Original Research ajog.

org

OBSTETRICS
Prenatal therapy with pyrimethamine D sulfadiazine vs
spiramycin to reduce placental transmission of
toxoplasmosis: a multicenter, randomized trial
Laurent Mandelbrot, MD; François Kieffer, MD; Rémi Sitta, MSc; Hélène Laurichesse-Delmas, MD; Norbert Winer, MD, PhD;
Louis Mesnard, MD; Alain Berrebi, MD; Gwenaëlle Le Bouar, MD; Jean-Paul Bory, MD; Anne-Gaëlle Cordier, MD;
Yves Ville, MD, PhD; Franck Perrotin, MD, PhD; Jean-Marie Jouannic, MD, PhD; Florence Biquard, MD;
Claude d’Ercole, MD, PhD; Véronique Houfflin-Debarge, MD, PhD; Isabelle Villena, MD, PhD;
Rodolphe Thiébaut, MD, PhD; and the TOXOGEST Study Group

BACKGROUND: The efficacy of prophylaxis to prevent prenatal ramycin group (P ¼ .01). Two of these pregnancies were terminated.
toxoplasmosis transmission is controversial, without any previous ran- Transmission rates, excluding 18 children with undefined status, were 12/
domized clinical trial. In France, spiramycin is usually prescribed for 65 in the pyrimethamine þ sulfadiazine group (18.5%), vs 18/60 in the
maternal seroconversions. A more potent pyrimethamine þ sulfadiazine spiramycin group (30%, P ¼ .147), equivalent to an odds ratio of 0.53
regimen is used to treat congenital toxoplasmosis and is offered in some (95% confidence interval, 0.23e1.22) and which after adjustment tended
countries as prophylaxis. to be stronger (P ¼ .03 for interaction) when treatment started within 3
OBJECTIVE: We sought to compare the efficacy and tolerance of weeks of seroconversion (95% confidence interval, 0.00e1.63). Two
pyrimethamine þ sulfadiazine vs spiramycin to reduce placental women had severe rashes, both with pyrimethamine þ sulfadiazine.
transmission. CONCLUSION: There was a trend toward lower transmission with
STUDY DESIGN: This was a randomized, open-label trial in 36 French pyrimethamine þ sulfadiazine, but it did not reach statistical significance,
centers, comparing pyrimethamine (50 mg qd) þ sulfadiazine (1 g tid) with possibly for lack of statistical power because enrollment was discontinued.
folinic acid vs spiramycin (1 g tid) following toxoplasmosis seroconversion. There were also no fetal cerebral toxoplasmosis lesions in the
RESULTS: In all, 143 women were randomized from November 2010 pyrimethamine þ sulfadiazine group. These promising results encourage
through January 2014. An amniocentesis was later performed in 131 further research on chemoprophylaxis to prevent congenital
cases, with a positive Toxoplasma gondii polymerase chain reaction in 7/ toxoplasmosis.
67 (10.4%) in the pyrimethamine þ sulfadiazine group vs 13/64 (20.3%)
in the spiramycin group. Cerebral ultrasound anomalies appeared in 0/73 Key words: pregnancy, prenatal diagnosis, pyrimethamine-sulfadia-
fetuses in the pyrimethamine þ sulfadiazine group, vs 6/70 in the spi- zine, spiramycin, tolerance, toxoplasmosis

Introduction toxoplasmosis, the prevention program transmission to the fetus increases

In France, since 1978, there has been a has been criticized for lack of proof from sharply with gestational age at the time
policy of mandatory prenatal screening randomized trials to evaluate prophylac- of infection.8,10,11 Congenital toxoplas-
for toxoplasmosis. In case of primary tic treatment. A protective effect of S was mosis may lead to fetopathy, hydro-
infection, treatment with spiramycin (S) suggested by an observational study in cephalus, and death. Most often, the
is generally offered,1 with the aim of the 1960s.4 However, there was a major disease is asymptomatic at birth, but may
reducing the risk of mother-to-child confounding bias due to the gestational lead to chorioretinitis that can be diag-
transmission.2 Most other countries age at maternal seroconversion that was nosed only later in life. The risk of brain
have not adopted a systematic screening not taken into account.5 Further large damage in higher in case of infection in
policy.3 While considerable progress has observational studies failed to demon- early pregnancy.4,8,12 A hypothesis to
been made in prenatal diagnosis and strate the efficacy of prophylactic treat- explain that previous studies failed to
prognostic evaluation of congenital ment6,7 and a meta-analysis of individual demonstrate a protective effect of S may
observational data of 1745 infected be its insufficient effect on T gondii. In
pregnant women from 26 cohorts France, S has been used for >30 years,1
Cite this article as: Mandelbrot L, Kieffer F, Sitta R, et al.
Prenatal therapy with pyrimethamine þ sulfadiazine vs concluded that prophylaxis was not while in Austria and Germany,
spiramycin to reduce placental transmission of toxo- associated with a clinically relevant pyrimethamine-sulfadiazine (PS) is
plasmosis: a multicenter, randomized trial. Am J Obstet effect.8 The French High Authority for routinely used for prophylaxis >16
Gynecol 2018;volume;x.ex-x.ex. Health9 called for randomized trials to be weeks’ gestation.13,14 PS is more effective
0002-9378/$36.00 performed before reevaluating whether to than S in vitro15,16 and to treat children
ª 2018 Published by Elsevier Inc. maintain the French congenital toxo- and adults for cerebral or ocular toxo-
https://doi.org/10.1016/j.ajog.2018.05.031
plasmosis prevention program. plasmosis. PS is widely used during
In case of primary Toxoplasma gondii pregnancy following a prenatal diagnosis
infection during pregnancy, the risk of of congenital toxoplasmosis,12,17,18

