Ultrasound features of congenital cytomegalovirus infection in the first trimester: A case report

Abstract

BACKGROUND

Congenital cytomegalovirus (CMV) infection represents a significant public health concern as the most prevalent viral infection in newborns, potentially leading to severe neurological and developmental complications. The majority of cases are asymptomatic and remain undetected during pregnancy due to the absence of effective screening methods.

CASE SUMMARY

A 27-year-old primigravida presented for early pregnancy ultrasound, which revealed an atypical finding: A normal anechoic thalamus appearing hyperechoic on the mid-sagittal view of the fetal head. Subsequent ultrasound examinations during mid and late gestation demonstrated classic intracranial features suggestive of congenital CMV infection. Chromosomal karyotyping and microarray analysis of the fetus yielded no significant abnormalities. Following comprehensive prenatal counseling regarding potential adverse fetal outcomes, the patient elected to continue her pregnancy. She ultimately underwent cesarean delivery at 42 weeks gestation at another facility, resulting in the birth of a female neonate. At five months of age, the infant presented with epilepsy and significant growth and developmental delays.

CONCLUSION

Congenital CMV infection occurs during the first trimester may manifest as hyperechoic thalamus which can be revealed by ultrasound in the mid-saggital view of the fetal head. Future research should investigate the correlation between echogenic thalamus and developmental outcomes, as well as explore early screening techniques for suspected congenital CMV infection cases.

Key Words: Prenatal diagnosis; Congenital infection; Cytomegalovirus; Fetal ultrasound; Case report

Core Tip: We present a case of a fetus infected with cytomegalovirus, characterized by distinctive ultrasound findings during early gestation. The patient underwent a thorough diagnostic evaluation, systematically excluding chromosomal abnormalities and other potential infections. The definitive diagnosis was established based on characteristic ultrasound manifestations typically observed in the second and third trimesters of pregnancy.

INTRODUCTION

Cytomegalovirus (CMV) is a neurotropic virus and the leading viral cause of intrauterine infection, affecting approximately 0.7% of live neonates worldwide[1]. Major affected neonates will be asymptomatic at birth, and more than one fourth of infected children will have long-term sequelae, including sensorineural hearing loss and neurological impairments[2], when the infection happens in the first trimester of pregnancy[3]. Congenital CMV-infected fetuses may be categorized into three groups: Asymptomatic, mild to moderate symptomatic, and severely symptomatic, with outcomes varying significantly based on these classifications[4]. Asymptomatic fetuses are characterized by normal ultrasound, magnetic resonance imaging, and biological parameters, indicating the most favorable prognosis. Conversely, fetuses with mild to moderate symptoms present isolated biological abnormalities, with or without isolated ultrasound anomalies such as echogenic bowel or mild ventriculomegaly, leading to uncertain prognoses. Regular follow-up imaging is advised for further evaluation. Severely affected fetuses exhibit significant intracranial anomalies, including microcephaly, white matter abnormalities, intracranial hemorrhage, and cortical dysplasia, often resulting in poor outcomes. In these instances, termination of pregnancy may be considered as a potential option.

Owing to the limited effectiveness of screening tests, routine prenatal screening for CMV infection during pregnancy is not implemented in most countries globally[5]. Consequently, routine ultrasound examinations during pregnancy assume a crucial role in the prenatal diagnosis of CMV infection. However, prenatally detecting fetuses that are asymptomatic or exhibit mild to moderate symptoms often presents significant challenges. Ultrasound abnormalities associated with CMV infection, whether intracranial or extracranial, typically manifest during the second or third trimester. Intracranial abnormalities include ventriculomegaly, microcephaly, periventricular cystic lesions, intracranial calcifications, and malformations of cortical development, such as lissencephaly[6]. Although these findings are not specific, the presence of two or more of these abnormalities may strongly suggest CMV infection[7,8]. Since the majority of critically impacted fetuses occur during the first trimester[3], it is essential to identify the fetus promptly, which may significantly influence the management and outcome of pregnancy. The incidence of neurosensory impairment in newborns at birth ranges from 5% to 60%[9,10]. However, few studies focus on the manifestations of CMV infection during the first trimester. This report presents a case of CMV infection exhibiting abnormal intracranial manifestations in the first trimester, accompanied by characteristic ultrasound findings in the second and third trimesters.

CASE PRESENTATION

Chief complaints

A 27-year-old nulliparous woman presented at our hospital for a routine ultrasound examination.

History of present illness

The patient was healthy, and the pregnancy was uneventful.

History of past illness

The patient had no past illness.

Personal and family history

Both the pregnant woman and her husband had no significant personal or family history.

