Prenatal Treatment of Congenital Cytomegalovirus With Valganciclovir: A Case Report

Abstract

Cytomegalovirus (CMV) is the most common congenital infection and infectious cause of fetal anomaly and neurologic injury. However, treatment strategies for congenital CMV (cCMV) infection during pregnancy remain elusive. We report a case of hydrops fetalis secondary to cCMV infection with minimal sequelae after maternal and subsequent neonatal treatment with valganciclovir.

Congenital cytomegalovirus (cCMV) is estimated to affect 40 000 infants each year in the United States, making it the most common congenital infection [1]. Furthermore, cCMV is associated with significant morbidity. Symptoms of cCMV at birth can include jaundice, thrombocytopenia, hepatosplenomegaly, intracranial calcifications, hearing loss, and death [1]. Neonatal mortality from symptomatic cCMV at birth is as high as 7% in contemporary analyses [2]. For neonates who are asymptomatic at birth, the prognosis is more favorable. However, up to 25% may subsequently develop symptoms, which can include sensorineural hearing loss, intellectual disability, chorioretinitis, and seizures [3]. While asymptomatic patients diagnosed with cytomegalovirus (CMV) on newborn screen with normal hearing by age 2 show no differences in intelligence quotient, vocabulary, or academic achievement at 18 years of age compared with uninfected controls, those with sensorineural hearing loss by age 2 may have lower full-scale intelligence and receptive vocabulary scores [4]. These findings highlight the potential long-term neurodevelopmental effects of cCMV.

There are currently no vaccines available to prevent maternal CMV infection or reduce maternofetal transmission. Furthermore, treatment strategies for cCMV during pregnancy to decrease fetal and neonatal morbidity related to cCMV are limited. Studies of treatment with CMV intravenous immunoglobulin have not been successful in randomized trials, likely in part due to the inclusion of asymptomatic women with serologic conversion of CMV [5, 6]. We suspect that the most efficacious treatment is maternal anti-CMV therapy after identification of symptomatic maternal or fetal infection. However, maternal antiviral treatment with ganciclovir or valganciclovir has not commonly been used due to concerns for toxicity to fetal germ cells. Here we report a case of minimal postnatal cCMV-related sequelae after a strategy of antenatal maternal treatment with valganciclovir after a diagnosis of cCMV infection and hydrops fetalis.

CASE REPORT

Antenatal Presentation and Course

A 31-year-old healthy female gravida 2 para 1 presented to our hospital as a referral at 31 weeks’ gestation for detailed ultrasound after measuring large for dates. Prior fetal anatomy was documented as normal. Fetal growth ultrasound demonstrated polyhydramnios with an amniotic fluid index of 48 cm, bilateral pleural effusions, and skin edema along the fetal scalp, chest, and abdomen, consistent with hydrops fetalis. The estimated fetal weight was > 99th percentile, driven mainly by a large abdominal circumference. Intracranial anatomy was normal and no significant hepatomegaly was noted. Subsequent fetal echocardiogram revealed normal cardiac anatomy, a small pericardial effusion, moderate bilateral pleural effusions, and fetal ascites. The patient was offered a diagnostic amniocentesis. Further maternal serologic testing was performed and results are listed in Table 1.

Amniocentesis was uncomplicated with removal of 645 mL of straw-colored fluid that was sent for karyotype; microarray; and CMV, toxoplasmosis, and parvovirus qualitative polymerase chain reaction (PCR) (Table 1). Two weeks after amniocentesis, results returned with a positive CMV PCR. The remaining amniocentesis results were normal. Ultimately, the cause of hydrops fetalis was determined to be disseminated fetal CMV infection.

The patient and her partner were counseled that anticipated survival in the setting of nonimmune hydrops is < 50% [7, 8]. They were further counseled about the significant neonatal morbidity associated with cCMV should the fetus survive to delivery. The parents were offered expectant management with continued fetal surveillance or antenatal therapy with valganciclovir. The experimental nature of valganciclovir therapy and lack of any definitive evidence for use in the antenatal period was reviewed in depth and available literature shared with the family. The potential maternal and fetal risks of maternal valganciclovir therapy were also discussed, including the risk of maternal and fetal pancytopenia, maternal renal and hepatic impairment, the unknown teratogenic effects, and the risk of potential harm rather than improvement.

After thorough counseling, the patient pursued therapy with valganciclovir at a dose of 900 mg oral daily. This was continued until delivery with weekly monitoring of maternal complete blood counts and hepatic function. Twice-weekly fetal surveillance revealed persistent hydrops. The patient delivered via low-transverse cesarean delivery for arrest of descent at 37 weeks.

Infant Outcome at Delivery and Follow-up Care

The female infant was born with the following growth parameters: birth weight, 3.71 kg (95th percentile for gestational age); length, 52 cm (95th percentile); and head circumference, 35 cm (90th percentile). She was admitted to the intensive care nursery and required 4 L high-flow nasal cannula with 60% oxygen. She was well-appearing on admission with hepatomegaly and hypotonia, but no rash. Laboratory evaluation at birth was notable for relative thrombocytopenia to 194 × 10⁹/L (Table 2).

