What obstetricians should be aware of: serious side effects of antibiotic toxoplasmosis treatment in pregnancy

Background

Toxoplasma gondii is an intracellular protozoan parasite. Infection can be acquired by consumption of tissue cysts in raw or poorly cooked meat or oocysts on unwashed food or in water, contaminated with cat faeces.1–3 With an adequate immune response, the acute stage of infection with parasitaemia of rapidly dividing tachyzoites changes to a chronic stage with persistence of slow-growing, cyst-forming bradyzoites.1–3

Approximately one-third of the world′s population is infected with T. gondii (prevalence varies considerably from 11% in the USA to 78% in Brazil),1 2 but in immunocompetent individuals, infections usually show no or only mild flu-like symptoms (eg, fever, malaise and lymphadenopathy).1 2 However, in pregnant women, primary infection (and in very rare cases in immunocompromised women either reactivation of chronic disease or reinfection with a different Toxoplasma strain) can lead to vertical transplacental transmission to the fetus resulting in congenital toxoplasmosis of the infant.1–3 The risk of transplacental infection increases from approximately 5% transmission rate in the first trimester to 60%–90% in the third trimester. In contrast, the earlier in pregnancy the vertical transmission occurs, the more serious are the sequelae.1–5

Ultrasound signs of the infected fetus include morphological abnormalities like hydrocephalus, ventricular dilatation, brain or hepatic calcifications, splenomegaly, ascites and pericardial effusion. Furthermore, intrauterine growth restriction and a thickened placenta with increased hyperdensity have often been reported but are not very specific.1 The clinical manifestations at birth are very variable including the classic triad of hydrocephalus, chorioretinitis and intracranial calcifications. Irrespective of symptom severity at birth serious long-term sequelae (eg, chorioretinitis, motor and hearing deficits, mental retardation and learning disability) may develop later in childhood or even in young adulthood.2 3

Worldwide approximately 0.1–6 infants per 1000 live births are infected, but the seroprevalence of toxoplasma antibodies in women of childbearing age and the incidence of congenital toxoplasmosis differ significantly among the countries, even in more developed states.1 2 6 Accordingly, uniform guidelines for prevention and management of toxoplasmosis acquired in pregnancy and congenital toxoplasmosis do not exist.6–8

In principle, two different antibiotic drug regimens are used for toxoplasmosis treatment. Spiramycin has been reported to prevent vertical transmission to the fetus, and it is primarily used in the first trimester as a prophylaxis after primary infection of the mother is detected. If fetal infection is confirmed by a positive result in amniocentesis or highly suspected due to morphological abnormalities in fetal ultrasound, the antibiotic regimen will commonly be switched to the more potent combination of pyrimethamine and sulfadiazine (with folinic acid) to treat the fetus, as spiramycin barely crosses the placental barrier.1–3 9 If the primary infection occurs after 14 (or in some countries 16–18) weeks of gestation, the combination of pyrimethamine and sulfadiazine is commonly used as first-line choice.1–3 5 However, the efficacy of treatment for transmission rates and infant outcome became controversial in the early 2000s, and it still remains unclear whether or not pyrimethamine/sulfadiazine provides a benefit compared with spiramycin. Despite of the large number of studies, study designs are often poor, leaving only one prospective randomised study comparing the different antibiotic regimens.4 6 10–22 Nevertheless, existing studies showed a benefit for the treated patients compared with the untreated ones and therefore a clinically important effect cannot be ruled out. Thus, the possible fetal benefit has to be balanced against the side effects of the medication. Spiramycin is usually well-tolerated, but pyrimethamine is known for its haematotoxic and possibly teratogenic effects and sulfonamides often cause hypersensitivity reactions.9 14 18 23–27 However, although the main side effects of antibiotic drugs used in toxoplasmosis therapy are quite well known, further information about frequency of occurrence, degree of severity, associated risk factors and alternative treatment strategies for pregnant women are still lacking.9 23–25

Case presentation

A 31-year-old healthy pregnant woman (G1P0) tested positive for toxoplasmosis-antibodies in her serum at 26+0 weeks of gestation (T. gondii IgG >650 IU/mL, IgM positive, IgG-avidity low 0.02). Antibody status had been tested due to insufficient fetal growth with an estimated fetal weight <5% percentiles (small for gestational age (SGA)) but normal umbilical and cerebral doppler and without any evidence of morphological fetal abnormalities. There was a negative toxoplasmosis antibody-testing (T. gondii IgG negative, IgM negative) at 12+6 weeks of gestation as part of a routine screening. Thus, the primary infection must have taken place between 12+6 and 26+0 weeks of gestation. We discussed these findings with the patient and after obtaining informed consent we started an antibiotic therapy with pyrimethamine 25 mg per day, sulfadiazine 4 g per day and folinic acid, commencing at 28+1 weeks of gestation.

