Fetal intracranial calcifications

Alessandro Ghidini, MD, Marina Sirtori, MD, Patrizia Vergani, MD, Silvana Mariani, MD, Elio Tucci, MD, and Gian Carlo Scola, MD

Milan and Como, Italy

In utero sonographic visualization of fetal intracranial calcifications during the second trimester is reported. Its diagnostic process, which included percutaneous umbilical cord blood sampling and fetal paracentesis, is described. (AM J OBSTET GVNECOL 1989;160:86-7.)

Key words: Intracranial calcification, intrauterine cytomegalovirus infection, prenatal diagnosis

Fetal intracranial calcifications are rare sonographic findings and are thought to occur late in gestation, after localized neural cell death. Their visualization during the second trimester of pregnancy has never been de­scribed. They are most commonly associated with in utero infections and their presence implies a grave prognosis for the fetus.

Case report A 35-year-old white woman, gravida 2, para 1, was

referred to our Center at 21 weeks' gestation because a previous sonographic examination elsewhere had identified ventriculomegaly and hydrops fetalis. At that time an amniocentesis had been performed, and am­niotic fluid a-fetoprotein and karyotype were found to be normal (46,XX). Our ultrasonographic examination revealed a singleton fetus whose biometry was consis­tent with gestational age. Intracranial scans visualized bilateral dilatation of the posterior horns and atria of the later ventricles and small, hyperechogenic areas scattered along the ventricular walls and within the pa­renchyma, diagnosed as foci of calcification (Fig. 1). No structural abnormalities were seen. Amniotic fluid vol­ume was normal. The placenta was hypertrophic with a maximum thickness of 5.0 em. An intrauterine in­fection was thought to be the most likely cause of the sonographic findings. Maternal VDRL, hepati­tis B virus, and Listeria blood titers were negative. The rubella test was immunoglobulin M negative and immunoglobulin G positive at 1: 128. The cytomega­lovirus titer was immunoglobulin M negative and im­munoglobulin G positive at 1: 50. The toxoplasmosis test result by indirect hemoagglutination was 1: 320, with enzyme-linked immunosorbent assay immuno­globulin M negative.· A fetal paracentesis was per-

From the Department of Obstetrics and Gynecology, InstItute of Biomedical Sciences S. Gerardo, Monza, University of Milan, and the Departments of Obstetrzcs and G,vnecology and Pathology, S. Anna Hospital.

ReceIved for publication May 17, 1988; accepted June 12, 1988. Reprint requests: Alessandro Ghidim, MD. Department of Obstetrzcs

and Gvnecolog)', Yale University School of Medicine, 333 Cedar St., P.O. Box 3333, New Haven, CT 06510.

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Fig. 1. Cross-section of fetal head at level of biparietal di­ameter. Bilateral dilatation of posterior portions of ventricles (V) and scattered periventricular hyperechogenic deposits (cal­cifications) (anows) are clearly visible.

formed at 22 weeks' gestation. Laboratory findings on the ascitic fluid were consistent with exudate. Ascitic fluid cultures were negative. A percutaneous umbilical cord blood sample yielded fetal blood with minimal contamination of amniotic fluid and maternal blood.

Therefore, true values of fetal hemoglobin and he­matocrit could not be determined. However, 94% erythroblasts were found (mean at 22 weeks 13%, SD 9%).' Total immunoglobulin M was 13 mgldl (mean at 22 weeks 2.93, SD 0.83) (maternal immunoglobulin M 80 mgl dl); 'Y-glutamyltransferase was 190 U IL (normal range 30 to 35 U IL) (maternal 'Y-glutamyltransferase 25 U IL).1. 2 The parents were informed that the sonographic and laboratory data available (erythro­blastosis, elevated 'Y-glutamyltransferase) were highly suggestive of severe fetal intrauterine infection that car­ried significant risks of in utero fetal death or, in case of neonatal survival, a 95% chance of major neurologic sequelae. The parents opted for continuation of preg­nancy. At 23 weeks' gestation a spontaneous abortion

Volume 160 r,;umber 1

Congenital intracranial calcifications 87

Fig. 2. Cytomegalovirus encephalitis. Note diffuse reactive glial proliferation on right, whereas necrosis with calcification is visible in left part of figure. (Hematoxylin and eosin. Original magni­fication x 125.) Inset, Closer view of necrotic-calcified area. Note enlarged cells. many with intra­nuclear inclusions. (Hematoxylin and eosin. Original magnification x 500.)

occurred, and a female fetus was delivered without any overt malformations. A pathologic examination failed to demonstrate macroscopic anomalies with the excep­tion of mild early hydrocephalus. On microscopic ex­amination, the kidneys, pancreas, liver, thyroid, and lungs showed epithelial giant cells with intranuclear basophil inclusions, typical of cytomegalovirus infec­tion. In the central nervous system, foci of necrosis of the brain parenchyma with associated calcifications were found. Enlarged neuronal and glial elements with intranuclear cytomegalovirus inclusions were noted with no reactive microglial or astroglial proliferation (Fig. 2).

Comment

The natural history of congenital infections is poorly understood. Most data are derived from the neonatal and pediatric literature, and it is still unclear how timing of infection correlates with pathologic findings. Infec­tious agents, like toxoplasma, cytomegalovirus, type 2 herpes simplex virus, and rubella virus, reach the fetal central nervous system via the bloodstream and have a predilection for the rapidly growing subependymal or germinal matrix cells. All of these organisms may cause severe cerebral malformations (microcephaly, hydro­cephalus, porencephalic cysts) and meningoencepha­litis. Neuronal and glial necrosis also may be present, more commonly with cytomegalovirus and toxoplas­mosis infections. Necrotic cells may subsequently un­dergo a process of calcification, leading to the typical periventricular deposits.

Differential diagnosis of fetal intracranial calcifica­tions includes basically noninfectious and infectious

causes. The former are extremely rare at this early stage oflife and include intracranial teratomas, tuberous scle­rosis, Sturge-Weber syndrome, and sagittal or trans­verse sinus thrombosis. The latter are more commonly associated with extracranial findings, including hepa­tosplenomegaly, ascites, hydrops, intrauterine growth retardation, and hyperplacentosis. Fetal infections are most often accompanied by a seroconversion of ma­ternal titers. If maternal titers are not suggestive of a recently acquired immunity, as in our case, percuta­neous umbilical blood sampling may allow for the di­agnosis. The presence of specific fetal immunoglobulin M titers is diagnostic. However, the fetus does not pro­duce serum immunoglobulin M until the eighteenth to twentieth week of gestation.2

A characteristic of cytomegalovirus infection (as with other herpesviruses) is that, after primary infection, latency is established and periodic episodes of reacti­vation can occur. Most primary and reactivated infec­tions are subclinical, but during pregnancy they may cause serious infections in the fetus with a risk of per­manent sequelae and developmental impairments. The timing and extensions of intracranial calcifications par­allel the severity of the perinatal disease.

REFERENCES 1. Daffos F, Forestier F, Capella-Pavlovsky M. Acquisitions

recentes en medecine prenatale. Rev Med Assur Mal 1984;3:55-60.

2. Daffos F. Forestier F, Grangeot-Keros L, et al. Gradual appearance of total IgM in fetal serum during the second trimester of pregnancy: application to the prenatal diag­nosis of fetal infections. Ann Bioi Clin 1984;42: 135.