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Intrauterine therapy of cytomegalovirus infection with valganciclovir: review of the literature

Abstract

Congenital cytomegalovirus (CMV) infection is the leading cause for sensorineural hearing loss and mental retardation in children without genetic diseases worldwide. There is little evidence guiding therapeutic strategies during pregnancy when intrauterine fetal CMV infection is confirmed. We provide a systematic review of the use of ganciclovir (GCV) or VGCV during pregnancy discussing safety of its use for mother and fetus and describe two cases of intrauterine therapy of fetal CMV infection with valganciclovir (VGCV). A PubMed database search was done up to November 16, 2016 without any restrictions of publication date or journal, using the following keywords: “valganciclovir” or “ganciclovir” and “pregnan*”. Furthermore, citations were searched and expert references were obtained. Reported cases were considered if therapy was in humans and initiation of treatment of the CMV infection was during pregnancy. In total, seven case reports were retrieved which described GCV or VGCV use during pregnancy for fetal or maternal CMV infection. In the four cases of treatment for maternal CMV infection, no negative effects on the fetus were reported. Three cases of GCV administration to pregnant woman with the intention of fetal treatment after proven fetal infection were found. We additionally present two cases of VGCV treatment in pregnancy from our center of tertiary care. VGCV seems to be a safe treatment for congenital CMV infection for the mother and the fetus. Therapeutic concentrations can be achieved in the fetus by oral intake of the mother and CMV replication can be suppressed. Larger studies are needed to evaluate this therapeutic intervention and the long-term effects.

Introduction

Congenital cytomegalovirus (CMV) infection is the leading cause for sensorineural hearing loss and mental retardation in children without genetic diseases [25]. With an overall CMV IgG seroprevalence in pregnant women in Germany of 42.3% it means that 56.8% of pregnant women in Germany are at risk of acquiring primary CMV infection throughout the pregnancy [9]. Furthermore, CMV IgG seroprevalence provides only partial protection against intrauterine fetal infection [5]. In spite of numerous research endeavors, vaccination against CMV is not yet available [1, 35, 36].

Studies on the prevention of fetal infection with hyperimmune globulin (HIG) show conflicting results [6, 30, 41]. A study by Leruez-Ville et al. showed that infected fetuses with intrauterine treatment with valaciclovir (VACV) were asymptomatic at birth in 82% in comparison to a historic cohort with only 43% asymptomatic newborns, but a prospective randomized controlled trial to prove the efficacy of this treatment is still lacking [24]. New experimental therapeutic strategies to treat CMV infection have not been tested in pregnancy [11, 23].

Symptomatic CMV-infected newborns receive ganciclovir (GCV) for more than 10 years as the standard therapeutic regime [20]. A recent study could show that expanding the duration of the therapy from 6 weeks to 6 months with an oral regime of valganciclovir (VGCV) improves the outcome for symptomatic children [19]. Resistance to GCV can lead to therapy failure [17].

VGCV is the prodrug of the active antiviral agent GCV. VGCV is the 1-valyl ester of GCV and can be absorbed through the intestinal peptide transporters PEPT1 and PEPT2. While enteral resorption of GCV is poor with approximately 8% bioavailability, VGCV can be administered orally [8, 47]. In vitro GCV shows greater antiviral efficacy than ACV [50]. GCV can penetrate various body compartments, including transplacental passage and penetration into the cerebrospinal fluid of neonates [12, 15, 28, 32].

After treatment with GCV for 6 weeks or 6 months the child will remain serologically positive for CMV IgG livelong and excrete CMV virus at random time points [7, 45, 46]. Lowering the viral load (VL) during the first weeks or months of life, the time when the neonatal brain is most susceptible to damage by the virus, is most probably the explanation for the improvement in clinical outcome through timely suppression of the virus. One study discussed that a low viral count in the amniotic fluid (AF) correlates with better outcome of the neonate [22]. Condensing this information, we propose that beginning viral suppression earlier, namely in utero, might improve fetal outcome.