Physical examination

The physical examinations of the pregnant woman did not reveal any abnormalities.

Laboratory examinations

Prenatal aneuploidy screening indicated a high risk for trisomy 21. Subsequently, amniocentesis was performed at 18 weeks of gestation (GA), with both karyotype and chromosomal microarray analyses yielding normal results. A toxoplasmosis, rubella, CMV, herpes simplex examination conducted at 32 weeks of GA revealed positive immunoglobulin G (IgG) and negative IgM. On the fifth day of life, CMV-DNA was undetectable in the infant’s urine. At 6 months of age, tests for toxoplasmosis, herpes simplex, rubella, syphilis, human immunodeficiency virus, hepatitis B virus, hepatitis C virus, and tuberculosis all returned negative results.

Imaging examinations

The routine ultrasound examination at 12 weeks of GA showed a normal nuchal translucency of 1.0 mm and a crown-rump length of 59 mm, which is consistent with the expected gestational age. The ultrasound assessment was performed in accordance with the International Society of Ultrasound in Obstetrics and Gynecology guidelines[9] using a Voluson^™ E10 machine (GE Healthcare) with C2-9-D probe, operating at a frequency range of 2-9 MHz. By aligning the ultrasound beam with the mid-sagittal suture from the anterior fontanel perspective, a mid-sagittal view of the fetal brain is obtained. This view shows several midline cerebral structures, including the nasal bone, third ventricle, thalamus, brainstem, fourth ventricle, cisterna magna, aqueduct of Sylvius, and nuchal translucency. The anatomical examination was mostly normal, except for a round hyperechoic thalamus located above the non-obliterated third ventricle (Figure 1), which usually appears anechoic. A subsequent examination at 23 weeks of GA indicated that the fetus was small for gestational age and exhibited microcephaly and occipital calcification. The couple declined a repeat amniocentesis for CMV DNA detection. Follow-up ultrasound examinations at 30, 32, 35, and 38 weeks of GA revealed progressive manifestations of microcephaly, multiple intraventricular or parenchymal calcifications, subependymal multiseptal cysts, moderate ventriculomegaly, lissencephaly, and small for gestational age (Figure 2). The magnetic resonance imaging revealed hypoplasia of the brain and supratentorial hydrocephalus.

Figure 1 Midsagittal view of fetal head with cytomegalovirus infection at 12 weeks and 3 days of gestation demonstrating a hyperechoic thalamus, which is typically anechoic under normal conditions. The caudal anechoic band indicates the third ventricle. T: Thalamus; 3V: Third ventricle; BS: Brain stem; AS: Aqueduct of Sylvius; 4V: Fourth ventricle; CM: Cisterna magna; NT: Nuchal translucency.

Figure 2 Axial view of the fetal head in the third trimester. A: The transverse view of the fetal head at 35 weeks of gestation demonstrated midline and intraventricular calcifications (orange arrow); B: At 38 weeks of gestation, the transverse view exhibited multiple cysts, ventriculomegaly, and a smooth brain surface (lissencephaly).

FINAL DIAGNOSIS

The diagnosis of prenatal CMV infection was established based on the presence of characteristic intracranial features, clinical manifestations, serological findings for CMV-IgG and IgM, and normal karyotype and microarray results, while ruling out other potential infections.

TREATMENT

The infant did not receive any specific treatment due to the negative result of the CMV-DNA urine test. Only supportive care measures were administered.

OUTCOME AND FOLLOW-UP

At six months of age, the infant received a diagnosis of epilepsy and developmental delays. Subsequently, she commenced anti-epileptic treatment, which regrettably yielded limited efficacy.

DISCUSSION

The gold standard for diagnosing CMV involves detecting its DNA in amniotic fluid using polymerase chain reaction prenatally, or in urine or saliva within the first three weeks of life. However, Blázquez-Gamero et al[11] reported a case where CMV DNA was detected in the amniotic fluid. The patient received a dose of hyperimmune globulin for therapy after amniocentesis, but this treatment was later proven ineffective in a randomized controlled trial[12], and subsequently became negative in urine after birth. This scenario might be applicable to our case. IgG antibodies in an infected fetus can persist until the age of 2 years[13], while IgM typically lasts only a few months. Therefore, maternal CMV-IgM negativity does not preclude amniotic fluid sampling for CMV-DNA-polymerase chain reaction analysis when CMV infection is suspected[8]. These findings align with the serological results observed at 6 months in this case.