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of amniocentesis, protocol treatment was

AJOG at a Glance continued for 8 weeks, and whether any
Why was this study conducted? further treatment was used was left up to
The efficacy of prophylaxis for prenatal toxoplasmosis transmission is contro- the clinician. Ultrasound surveillance was
versial, for lack of a randomized clinical trial. Spiramycin (S) is usually prescribed continued monthly.
for maternal seroconversions. Pyrimethamine þ sulfadiazine (PS) is the treat- Follow-up and treatment of children
ment of choice for congenital toxoplasmosis and is used in some countries as with congenital toxoplasmosis was per-
prophylaxis. formed according to usual guidelines. In
case of a negative amniocentesis or in the
Key findings absence of prenatal diagnosis, children
The rate of placental transmission was lower with PS vs S; however, the difference were to be followed up until definitive
fell short of statistical significance. The difference was stronger when treatment diagnosis.
started rapidly. During prenatal follow-up, the incidence of abnormal ultrasound
findings was significantly lower in the PS than in the S group. Diagnosis of congenital
toxoplasmosis
What does this add to what is known? The diagnosis of congenital toxoplas-
In the first randomized trial of medications to prevent placental transmission of mosis was defined as a positive result of
toxoplasmosis, PS appeared more effective than S, but a definitive conclusion PCR or mouse inoculation on amniotic
would require further randomized studies. fluid, PCR on cord blood, mouse inoc-
ulation of placenta, and/or the synthesis
based on evidence from observational deficiency, liver or renal insufficiency or of specific antibodies (IgM and/or IgA,
cohorts suggesting that it reduced the other serious illness in the mother, or IgG neoantibodies by a Western blot or
incidence of severe cerebral signs or major fetal anomaly. immunoblot) in the infant.20 All
symptoms, when taking into account the amniocentesis samples were tested by
gestational age of maternal infection.19 Procedures real-time PCR in certified laboratories in
We hypothesized that PS would be Treatment was to be started as soon as reference centers, then retested in the
more effective than S in reducing the risk possible after the diagnosis of serocon- coordinating National Reference Center
of transplacental transmission of version. Follow-up was performed ac- in Reims.
toxoplasmosis. cording to usual care. Blood cell counts The absence of transmission was
and differentials were performed twice definitively established by the decline
Materials and Methods weekly in mothers during treatment until disappearance of specific IgG anti-
Study design with PS. In the event of severe adverse bodies in the infant, in the absence of any
We performed a multicenter random- clinical or biological events possibly due postnatal antitoxoplasma medication in
ized phase-III clinical trial in 2 parallel to the study drugs, this was reported and the last 2 months, confirmed on a second
groups, pyrimethamine (50 mg once treatment was discontinued immedi- sample 1 month later to rule out
daily orally) and sulfadiazine (1 g tid ately. An amniocentesis was offered serological rebound.
orally), with supplemental folinic acid (with the patient’s consent) >18 weeks’ Secondary outcome measures were:
(50 mg once a week) vs S (1 g tid orally). gestation, at least 4 weeks after the esti- the incidence of congenital toxoplasmosis
Drugs were given open-label because mated date of primary infection. in each group according to the time be-
more invasive follow-up was required for In cases of fetal infection, prenatal tween maternal primary infection
the PS group. A total of 36 centers in therapy with PS was offered as per usual (defined as the midpoint between the last
mainland France participated. care, and the prognosis was assessed negative and the first detection of anti-
taking into account serial ultrasound toxoplasmosis antibodies) and the start of
Study population findings. In case of anomalies with poor antiparasitic prophylaxis and the inci-
Inclusion criteria were: age >18 years, prognosis, termination of pregnancy was dence of adverse reactions in mothers and
proven maternal seroconversion for considered by a multidisciplinary center newborns in each treatment group.
toxoplasmosis defined as a negative for prenatal diagnosis if requested by the
serology during pregnancy followed by woman, in accordance with French law. Sample size
synthesis of specific IgG, gestational age In case of a negative polymerase chain Based on meta-analysis data, a potential
at enrollment at least 14 weeks’ gesta- reaction (PCR) at amniocentesis: (1) in protective effect of treatment (based on
tion, and signed informed consent. the S group, treatment was continued the effect of treatment delay8), with an
Criteria for noninclusion were: until delivery according to usual proced- average transmission risk of 40% for
treatment with S or pyrimethamine- ures; and (2) in the PS group, the treat- second- and third-trimester serocon-
sulfamide for >10 days before random- ment could be stopped to reduce the risk versions, 330 patients (165 per group)
ization, allergy to any of the trial drugs or of intolerance, when the mother received would be required to demonstrate a 40%
a history of severe skin allergy, G6PD at least 4 weeks of therapy. In the absence reduction in transmission to 25% in the

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FIGURE 1
Toxogest study flowchart

Flow chart.
Mandelbrot et al. Congenital toxoplasmosis prevention. Am J Obstet Gynecol 2018.