We present a review on the data available up to this day on safety of intrauterine GCV exposure. Furthermore, we present two cases in which absence of CMV urine shedding at birth indicates effective suppression of viral replication through intrauterine treatment.

Review on safety of intrauterine GCV-exposure methods

A literature research was performed up to November 16, 2016 using the Database PubMed with no time restrictions with the following keywords: valganciclovir OR ganciclovir AND pregnan*. Both English-language and non-English-language literature was reviewed; citations within the retrieved papers were followed up and additionally expert references were taken into account. For inclusion, primary data of VGCV or GCV therapy in pregnant humans had to be presented and initiation of treatment of the CMV infection had to be during pregnancy. We focused on the following criteria: context/intention of therapy, therapy, concentration in fetal and maternal components, cumulative therapy duration, outcome, signs of fetal infection, side effects for the mother, and co-medication.

Results

Literature review

The initial search revealed 110 results. 105 publications did not meet inclusion criteria. In total, five case reports were retrieved which described GCV or VGCV during pregnancy for fetal or maternal CMV infection [2, 3, 27, 33, 37]. Cross-referencing revealed one additional case report [40]. Expert referencing revealed one congress abstract reporting fetal therapy with VGCV administration to the mother [51] (Table 1).

Table 1 Overview of documented cases of ganciclovir during pregnancy

The case reports meeting our inclusion criteria can be divided into two different intentions of the treatment. Four cases concern symptomatic CMV infections in pregnant women and report on possible side effects for the fetus. The cases vary in exposure from the periconceptional period, first, second and third trimester and range from 3 weeks to more than a full trimester. These cases are extremely heterogeneous also in terms of underlying comorbidity of the mother: HIV-coinfection necessitated the simultaneous application of an antiretroviral regimen in two cases [2, 3]. Because of kidney [27] or liver [33] transplantation immunosuppressive therapy was given. The main conclusion is that despite possible embryotoxic [21] effects and a possible effect on germ cells [31, 52], there are so far no reports of malformations due to in utero GCV or VGCV exposure. Unfortunately in none of the case reports long-term outcomes are reported.

The other three articles report on GCV or VGCV administration to pregnant woman with the intention of fetal treatment after proven fetal infection. Intrauterine GCV administration via cordocentesis to a fetus was associated with preterm stillbirth [40]. Puliyanda et al. report the management of a fetal infection most probably due to maternal recurrent infection after renal transplantation [37]. Welz et al. report fetal treatment in a case of symptomatic CMV infection with ultrasonographic correlates. VGCV therapy was initiated at 30 weeks of gestation. Amniocentesis showed therapeutic concentrations of VGCV in the fetal blood with a fetal/maternal ratio of 2.15. The VL in the AF was decreasing within the course of the treatment from >68.8 × 106 IU/ml in 27 + 2 weeks of gestation to 14.8 × 106 IU/ml. No maternal side effects were reported. The sonographically monitored structural correlates of CMV infection in the brain did not progress during treatment. Therapy for the child was continued after birth. Except for a unilateral hearing deficiency affecting the right ear the child remains asymptomatic at 2 weeks of life [51]. In all three cases of treatment of fetal infection during pregnancy, no side effects in the mother were reported.

Experience in our center of tertiary care

In our center of tertiary care, intrauterine fetal infection was confirmed in two women with primary CMV infection in pregnancy. Treatment of fetal infection with VGCV was initiated during pregnancy.

