American journal of obstetrics and gynecology 2016 4 12() pii 10.1016/j.ajog.2016.04.003
Congenital infection with human cytomegalovirus (CMV) is a major cause of morbidity and mortality. A randomized controlled trial (RCT) showed that high-dosage valacyclovir prevents CMV disease in transplant recipients. Fetuses showing ultrasound features of infection are at high risk of being symptomatic at or before birth. In a pilot study, oral administration of high-dosage valacyclovir to mothers significantly decreased viral load and produced therapeutic concentrations in the blood of infected fetuses. An RCT comparing prenatal treatment with valacyclovir against placebo in infected fetuses failed to recruit because women declined randomization. RCTs in fetal medicine have often proven unacceptable by women who decline termination of pregnancy (TOP) and are not prepared to resign themselves to the odds of the natural history of the disease.
We evaluated the efficacy of oral valacyclovir, 8 grams daily, for pregnant women carrying a symptomatic CMV-infected fetus; targeting a high-risk group for developing both neurosensory- and neurological impairment.
We designed a multicentre, open-label, phase II study with one arm, using one of Simon’s optimal two-stage designs. Symptomatic fetuses were defined by the presence of measurable extracerebral or mild cerebral ultrasound symptoms. They were treated in utero from prenatal diagnosis at a median of 25.9 weeks’ gestation until delivery or TOP. Fetuses with severe brain anomalies on ultrasound were not included as were cases completely asymptomatic at presentation, because treatment was unlikely to modify either outcome. The primary endpoint was the proportion of asymptomatic neonates born to treated mothers.
At the interim analysis, 8 of 11 women delivered an asymptomatic neonate (required: ≥ 7). In step 2, 32 additional cases were included for a total of 43; the final number of asymptomatic neonates was 34, more than the 31 required to indicate efficacy according to the Simon two-stage design. They remained asymptomatic at 12 months. High dosage valacyclovir given for a median of 89 days to pregnant women carrying a moderately infected fetus was efficient at giving birth to asymptomatic neonates. Fetal blood viral loads decreased and platelet counts increased, both significantly (p=0.01 and p<0.001 respectively), between treatment initiation and birth after treatment completion, regardless of duration of fetal infection. Compared with a historical cohort obtained by a metanalysis of the literature, the use of valacyclovir (8 grams daily) significantly increased the proportion of asymptomatic neonates from 43% without treatment to 82% with treatment. Although the pill burden was high (16 pills a day) adherence to treatment was over 90%. Finally, valacyclovir at this high dosage was extremely well tolerated. CONCLUSION
Our results indicate that high-dosage valacyclovir given in pregnancy is effective for improving the outcome of moderately symptomatic infected fetuses. Although this study is not an RCT, this is the first study reporting the efficacy of an antiviral drug to treat CMV infected fetuses. Moreover, this first study will allow new trials to be conducted, using valacyclovir as a baseline safe and effective treatment in pregnancy, to be compared to the new emerging and more potent anti-CMV drugs that have not currently been tested in pregnancy.