At 29+3 weeks of gestation the patient presented with fever and cough and was admitted to our feto-maternal pregnancy unit. The blood test showed slightly elevated infection parameters (white cell count (WCC) 8.3 x10⁹/L, C reactive protein (CRP) 65 mg/L), normal kidney and liver function and chest radiography showed left-sided basal pneumonia. Antibiotic therapy with ceftriaxone was initiated but had to be stopped due to an allergic reaction with mild skin exanthema after the first dose. The patient had no prior history of allergic reactions. Antibiotic therapy was changed to coamoxicilline 2.2 g three times a day, but after the third dose, the patient showed another allergic reaction with dyspnoea, oedema and increasing full-body skin exanthema. Thus, we switched the antibiotic regimen to azithromycine 500 mg per day. This therapy was well tolerated, but the initial symptoms did not improve and the patient needed supplemental oxygen due to low blood oxygen levels (saturation of peripheral oxygen (SpO2) minimal 93%). Urine analysis, blood cultures and nasopharyngeal swabs (including adenovirus, bordetella pertussis, chlamydia pneumoniae, coronavirus, influenza virus A/B, human metapneumovirus, mycoplasma pneumoniae, parainfluenza virus 1–4, rhinovirus/enterovirus, respiratory syncytial virus) remained sterile. Serum infection parameters increased (WCC 9.5 x10⁹/L, CRP 215 mg/L) and repeated chest radiography showed increasing infiltrates in both lung with diagnosis of bilateral pneumonia (figure 1). In addition, the patient developed a moderate mitral regurgitation. With regard to the clinical course, we interpreted the pneumonia as an adverse reaction against the continued antibiotic treatment with pyrimethamine and sulfadiazine and suspected a hypersensitivity pneumonia. After the antibiotic therapy with pyrimethamine and sulfadiazine was stopped at the fifth day of hospitalisation and treatment with systemic corticosteroids was started, the patient′s general condition improved significantly 2 days later. Therefore, the antibiotic therapy with azithromycine was stopped at the seventh day of hospitalisation and the patient was discharged from hospital 3 days later at 30+6 weeks of gestation.

Due to the toxoplasmosis, we recommended a therapy with spiramycin 9 Mio IU per day at 34+0 weeks of gestation and continued treatment until delivery. Repeated ultrasound scans revealed a persistently low fetal weight (<5% percentiles), but otherwise there was no sonographic evidence of a fetal infection.

The fetus was delivered at 40+5 weeks of gestation via secondary caesarean section due to non-reassuring fetal heart rate after induction of labour. The female newborn weighted 2340 g (<3% percentiles) and required initial respiratory support with continuous airway pressure (CPAP) until the second hour of life. Except moderate pulmonary hypertension all examinations (including echocardiography and neurosonography) were normal. Umbilical cord blood sampling did not show any evidence of congenital toxoplasmosis (T. gondii IgG >650 IU/mL, IgM and IgA negative).

The newborn was moved from neonatal unit to maternity unit at the third day of life and was discharged from hospital together with its mother at the fourth day of life.

Outcome and follow-up

The child is currently 14 months old and developing normally. Cardiac examination at 1 month and the ophthalmological examinations at 1 and 4 months were normal. T. gondii antibody testing at 3 months showed decreasing levels of IgG (47 IU/mL) and still did not detect any IgM. Therefore, congenital toxoplasmosis was likely to be ruled out and no further supplementary checks in addition to the usual routine paediatric examinations were planned.

The mother recovered well: during later pregnancy dyspnoea disappeared and mitral regurgitation decreased to a minimal degree without clinical relevance.