Case report 1

We present the case of a 35-year-old gravida 2, para 1 with a periconceptional asymptomatic CMV infection and consecutive fetal CMV infection confirmed by high CMV VL in AF. Serologic findings in the first trimester hinted at a primary CMV infection. The first examination at 7 weeks gestation showed a low concentration of anti-CMV IgG (16 U/ml) and a positive anti-CMV IgM (72 U/ml). At 9 weeks gestation repeat testing supported the diagnosis of a periconceptional primary CMV infection [IgG 55 U/ml with low avidity and highly positive IgM (>140 U/ml)]. CMV DNA in the plasma of the patient was positive. After detailed counseling about current therapeutic options [39], the patient requested intravenous (i.v.) therapy with HIG, which was administered at 10 weeks gestation and 12 weeks gestation. A first and a second trimester screening by an ultrasonography specialist showed a structurally normal fetus. A third ultrasonography at 31 weeks gestation revealed one periventricular cyst in the brain. A subsequent amniocentesis revealed a high VL of >6 × 106 copies/ml in the AF. Oral VGCV therapy of 450 mg 3×/day was initiated as an individual therapeutic approach in informed consent with the patient. A fetal magnetic resonance imaging (MRI) scan at 33 weeks gestation confirmed the periventricular cyst, without any other signs of central nervous system (CNS) infection. VGCV therapy was continued. No progression of brain pathology was detected in a subsequent ultrasonographic exam at 38 weeks gestation. No side effects were seen in the mother.

At 39 weeks gestation, a female infant was born by spontaneous vaginal delivery with a birth weight of 3200 g (49th percentile), a head circumference of 35 cm (74th percentile) and a length of 48 cm (14th percentile) [4]. The pH in the umbilical cord artery was 7.22 and the Apgar score at 1/5/10 min was 9/10/10. GCV in the plasma of the patient at the time of delivery detected by C–MS/MS technique (liquid chromatography—mass spectrometry and liquid chromatography—tandem mass spectrometry) measured 1.65 µg/ml and in the umbilical cord blood of the child 1.88 µg/ml, resulting in a fetal/maternal ratio of 1.14. GCV was also detected in the AF, but because the assay is not validated for AF quantification was not possible.

The child showed no obvious malformations. The postnatal auditory brainstem evoked potentials (ABEP) were normal at 1 and 17 days of life. A sonography of the head showed a slight ventricle asymmetry within the normal range and a small subependymal cyst. The abdominal sonography was normal. The PCR in the urine and blood was negative for CMV DNA on the day of birth. The child had a normal red blood cell (18.1 g/dl), leukocyte (10.4/nl) and platelet count (272/nl) on the second day of life. No VGCV was administered.

At 10 days of life a viruria of 21,600 cop/ml was detected, a control at 13 days of life revealed viruria of 85,300 cop/ml. GOT (glutamic oxaloacetic transaminase) remained normal, but GGT (gamma-glutamyltransferase) was elevated to 114 U/l (normal range < 36 U/l). The VL in the serum was <2000 cop/ml (limit of detection 750 cop/ml, linear range 2000–3 × 10E8 cop/ml). Although not generally recommended for asymptomatic children, after extensive counseling parents requested VGCV therapy for 6 weeks. It was started with a dosage of 2 × 16 mg VGCV/kg body weight according to the recommendations by Kimberlin et al. [18, 19]. After 8 days of therapy the child presented with a neutropenia (770/µl), i.e., Grade 2 toxicity [29]. VGCV was reduced to half the dosage. Treatment was continued at the adapted dosage for a total of 42 days. Absolute neutrophil count remained in the slight subnormal range and normalized after end of VGCV therapy.

During the 6 weeks of VGCV therapy the urine was repeatedly negative for CMV DNA. Blood controls revealed a slight elevation of liver enzymes with maximum values of GPT (glutamate-pyruvate transaminase) 76 U/l (normal range < 31 U/l), GGT (gamma-glutamyltransferase) 167 U/l and an icterus prolongatus with a maximum bilirubin of 8.77 U/l on the 24th day of life. Liver values normalized after stoppage of treatment.

At 5 months of age, the neurological exam and ABEP were normal. At 7 months of life CMV DNA was as expected detectable again (398,000 cop/ml) in the urine.

