43% without treatment to 82% with treatment. This study also provided safety data for the use of valacyclovir in pregnancy.[45] However, the study design and the small number of ValACV-treated women are limitations, and, therefore, further studies are currently being planned (none listed in clinicaltrials.gov yet).

A proposal for management of CMV fetal infection is illustrated in Fig. 2. In neonates with symptomatic congenital CMV infection, there is a role for postnatal val/ganciclovir treatment, which should be commenced within the first 4 weeks of life. There is evidence that treatment can reduce or prevent progression of SNHL in some infants.[46]

Figure 2.

Proposed management of congenital cytomegalovirus infection.

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