Prevention of Congenital Toxoplasmosis With Pyrimethamine + Sulfadiazine Versus Spiramycine During Pregnancy

The protocol is a comparison of 2 strategies to prevent mother-to-child transmission of T. gondii following maternal seroconversion.

Screening for toxoplasmosis is mandatory in France. Patients with confirmed seroconversion will be eligible for the trial, after 14 weeks gestational age.

Participants will be randomly allocated to one of the treatment groups, and will receive open-label pyrimethamine + sulfadiazine or spiramycin.

The protocol will not change the usual procedures for prenatal diagnosis, nor will it change the management of infected fetuses and neonates.

• Pyrimethamine/Sulfadiazine (Drug), also known as Pyrimethamine = Malocide®, Sulfadiazine = Adiazine®: Pyrimethamine + sulfadiazine group : Pyrimethamine 50 mg once daily orally and sulfadiazine 1g tid. orally, with supplemental folinic acid 50 mg once a week. Follow-up includes clinical and biological tolerance, according to usual recommendations. Monthly fetal ultrasound is performed. Prenatal diagnosis with amniocentesis is offered after 18 weeks gestation, usually 4 weeks after the maternal infection. Treatment is be stopped or changed in case of toxicity. If prenatal diagnosis shows fetal infection with T. gondii, management is to be determined by the clinicians with the patient. If the prenatal diagnosis is negative the treatment can be stopped in order to reduce the risk of intolerance, providing that the mother receives at least 4 weeks of therapy.
• Spiramycine (Drug), also known as Spiramycine = Rovamycine®: Spiramycin group : spiramycin 1g tid orally Follow-up includes clinical and biological tolerance, according to usual recommendations. Monthly fetal ultrasound is performed. Prenatal diagnosis with amniocentesis is offered after 18 weeks gestation, usually 4 weeks after the maternal infection. Treatment is be stopped or changed in case of toxicity. If prenatal diagnosis shows fetal infection with T. gondii, management is to be determined by the clinicians with the patient. If the prenatal diagnosis is negative the treatment is continued according to usual procedures

Primary outcomes

• Rate of mother-to-child transmission [Up to six months after birth]: Rate of mother-to-child transmission of toxoplasma gondii, determined by PCR on amniocentesis and/or synthesis of specific antibodies by the neonate

Secondary outcomes

• Secondary Outcome Measure [Up to six months after birth]: * Mother-to-child transmission rate according to the time between primary infection and start of therapy * Tolerance in mothers and neonates (grade 3-4 toxicities) * Severity of infection at birth in case of congenital toxoplasmosis (parasite load in amniotic fluid, clinical and biological signs)

Sex: Female, ages: 18 Years to any

Inclusion Criteria:

* > 18 years old
* Toxoplasmosis infection acquired during the pregnancy documented by at least one negative serology in the first trimester and seroconversion with presence of specific IgG antibodies
* Gestational age > 14 weeks from last menstrual period
* Signature of informed consent

Exclusion Criteria:

* Lack of a documented negative serology during the pregnancy
* Antiparasitic therapy with spiramycin, pyrimethamine or sulfa drugs for more than 10 days after seroconversion and before randomization,
* Known allergy to any of the study drugs, serious allergic conditions or G6PD deficiency,
* Known hepatic or renal insufficiency,
* Other ongoing severe conditions in mother or fetus
* Lack of public health insurance

• Laurent Mandelbrot, MD, Principal investigator, Assistance Publique - Hôpitaux de Paris