Case report 2

In a 37-year-old gravida 2, para 1 polyhydramnion was detected at 22 weeks gestation. Anti-CMV IgG and IgM were positive (74 IU/ml and 51 U/ml, respectively) with a low avidity of the IgG-antibodies, and seroconversion during the pregnancy was suspected. An amniocentesis at 33 + 0 weeks gestation showed a VL of 2 × 106 copies/ml in the AF. Except for the slight polyhydramnion the ultrasound examinations showed no fetal signs of CMV infection. Oral VGCV therapy of 450 mg 3×/day was initiated. No side effects were seen in the mother.

The patient delivered a male neonate at 39 + 6 weeks gestation by spontaneous vaginal delivery with a birth weight of 3610 g (58th percentile), a head circumference of 35 cm (39th percentile) and a length of 54 cm (83rd percentile) [4]. The pH in the umbilical cord artery was 7.30 and the Apgar score at 1/5/10 min was 9/10/10. GCV in the plasma of the patient at time of delivery 5.5 h after the last intake detected with C–MS/MS technique was 2.51 µg/ml and in the umbilical cord blood 3.03 µg/ml, resulting in a fetal/maternal ratio of 1.21. GCV was also detected in the AF.

The child showed no obvious malformations. The postnatal ABEP, the sonography of the head and the abdomen on the second day of life were normal. The PCR in the urine was negative for CMV on the day of the birth. Blood work for neutrophil count or liver function was not done during the first 48 h after delivery.

At 15 days of life a viruria of 179,000 cop/ml was detected, 2 days later in the plasma CMV was detected at a level of 5720 cop/ml. On day 23 VGCV therapy was started with 2 × 16 mg/kg body weight. Within 6 days the child developed a neutropenia with a minimal absolute neutrophil count (ANC) of 610/µl, i.e., a Grade 2 toxicity [29]. The VGCV dosage was lowered to half. The child also had elevated GGT with a maximum of 135 U/l, which was spontaneously regressing under treatment. No icterus was observed. Neutrophils recovered only slightly to 920/µl on the 18th day of therapy. Subsequently in his 7th week of life the child developed a systemic enterovirus-infection with enterovirus detectable in the liquor. Clinical recovery was uneventful. VGCV therapy was continued at the adapted half dosage for a total of 6 weeks.

In a control at 3 months of life blood values had recovered to normal, the ABEP and neurologic exam were normal. No consecutive PCR of the child’s urine for CMV was done as detection of CMV in the urine without clinical symptoms would have had no therapeutic consequence.

Discussion

The study by Kimberlin et al. showed that VGCV-treated symptomatic newborns with congenital CMV infection have modestly improved hearing and developmental outcomes in the longer term [19]. Immaturity of the cells in the central nervous system appears to play a role in the deleterious effects of CMV infection. The literature suggests that VGCV treatment of the mother and/or fetus during pregnancy might be of benefit. We could show that VGCV can suppress CMV VL in the fetus and therapy during pregnancy may therefore result in better neurological outcome. Concerns have been raised in animal studies about possible embryotoxic effects and effects on fetal germ cells [21, 31, 52]. In these animal studies intrauterine GCV exposure was much higher than those usually applied in humans. A study of intrauterine GCV exposure of 300 mg/kg in rats, leading to mean serum concentrations of GCV of 167.8 µmol/l, induced germ cell deficiency in both fetal and adult testes. These were peak concentrations approximately four to five times higher than peak concentrations reported in humans who received i.v. GCV 5 mg/kg. At a lower exposure to GCV of 75 mg/kg, leading to a mean serum concentration of 29.82 µmol/l, no such effects were observed [31].

The two case reports showed therapeutic concentrations of GCV in the AF [37, 51]. For effective and safe dosage of fetal therapy during pregnancy measurement of the concentration in the fetal blood is essential. To our knowledge, only in one case by Welz et al. measurement of GCV in the fetal blood after VGCV administration to the mother had been performed so far. With our two case reports we could confirm that by oral administration of VGCV to the mother, therapeutic concentrations of GCV can be achieved in the fetal blood. The fetal/maternal ratio was 2.15 in the study by Welz et al. and 1.14–1.21 in our cases. This could be due to different time points of measurement after oral administration. In future studies pharmacokinetics should be investigated more closely. Most probably the total duration of exposure and trough concentrations are more important for antiviral activity than peak concentrations [10, 16]. With a concentration of 1.88 and 3.03 µg/ml, respectively, the plasma level was within the therapeutic range in both cases according to the recommended concentrations by Schulz et al. [43].