She was started on ganciclovir 6 mg/kg every 12 hours intravenously within several hours of birth. Imaging on her first day of life (DOL) was pertinent for normal biventricular function on echocardiogram with a small apical pericardial effusion, chest radiograph with heterogenous pulmonary opacities and left pleural effusion, abdominal ultrasound with splenomegaly, and a right frontoparietal periventricular calcification on brain magnetic resonance imaging on DOL 4. Dilated ophthalmology examination on the first DOL did not demonstrate any retinitis or other lesions. Newborn hearing screen was passed in both ears on DOL 7. She was weaned to room air by DOL 3. Intravenous ganciclovir was transitioned to oral valganciclovir on DOL 4. CMV saliva PCR and urine shell viral culture collected on the first DOL were positive. CMV plasma quantitative DNA PCR was 527 IU/mL on DOL 4. She was discharged home on room air and oral feeds on DOL 10, at which time her thrombocytopenia had resolved (Table 2). She did develop neutropenia requiring a reduced dose of valganciclovir to 12 mg/kg on DOL 75. CMV viral load increased to 1291 IU/mL after the dose reduction, at which point the 16 mg/kg dose was resumed. Growth and development continued to be appropriate up to 4 months of age (Table 2). Unfortunately, the family was lost to follow-up at our institution after her 4-month visit when they moved out of the region.

Discussion

Prevention of cCMV is difficult due to the nonspecific, and often asymptomatic, nature of maternal infection and the risk of transmission with both primary and nonprimary maternal infections. Until successful development of a CMV vaccine can be achieved, treatment is the best option for maternofetal dyads affected by CMV. Randomized trials of CMV hyperimmune globulin therapy have been disappointing, finding no neonatal benefit and possible harm from CMV hyperimmune globulin therapy for maternal primary CMV infection [6, 9].

Neonatal antiviral therapy with ganciclovir and valganciclovir may prevent hearing loss and improve developmental outcomes in some neonates with cCMV [10, 11]. Data on the use of maternal antiviral administration for in utero treatment of cCMV infection are limited. One recently presented randomized, placebo-controlled trial compared valacyclovir 8 g/day to placebo in pregnant women with serologic evidence of primary CMV. The rate of transmission of CMV confirmed by amniocentesis was 11% in women who received acyclovir compared to 29.8% in the placebo group [12]. This study followed a preliminary trial that compared neonatal outcomes for fetuses with mild cerebral or extracerebral manifestations of cCMV and confirmed CMV by PCR of amniotic fluid who were treated with valacyclovir to outcomes of a historical control group. A 43% increase in the proportion of asymptomatic neonates compared to the historical comparator group was noted [13]. While studies examining the use of CMV-specific antivirals are even more limited, a case report published in 2005 did demonstrate clearance of CMV DNA from the amniotic fluid of a patient with a renal allograft found to be positive for CMV in pregnancy who was treated with ganciclovir, suggesting potential benefit from CMV-specific antivirals [14].

Ganciclovir and valganciclovir are specifically approved for the treatment and prevention of CMV. Valganciclovir, a prodrug derivative of ganciclovir that can be administered as a once-daily dose, has good oral bioavailability and study of its administration in the setting of known fetal CMV infection has been proposed [15]. Potential risks associated with valganciclovir therapy include neutropenia and teratogenicity, although animal models of intrauterine ganciclovir have only demonstrated fetal germ cell toxicity at drug concentrations much higher than standard clinical dosing [15]. Reported clinical experience with ganciclovir and valganciclovir is limited, but a series of 9 cases described no or minimal symptoms at birth in 8 of 9 exposed neonates [15]. In the 4 cases with amniotic fluid, cord blood, or neonatal blood ganciclovir levels reported, drug concentrations remained less than half of concentrations shown to have no fetal side effects in animal models [15]. Furthermore, the frequency of cytopenic adverse effects likely varies depending on the population being treated. In otherwise healthy young women, such as those likely to be encountered in pregnancy, neutropenia may be less of a concern.

In this case, we report the successful maternal administration of valganciclovir 900 mg oral daily in pregnancy for treatment of a fetus suspected to have cCMV. Neonatal outcomes in this setting were expected to be poor. After maternal treatment with valganciclovir in utero and neonatal treatment with ganciclovir followed by valganciclovir, the infant progressed well with normal development through follow-up at 4 months of age. While this therapy remains highly experimental and is associated with potential risk, studies comparing neonatal outcomes after valganciclovir therapy to expectant management or valacyclovir in cCMV infection are warranted.

Note

Potential conflicts of interest. B. L. H. has served as a consultant for Merck. S. R. P. has received grants from Moderna, Merck & Co Vaccines, and the Bill & Melinda Gates Foundation and personal fees from Moderna, Pfizer Vaccines, Merck & Co Vaccines, and Sanofi, outside the submitted work. All other authors report no potential conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

References