Severe fetal anaemia caused by congenital cytomegalovirus infection
- 1 Department of Obstetrics and Perinatology, Instituto Nacional Materno Perinatal, Lima, Peru
- 2 Fetal Medicine Unit, Grupo CERAS, Clínica Anglo Americana, Lima, Peru
- Correspondence to Dr Walter Ventura; walterichard@hotmail.com
Abstract
A 22-year-old pregnant woman was referred to our fetal medicine unit due to severe fetal growth restriction at 26 weeks of gestation. An extensive detailed ultrasound revealed signs of bilateral periventricular hyperechogenicity, suggesting fetal infection potentially due to cytomegalovirus (CMV). Doppler ultrasound showed a high peak systolic velocity in the middle cerebral artery. Percutaneous umbilical cord blood sampling confirmed fetal CMV infection and severe fetal anaemia. We present this case to highlight the importance of fetal anaemia, which can be fatal regardless of whether it is associated with generalised oedema or hydrops fetalis.
Background
Cytomegalovirus (CMV) infection is the most frequently occurring congenital viral illness that causes sequelae such as sensorineural hearing loss and severe mental retardation. Its prevalence is variable but has been reported to be 1% of all live births, on average.1 Approximately 10% of congenitally infected infants are symptomatic at birth, but the proportion of infants with long-term sequelae is higher as severe sequelae can be found later in life, even among those labelled asymptomatic at birth.2 The risk of transmission for primary infection is approximately 30% in the first trimester, 40% in the second trimester and up to 70% in the third trimester. However, the risk of fetal complications is highest in the first trimester of pregnancy and decreases as pregnancy progresses.3 Common features during ultrasound examination include bilateral periventricular hyperechogenicity and ventriculomegaly,4 but severe fetal anaemia is rarely reported in association with fetal CMV infection.5 The purpose of this report is to describe a rare case of fetal CMV infection that caused severe fetal anaemia in addition to brain abnormalities and fetal growth restriction (FGR).
Case presentation
A primigravida aged 22 years old was referred to our unit due to severe early FGR at 26 weeks of gestation. Her medical history was unremarkable.
Investigations
Ultrasound examination revealed an estimated fetal weight of 559 g (first percentile), confirming diagnosis of FGR. The amniotic fluid was in normal range. Remarkable ultrasound findings included microcephaly, mild ventriculomegaly (posterior horn: 11.0 mm; figure 1) and bilateral periventricular hyperechogenicity (figure 2). In addition, placentomegaly (placental thickness: 56 mm) (figure 3) and hyperechogenic bowel were present. Fetal echocardiography findings and umbilical artery Doppler pulsatility index (PI) were normal. Uterine artery-related mean PI was in the 94th percentile, middle cerebral artery (MCA)-related PI was in the first percentile (IP: 1.17) and the cerebroplacental ratio was 0.94 (1th percentile). Remarkably, the MCA peak systolic velocity (PCV) was high at 51.9 cm/seg (1.59 multiples of the median (MoM)). An infectious disease panel on the maternal blood sample revealed high titres of rubeola IgM (2.3 IU/L, normal value: 0–0.8 IU/L) and IgG (63.3 IU/L, normal value: 0–5 IU/L) antibodies. There was no suspicion of CMV infection based on the maternal blood sample. However, the fetus was tested for both rubeola and CMV due to sonographic findings. Fetal blood sampling was positive for CMV IgM, and reverse transcription PCR was negative for rubeola but positive for CMV. In addition, fetal haemoglobin level was 55.0 g/L (normal value: 110–150 g/L), and platelet count was 148 (normal value: 120 –300 ×109/L).
Prenatal ultrasound showing ventriculomegaly.
Prenatal ultrasound showing periventricular calcifications.
Prenatal ultrasound showing placentomegaly.
Treatment
The patient refused an intrauterine blood transfusion. The parent was counselled regarding expected poor perinatal outcomes, including high risk of intrauterine demise and long-term sequelae. In Peru, termination of pregnancy is legally restricted. A close follow-up was conducted with no remarkable changes.
Outcome and follow-up
A spontaneous vaginal delivery occurred at 40 weeks of gestation. The newborn weighed 1730 g. Furthermore, Apgar score at 1 min and 5 min was 8 and 9, respectively. Haemoglobin level at birth was 6.4 g/dL, leading to three total consecutive blood transfusions. Neonatal brain imaging confirmed prenatal ultrasound findings. The patient was referred to a paediatric hospital for further management. Antiretroviral therapy with ganciclovir was administered for 6 months. Breast feeding was continued. No further episodes of fetal anaemia occurred. At the time of writing of this report, the patient was 4 years old and presented neurodevelopmental sequelae, including mental retardation, severe neuromuscular impairment and severe neurosensory hypoacusis.
