Prenatal diagnosis and in utero treatment of severe congenital toxoplasmosis: a case report

A 41-year-old Thai gravida 3, parity 2, at 31⁺¹ weeks of gestation, was referred for evaluation of abnormal cerebral ultrasound findings in her fetus. Her previous pregnancy history, antenatal history, and ultrasonographic findings at 17 weeks of gestation for amniocentesis were unremarkable. The fetal chromosomal study was normal. She did not own a cat, but had been feeding a stray cat near her home. She had never been screened for T. gondii antibodies.

Ultrasonography at 31⁺¹ weeks of gestation revealed severe bilateral ventriculomegaly with areas of hyperechogenicities in the periventricular region (Figure 1), cardiomegaly, hepatosplenomegaly with intrahepatic hyperechogenicites (Figure 2), and polyhydramnios. Fetal congenital infection was suspected and fetal blood sampling was performed and sent for serologic testing. The result was positive for T. gondii IgG and IgM antibodies.

Figure 1

Figure 2

After counseling, the patient was started with written informed consent on pyrimethamine, sulfadiazine and folinic acid (PSF regimen) at 32⁺¹ weeks of gestation. No adverse effects related to the medications were observed during the treatment period. Ultrasonography was repeated at 34⁺² weeks of gestation and showed similar findings. On the same day, she developed premature amniorrhexis and went into labor.

The fetus was delivered by cesarean section because of previous section. The female neonate weighed 1,920 g, which was appropriate for her gestational age. The Apgar scores at 1 and 5 minutes were 7 and 8, respectively. She was intubated because of respiratory distress, which later was diagnosed as congenital pneumonia and respiratory distress syndrome. An initial examination revealed a normal head circumference of 30 cm, jaundice, and hepatosplenomegaly. An eye examination showed iris atrophy and vitreous haziness compatible with toxoplasmosis. The IgG test was positive in serum and cerebrospinal fluid. The placental showed chronic villitis with calcifications and encysted organisms in trophoblastic cells (Figure 3), findings compatible with toxoplasmosis.

Figure 3

The PSF regimen was given to the newborn. Despite this treatment, her clinical course was complicated with neonatal sepsis, meningitis and ventilator-associated pneumonia. Death occurred at the age of 11 days.

We report a case of congenital toxoplasmosis diagnosed at late gestation when the fetus demonstrated multiple abnormalities on ultrasonography including ventriculomegaly, periventricular calcifications, cardiomegaly, hepatosplenomegaly with intrahepatic hyperechogenicities, and polyhydramnios.

Humans are usually infected via eating under-cooked infected meat, or ingesting food contaminated with toxoplasma oocysts. The seroprevalence of toxoplasmosis in women of a child-bearing age varies by geographical region, ranging from 0.8% in South Korea to 77% in Brazil [2]. In Thailand, 19%–28.3% of pregnant women have been found to be seropositive for T. gondii antibodies [5, 6].

When pregnant women become infected with T. gondii, most remain asymptomatic, yet parasites can be transmitted to their fetus across the placenta. Risk depends on timing of infection and is estimated to be 10%-25% in the first trimester and increases to 60%–90% in the third trimester. Conversely, clinical manifestations are more severe the earlier the infection occurs [1]. Ultrasonographic findings include hydrops, ventricular dilatation, intracranial calcifications, intrahepatic calcifications, pleural effusion, pericardial effusion, and a thick, echogenic placenta. Abnormal intracranial findings indicate severe fetal infection and a poor prognosis [7]. Fetal infection is usually diagnosed by fetal blood sampling for antibody detection or amniotic fluid polymerase chain reaction (PCR).

When the fetuses are severely affected, therapeutic termination of pregnancy is usually offered [8, 9]. According to the International Federation of Gynecology and Obstetrics (FIGO), when termination of pregnancy following prenatal diagnosis is performed beyond 22 weeks of gestation, it must be preceded by feticide to ensure delivery of a stillborn fetus [10].

In Thailand, abortion is legal if performed by a physician to protect the health of the mother and in pregnancy that resulted from sexual crimes. Pregnancy termination, when severe fetal anomalies are diagnosed, and in order to preserve the mothers’ mental health is acceptable according to new medical legislation published in the Royal Thai Government Gazette [11]. However, for nonlethal anomalies, pregnancy termination is possible only before the pregnancy reaches the threshold of viability, usually before 22 to 24 weeks of gestation, depending on the institution. Feticide for fetal anomaly is not acceptable in Thailand and termination of pregnancy at late gestation for nonlethal anomaly is considered inappropriate because the fetus may be born alive and suffer additional complications from prematurity.

In the present case, the gestational age of the fetus at diagnosis was beyond the threshold of viability and the abnormalities found were nonlethal. These ethical and legal limitations were discussed with the patient and invasive fetal testing was recommended only to confirm the diagnosis and to guide whether further fetal treatment can be offered.

After the diagnosis of congenital toxoplasmosis was confirmed, the patient and her husband were informed about the results and that the fetus carried the risk of stillbirth and severe neurological deficits if she survived. Despite the poor prognosis, and after discussion with parents, we decided to administer antibiotics in the hope of minimizing morbidity. This management was based on few reported cases of clinically-affected fetuses that were treated. Two cases in 2005 and 2011 involved severely-affected fetuses, who had residual abnormalities in postnatal life despite treatment in utero [12, 13]. However, Friedman, reported a case in 1999, of fetal hydrops caused by congenital toxoplasmosis, in which the fetus showed improvement after the initiation of the PSF regimen, and the neonate had only minimal abnormalities in postnatal life [14]. A large retrospective analysis from Germany in 2010, also indicated effectiveness of prenatal treatment of toxoplasmosis, even in fetuses with abnormal prenatal findings [3]. In that study, there were 3 cases of prenatally-diagnosed fetal ventriculomegaly; all of them experienced disease improvement, as evidenced via either subsequent prenatal ultrasonography or other postnatal imaging. The authors postulated that if the treatment was initiated as early as possible (not later than 12 weeks following maternal infection) it could be beneficial. The details of each case are summarized in Table 1.

For the present case, the duration of maternal infection could not be determined because the mother was asymptomatic and no T. gondii screening was conducted before presentation. The patient received only 2 weeks of medications before delivery. The poor perinatal outcome resulted not only from the toxoplasmosis infection, but also from the preterm delivery and superimposed complications of prematurity, such as respiratory distress syndrome. However, multiple clinical manifestations of congenital toxoplasmosis were demonstrated in the newborn and in the placental histology, indicating poor response to prenatal medical therapy. We conclude that late detection of the infection, severe clinical manifestations in the fetus, late treatment, and the short duration of treatment-to-delivery time contributed to the poor outcome.

From our experience, when fetal congenital toxoplasmosis is diagnosed late in pregnancy with severe ultrasonographic abnormalities, the neonatal outcome is likely to be poor despite in utero treatment with antibiotics. Premature delivery and short treatment duration may worsen the prognosis for the fetus.