Serial Monitoring and Hyperimmunoglobulin versus Standard of Care to Prevent Congenital Cytomegalovirus Infection: A Phase III Randomized Trial

Abstract

<b><i>Introduction:</i></b> Nonrandomized studies support the potential of cytomegalovirus hyperimmunoglobulin (CMV-HyperIg) in preventing maternofetal CMV transmission, but prospective interventional studies show equivocal results. We pre­sent a prospective phase-III international randomized open-label trial on the potential effect of CMV-HyperIg following serial monitoring of CMV serostatus. <b><i>Methods:</i></b> CMV-seronegative pregnant women (gestational age [GA] <14 weeks) were 1:1 randomized to monthly CMV-serostatus monitoring and CMV-HyperIg upon seroconversion (treatment), or routine prenatal care with CMV-serostatus testing at end of pregnancy (control). Ethical considerations required that control subjects with confirmed seroconversion be offered Cytotect®. The primary endpoint was the proportion of fetuses/newborns with congenital CMV infection. Secondary endpoints included neonatal CMV disease and safety during the 24-month follow-up. <b><i>Results:</i></b> The treatment arm counted 4,800 randomized subjects: 52 seroconverted (median GA 24 [11–35] weeks), of which 45 completed follow-up. The control arm counted 4,735 randomized subjects: 42 seroconverted, of which 34 completed follow-up (evaluable data for 28 newborns) and 8 subjects chose off-label Cytotect®. Congenital CMV rates were 13/28 newborns (46.4% [CI 27.51; 66.13]) vs. 16/45 newborns (35.6% [CI 21.87; 51.22]) in control and treated arms, respectively (<i>p</i> = 0.46). Newborn CMV disease was mostly mild and spontaneously resolving. There were no major safety concerns. The target sample was not reached within an acceptable time frame. <b><i>Conclusions:</i></b> Serial monitoring of CMV serostatus with CMV-HyperIg treatment was associated with a mild nonsignificant reduction in the vertical CMV transmission rate. Studies on the optimal preventive strategy are hampered by epidemiological and ethical challenges and should focus on GA-dependent transmission rates and accurate dating of infection.

Primary, Secondary, and Tertiary Prevention of Congenital Cytomegalovirus Infection

“…Another alternative is the administration of CMV hyperimmune globulins to infected pregnant women during their first trimester of pregnancy. Although some recent randomized controlled trials investigating the efficacy of hyperimmune globulins did not find a significant reduction in the incidence of cCMV infection [116,155,156], an observational study with the administration of hyperimmune globulins twice a month showed promising results in decreasing mother-to-child transmission rate [157]. However, the fact remains that hyperimmune globulin therapy during pregnancy is much more expensive than valaciclovir, and it may cause severe allergic reactions in rare cases (1/203 in the study by Hughes et al [111]).…”

Cost‐effectiveness of screening and valacyclovir‐based treatment strategies for first‐trimester cytomegalovirus primary infection in pregnant women in France

“…Cahill et al 35 and Albright et al 36 each carried out a cost-effectiveness analysis of maternal CMV screening but their conclusions are not applicable to the French healthcare system because they included treatment with hyperimmunoglobulin to reduce vertical transmission of CMV, but this is not readily available in France and does not seem to be efficient in significantly reducing vertical transmission 37,38 . In our model, the antenatal costs and effectiveness (number of infected fetuses and children diagnosed) were concordant with those of the recent French study published by Seror et al 34 , who focused on the costs and effectiveness of screening for T1 CMV PI during pregnancy, in conjunction with valacyclovir treatment.…”

Cytomegalovirus seronegativity rate in pregnant women and primary cytomegalovirus infection during pregnancy in rural Germany

“…To date, there are no evidence-based treatment options to prevent fetal CMV infection following CMV seroconversion during pregnancy [ 12 ]. Many questions remain unanswered.…”

“…The virus is transmitted, for example, through infectious urine (diaper changes) or saliva (shared cutlery) of the infected child [ 11 ]. Unfortunately, basic prevention methods, such as vaccines, have not been shown to be effective [ 12 – 14 ]. Treatment options for CMV during pregnancy are limited and controversial (cytomegalovirus immunoglobulin or antiviral drugs) [ 15 , 16 ].…”

“…Treatment options for CMV during pregnancy are limited and controversial (cytomegalovirus immunoglobulin or antiviral drugs) [ 15 , 16 ]. The serial surveillance of the CMV serostatus with CMV Hyperimmunglobulin therapy was associated with a milde non-significant decrease in vertical CMV transmission rates in a European Phase III Randomized Trial [ 12 ].…”