As neither Brandy et al. [3], who administered GCV i.v. to the mother to treat the fetus, nor Welz et al. nor we noted any side effects for the mothers, we regard fetal treatment via the mother as ethically justifiable. It seems to be a safe alternative to intrauterine intravenous application of GCV. Treatment via cordocentesis avoids maternal drug exposure, but carries significant risks such as premature birth, intrauterine bleeding and possibly intrauterine fetal death [40].

Our cases showed that even when there is no viruria after intrauterine treatment of the fetus, the virus might persist and without suppression therapy viruria can reoccur as quickly as 2 weeks postnatally. Re-initiation of VGCV therapy led to sufficient viral suppression, thus development of resistance during intrauterine treatment seems unlikely. Postnatal treatment led to neutropenia in both cases. Potentially there is a cumulative effect with antenatal treatment, thus toxicity of the treatment should be closely monitored. Neutropenia due to in utero exposure was not monitored in our two cases. For further studies, we recommend the differential blood count of the neonate on the first day of life to monitor toxicity of prenatal treatment more closely.

There is no established way to predict postnatal outcome in fetal CMV infection [14, 26, 44, 49]. Data on correlation between VL and outcome is conflicting [13, 22, 34, 42]. CMV has a tropism for stem/progenitor cells in the fetal brain [48]. Probably the earlier initiation of therapy, i.e., in the intrauterine period, when, e.g., brain cells are highly susceptible to damage, could improve neonatal outcome. As evidence on safety is lacking, GCV or VGCV administration during pregnancy in the setting of fetal CMV infection is not recommended in a recently published consensus statement [38]. However, if patients desire in utero treatment for fetal infection, limited evidence and potential risks should be explained in detail. If GCV or VGCV is given during pregnancy, data on the outcome should be collected systematically and published.

Conclusion

The limited literature and our two cases suggest that VGCV might be a therapeutic option for proven fetal CMV infection. The current number of reported cases is too small to make general conclusions. Larger trials with long-term follow-ups of in utero-exposed children are needed to find out if this therapeutic strategy is of long-term benefit.

After treatment with GCV or VGCV during pregnancy initial urine PCR in the newborn may be negative even if infection occurred. We therefore recommend repeated testing in the first weeks of life. Clinicians should keep this in mind when decisions about further treatment and follow-up are made.

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Acknowledgements

Dr. Seidel is participant in the BIH-Charité Clinical Scientist Program funded by the Charité—Universitätsmedizin Berlin and the Berlin Institute of Health. We thank Torsten Binscheck-Domaß, MD, Medical Director of the Department of Toxicology at Labor Berlin, for his information regarding measurement of GCV in human liquids. We thank Thorsten Braun, MD, Charité—Universitätsmedizin Berlin for the calculation of the percentiles of the biometric measures of the children in the two case reports at birth. The mothers whose cases are presented gave their written consent to the antenatal treatment and postpartum blood tests as well as publication of their data. Ethics approval was obtained from the ethics committee of the Charité—Universitätsmedizin Berlin.

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Seidel, V., Feiterna-Sperling, C., Siedentopf, JP. et al. Intrauterine therapy of cytomegalovirus infection with valganciclovir: review of the literature. Med Microbiol Immunol 206, 347–354 (2017). https://doi.org/10.1007/s00430-017-0512-3

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  • DOI: https://doi.org/10.1007/s00430-017-0512-3

Keywords

  • Cytomegalovirus
  • Congenital infection
  • Valganciclovir
  • Intrauterine treatment