Definitive diagnosis of fetal infection typically requires invasive testing, primarily amniocentesis, performed 6-8 weeks after the initial maternal infection. Amniocentesis is generally delayed until 18-20 weeks of GA, as fetal urination is not sufficiently developed before this stage. Consequently, diagnosing fetal CMV infection during the first trimester remains challenging. However, the ultrasound manifestations of CMV infection during the second and third trimesters of pregnancy have been extensively documented in the medical literature[4,6,14]. In our particular case, we observed and documented the typical intracranial features indicative of CMV infection, which included microcephaly (below two standard deviations), ventriculomegaly, lissencephaly, intracranial multiple cysts and calcifications. In our experience, typical intracranial findings of CMV infection - usually two or more - can often be confirmed virologically. This observation is consistent with Leruez-Ville et al’s review[15], which found that targeted ultrasound had a 91% sensitivity when sonologists were aware of CMV infection.

This case provides significant insights into the complex dynamics of CMV infection affecting the fetal brain during the critical first trimester of pregnancy. It suggests that the thalamus may be the initial brain region impacted by CMV infection, emphasizing its vulnerability during early development. The study meticulously delineates the midsagittal anatomical structures of both the thalamus and the third ventricle within the fetal head during the first trimester, as referenced in previous works[16,17]. Specifically, it describes the thalamus as a round, hyperechoic structure situated cephalically, while the third ventricle is characterized by its slit-like, anechoic appearance located caudally. Clinically, this may indicate a need for invasive assessment due to an unidentified irregularity that has not been fully understood or diagnosed. This raises concerns among medical professionals about its implications for patient care and the need for further investigation into this anomaly. To our knowledge, this research is the first comprehensive study to accurately depict the anatomical structures of the third ventricle and thalamus during the first trimester. This is particularly important as previous pathological studies have often reported the third ventricle as obliterated[17].

Several researchers have documented various thalamic hyperechogenicities[8,18], some associated with CMV infection and others not. Bronshtein et al[18] reported seven cases of isolated hyperechogenic foci in the fetal thalamus at 14-16 weeks of GA; six fetuses exhibited one hyperechogenic focus, while one presented two foci. These foci ranged in size from 2 mm to 4 mm. In all instances, serologic work-up and karyotype were normal, the hyperechogenic foci resolved by mid-pregnancy, and all fetuses were normal at delivery, remaining healthy during follow-up until nine years of age. They concluded that isolated hyperechogenic foci in the thalamic region in early pregnancy are probably benign in nature. In contrast to previous cases, this instance of thalamic hyperechogenicity was detected at 12 weeks of GA, manifesting as a round hyperechoic thalamus. While this finding disappeared in the mid-trimester, other intracranial signs of CMV infection emerged. Our observations during the first trimester of pregnancy provided a novel, non-invasive approach that potentially facilitates early diagnosis of fetal CMV infection, which is essential for safeguarding fetal health and development. The identification of hyperechoic thalami during the first trimester, a critical period for fetal brain development, may indicate potential developmental abnormalities warranting further investigation and monitoring. These findings could have significant implications for the overall health and neurological outcomes of the developing fetus. Interestingly, the abnormal thalamus identified by ultrasound during the first trimester was not recognized until the imaging was reviewed in the third trimester.

A multicenter study showed that fetal brain magnetic resonance imaging (MRI) can detect approximately 10.5% additional anomalies in fetuses with CMV infection and normal neurosonography[19]. However, both fetal and neonate MRI did not reveal more information compared with fetal neurosonography in our case. This may be attributed to a lack of awareness about CMV infection among radiologists and inadequate training of technologists in performing advanced fetal MRI[20]. Fetal MRI is not recommended prior to 18 weeks of GA because it does not usually provide additional information than ultrasound examinations[20].

This study presents potential limitations. This case report examines a unique instance of a fetus exhibiting classic ultrasound findings indicative of CMV infection, emphasizing the critical importance of prompt virological diagnosis. However, due to the absence of immediate viral testing, a definitive virological diagnosis was not established, highlighting a significant limitation of this study. Additionally, as this report is based on a single case, it lacks comprehensive clinical data to validate the observed ultrasound characteristics of early pregnancy CMV infection.

CONCLUSION

CMV infection, especially when occurring during the critical first trimester of pregnancy, may manifest as a hyperechoic thalamus. This condition can be effectively visualized through ultrasound imaging in the mid-sagittal view of the fetal head, offering crucial insights into the developing brain. Future research should focus on thoroughly investigating the complex relationship between the presence of an echogenic thalamus and various developmental outcomes in affected infants. Additionally, exploring innovative early screening methods for suspected congenital CMV infection could significantly improve early diagnosis and intervention strategies.