Congenital infection with human cytomegalovirus is a major cause of morbidity and mortality. A randomized controlled trial showed that high-dosage valacyclovir prevents cytomegalovirus 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. A randomized controlled trial comparing prenatal treatment with valacyclovir against placebo in infected fetuses failed to recruit because women declined randomization. Randomized controlled trials in fetal medicine have often proven unacceptable by women who decline termination of pregnancy 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 g daily, for pregnant women carrying a symptomatic cytomegalovirus-infected fetus, targeting a high-risk group for developing both neurosensory and neurological impairment. We designed a multicenter, open-label, phase II study with 1 arm, using one of Simon's optimal 2-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 termination of pregnancy. 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 2-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 = .01 and P < .001, respectively), between treatment initiation and birth after treatment completion, regardless of duration of fetal infection. Compared with a historical cohort obtained by a metaanalysis of the literature, the use of valacyclovir (8 g 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 >90%. Finally, valacyclovir at this high dosage was extremely well tolerated. 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 a randomized controlled trial, this is the first study reporting the efficacy of an antiviral drug to treat cytomegalovirus-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 anticytomegalovirus drugs that have not currently been tested in pregnancy.

Objectives  To report early experience with treatment of intrauterine cytomegalovirus (CMV) infection using maternal oral administration of valaciclovir (VACV).Design  Observational study of fetuses infected with CMV with or without treatment with valaciclovir.Population  Pregnancies with confirmed fetal CMV infection were treated with oral VACV (8 g/day).Main outcome measures  Fetal viral load and drug concentration were monitored in amniotic fluid and in fetal blood. Data on the course and outcome of a group of untreated symptomatic fetuses infected with CMV are also reported.Results  Therapeutic concentrations were achieved in maternal and fetal bloods. The viral load in the fetal blood (VLFB) decreased significantly after 1–12 weeks of treatment (Wilcoxon paired test P= 0.02). Twenty pregnancies including 21 fetuses were treated at 28 weeks (median, range: 22–34) for 7 weeks (median, range: 1–12). Ten infants were developing normally at between 1 and 5 years of age. Two infants (both aged 2 years) had severe isolated unilateral deafness. One neonate presented with microcephaly and severe deafness but was also diagnosed with incontinentia pigmenti. Six out of seven cases that eventually required termination of pregnancy (TOP) had evidence of in utero progression of the disease with worsening cerebral lesions. One fetus died in utero. The outcome of 14/24 (58.3%) untreated symptomatic infected fetuses was poor with either TOP, intrauterine fetal demise or severe congenital infection disease of the neonate; the remaining ten infants were healthy at follow up.Conclusion  Maternal oral administration of VACV leads to therapeutic concentrations in the maternal and fetal compartments, with a decrease in VLFB. Our results suggest that in cases where TOP is declined, a randomised controlled trial to study this treatment option further is indicated.

Objective: To evaluate the relative contributions to the diagnosis of fetal brain abnormalities of targeted ultrasound examination and magnetic resonance imaging (MRI) in fetuses infected with cytomegalovirus (CMV).Methods: This was a retrospective analysis of targeted brain ultrasound examination and fetal brain MRI performed in fetuses diagnosed with CMV infection following proven maternal primary infection. The prenatal findings were compared with findings from postnatal transfontanellar ultrasound examination during the first week following delivery or from postmortem when the pregnancy was terminated.Results: Both targeted prenatal ultrasound and MRI were performed on 49 fetuses. Brain abnormalities were present in 15/49 (30.6%) cases at postnatal/post‐mortem follow‐up. Fetal cerebral abnormalities were observed in 19/49 (38.8%) cases by ultrasound and/or MRI. The most frequent cerebral lesions induced by CMV and seen on ultrasound and MRI, respectively, included ventricular dilatation in nine and five cases, subependymal cysts in two cases each, microcephaly in five and three cases and periventricular calcifications in five cases on ultrasound only. Termination of pregnancy was performed in 10/49 cases. Sensitivity, specificity and positive and negative predictive values for the presence of cerebral lesions were 88.9%, 93.3%, 88.9% and 93.3%, respectively, when both prenatal ultrasound and MRI findings were abnormal, 85.7%, 85.3%, 70.6% and 93.5%, respectively, for ultrasound alone, and 42.9%, 91.2%, 66.7% and 79.5%, respectively, for MRI alone. Prenatal ultrasound, MRI and postnatal or postmortem examinations were concordant with the presence of brain abnormalities in six cases; however, their conclusions were exactly concordant in only two (33.3%) of these cases. In cases without cerebral abnormality, the results of prenatal and postnatal/postmortem examinations were concordant in 28/34 cases.Conclusions: The addition of MRI to ultrasound increases the positive predictive value for the diagnosis of fetal brain abnormalities in fetuses with CMV. The two techniques appear to be complementary and should not be mutually exclusive in high‐risk fetuses. Their high predictive value for the presence or absence of cerebral lesions provides a useful tool for appropriate counseling since current evaluation of the prognosis is based mainly on the presence of fetal brain lesions. The lack of concordance between ultrasound and MRI should stimulate standardization of the interpretation of both ultrasound and MRI prospectively. Copyright © 2008 ISUOG. Published by John Wiley & Sons, Ltd.

Objective: The prognosis of fetal lower urinary tract obstruction (LUTO) depends upon renal function and also upon the underlying etiology. Precise identification of the latter remains a challenge antenatally. Our objective was to examine the underlying pathology in male fetuses with sonographic evidence of severe and isolated LUTO.Methods: Detailed postmortem examination was carried out after termination of pregnancy in 24 male fetuses presenting before 25 weeks of gestation with ultrasound evidence of isolated severe LUTO.Results: All fetuses had megacystis and hyperechogenic kidneys. There was anhydramnios/oligohydramnios and pelvicalyceal dilatation in 20 and 15 cases, respectively. Posterior urethral valves (PUV) were suspected antenatally in 20 cases and urethral atresia was not suspected antenatally. However, postmortem examination of the urethra demonstrated atresia in six cases, severe stenosis in eight cases, PUV in nine cases and an apparently normal urethra in one case. Renal dysplasia was found in all cases but one. Urethral atresia was the most common urethral anomaly at 12–17 weeks. Hydronephrosis was more frequent in cases with PUV (8/9) and urethral stenosis (6/8) than with urethral atresia (0/6). In LUTO presenting in the first and second trimester, hyperechogenic kidneys were predictive of renal dysplasia in 95% of cases. The association of a sagittal diameter of the bladder of at least 40 mm with hydronephrosis before 28 weeks was predictive of PUV with a positive (PPV) and negative (NPV) predictive value of 44.4% and 66.6%, respectively. Absence of hydronephrosis and a sagittal diameter of the bladder of less than 40 mm were predictive of urethral atresia or stenosis with a PPV and NPV of 100% and 47.6%, respectively. The absence of hydronephrosis was predictive of urethral atresia with a PPV and NPV of 66.6% and 100%, respectively.Conclusion: LUTO in a male fetus presenting with megacystis in the first or second trimester of pregnancy is as likely to reflect urethral atresia or stenosis as it is PUV. The size of the bladder and the presence of hydronephrosis should be considered in order to improve prenatal diagnosis and counseling. Copyright © 2005 ISUOG. Published by John Wiley & Sons, Ltd.