Discussion
Common findings in fetal CMV infection
Here, we present a prenatal case of CMV infection associated with severe fetal anaemia with no progression to hydrops. Cerebral sonographic abnormalities, including intracranial calcification, periventricular or cortical heterogeneity, mild ventriculomegaly and microcephaly, are commonly seen in patients with CMV fetal infection. FGR is usually reported in patients infected with CMV. The cause of FGR is thought to be impaired placental development due to lack of new villus growth, as CMV dysregulates key proteins required for self-renewal and differentiation of trophoblast progenitor stem cells into mature placental cells.6 Other extracerebral sonographic findings commonly seen in patients with fetal CMV infection include placentomegaly, characterised by a thick and heterogeneous placenta, and hyperechogenic bowels, as seen in the case presented here. Oligohydramnios, hepatosplenomegaly, ascites and thin miliary calcification in the liver or myocardium can also be found, among other rare findings.7
Fetal anaemia associated with CMV infection
The rarity of fetal CMV infection associated with the development of severe anaemia prompted us to report this case. Although it is well known that PSV in the MCA is high in fetuses with anaemia due to parvovirus B19 infection,8 CMV is rarely reported to cause fetal anaemia.9 Table 1 summarises the studies reporting fetal anaemia as a consequence of CMV infection. The rationale for the development of fetal anaemia over the course of CMV infection is unknown. Duncan et al reported four cases of CMV fetal infection with high PSV in the MCA, but only two of the cases were truly associated with fetal anaemia.5 One could argue that the high PSV in the MCA is due to brain inflammation and hyperaemia.10 Severe fetal anaemia was also reported following a primary maternal CMV infection, which led to cerebellar haemorrhage and subsequent anaemia and hydrops.11 Kiyokoba et al reported transient pancytopenia in the second trimester during an active CMV infection. They hypothesised that haematophagocytosis is triggered by CMV, leading to T-cell-mediated damage in the progenitor cells and proliferation of mature histiocytes, which destroyed the haematopoietic cells.12 In our case, we found that platelet count was not too low but did not perform complete blood count. Immune haemolytic anaemia has been reported in infants with CMV infection. Abnormal immunological activation may lead to haemolysis13 during an active CMV infection, which is supported by the clinical improvement observed on administration of high-dose gamma-globulin therapy to adult patients with acute CMV infection. Similarly, antinuclear antibodies, cold agglutinins, cryoglobulins and rheumatoid factors are frequently found in adults infected with CMV. Therefore, an underlying autoimmune mechanism could cause fetal anaemia, even given a negative Coombs test.
Reported cases showing an association between congenital CMV and fetal anaemia
| Author | GA at diagnosis in weeks | Hydrops/ascites | MCA PSV in cm/seg (MoM) |
Fetal haemoglobin in g/dL | Outcome |
| Ortiz et al 11 | 23+3 | Yes | 50.8 (>1.50) | 4.8 | Termination |
| Kiyokoba et al 12 | 21+2 | Yes | 52.3 (1.96) | 6.6 | Alive |
| Duncan et al 5 | 28+0 | Yes | 150 (4) | 8 | Neonatal death |
| Duncan et al 5 | 24 | Yes | 131 (4.3) | 2.7 | Neonatal death |
| Salazar-Sanchez et al. (2021) (this study) | 26+0 | No | 51.9 (1.59) | 5.5 | Alive |
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CMV, cytomegalovirus; GA, gestational age; MCA, middle cerebral artery; PSV, peak systolic velocity.
This report highlights that fetal anaemia could be present along with fetal CMV infection and should be suspected when MCA Doppler assessment shows a high systolic velocity.
Learning points
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Intrauterine cytomegalovirus infection can cause severe fetal anaemia.
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Intrauterine cytomegalovirus infection can cause severe early fetal growth restriction.
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Hydrops fetalis is unusual in cases of severe fetal anaemia caused by cytomegalovirus.
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Cytomegalovirus infection could be a cause of fetal anaemia when hydrops is not present.
Ethics statements
Patient consent for publication
Footnotes
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Twitter @PedroLlancari, @RommyHelena
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Contributors CSS was responsible for the conception and design of the study. Data acquisition was performed by CSS and PLL. Analysis and interpretation of data were performed by RHN, CSS and WV. CSS wrote the first draft, and critical revision of publication was done by WV. Supervision was done by RHN and WV.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.
References
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