PS group in the effective group using rates between groups, used Fisher exact were performed with software (SAS,
Fisher exact test with a 5% type-1 2- 2-sided test and all confidence intervals version 9.3; SAS Institute Inc, Cary, NC).
sided risk and a statistical power of 80%. (CI) for dichotomous outcomes used
exact binomial distribution. For adjusted Ethics
Statistical analyses estimates, we used logistic regression The protocol was approved by the ethics
All analyses were performed as intent-to- models, whose parameters were esti- committee, the Protection des Personnes
treat.21 The main analysis was conducted mated using an integrated maximum Kremlin-Bicêtre on June 10, 2010, under
including only children with definitive likelihood method8,22 to take into ac- protocol no. 10-014 and authorized by the
infection status. In the absence of defin- count the interval censoring of the French Drugs Agency (Agence nationale
itive infection status, all the available data gestational age at seroconversion and the de sécurité du médicament) on July 9,
were used according to an algorithm timing of treatment initiation. We 2010. All patients gave written, informed
analyzing the available serological follow- considered whether the first positive IgM consent.
up, and cases with probable or possible test was IgG negative or IgG positive to
infection were considered as infected. estimate the probabilities of seroconver- Results
Children with insufficient follow-up to sion at each possible date between the last Study population and follow-up
conclude were considered as indefinite negative and first positive date.22 We A total of 151 women were enrolled from
status. The algorithm was applied blindly, examined whether the treatment effect November 2010 through January 2014 in
ie, without knowledge of the treatment was modified according to explanatory 36 centers. Enrollment was stopped
group. Robustness analyses were per- variables using the likelihood ratio before achieving the planned recruitment
formed considering cases with indefinite test for interaction between variables. because the recruitment was slower than
status as: (1) missing ¼ failure; and (2) In sensitivity analyses, the results planned and funding to prolong the study
according to maximum bias hypotheses. were robust to each of the functions used was not obtained. As shown in the flow
All univariate tests, thus including the to estimate the gestational age at sero- chart (Figure 1), 70 patients were ran-
principal comparison of transmission conversion (data not shown). All analyses domized to S and 73 to PS. The baseline

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TABLE 1
Characteristics of study population
Spiramycin group Pyrimethamine þ sulfadiazine
Variable N ¼ 70 group N ¼ 73
Maternal age, y 30 (26; 33) 29 (26; 32)
Maternal weight, kg 68 (62; 78) 68 (60; 76)
Gestational age at enrollment, wk 23 (18; 28) 23 (19; 28)
Parity
0 19 (27.1%) 24 (32.9%)
Multiparous 49 (70.1%) 46 (63.0%)
Not available 2 (2.9%) 3 (4.1%)
Allergies
No 60 (85.7%) 65 (89.0%)
Yes 9 (12.9%) 8 (11.0%)
Not available 1 (1.4%)
Estimated time of maternal infection, WGa 18 (13; 25) 19 (16; 24)
Time between last negative and first positive IgG 37 (22; 46) 30 (16; 45)
serology, days
Time between first positive serology and start of study 11 (7; 21) 13 (6; 23)
drug, days
Treatment with antiparasitic drug before enrollment 21 (30.0%) 21 (28.8%)
Amniocentesis performed 64 (91.4%) 67 (91.8%)
Ultrasound scan findings at enrollment:
Normal 65 (92.9%) 68 (93.2%)
b
Abnormal 2 (2.9%) 2 (2.7%)
Not available 3 (4.3%) 3 (4.1%)
Duration of antiparasitic treatment as randomized
<4 weeks 6 (8.6%) 21 (28.8%)
4e8 weeks 14 (20.0%) 27 (37.0%)
8 weeks 43 (61.4%) 17 (23.3%)
Not available 7 (10.0%) 8 (11.1%)
Data are median (Quartile1; Quartile3) or number (percentage).
WG, weeks of gestation.
a
Time of maternal infection in WG defined for description’s sake as midpoint between last negative serology and first detection of antitoxoplasma antibodies; b Fetal anomalies not suggestive of
congenital toxoplasmosis.
Mandelbrot et al. Congenital toxoplasmosis prevention. Am J Obstet Gynecol 2018.

characteristics of the study population received pyrimethamine and a sulfon- certain and 20 probable), and remained
are shown in Table 1. Ultrasound exam- amide. Following negative amniocente- undefined in 18 children. There were 6
ination at enrollment showed no abnor- ses, patients in the S group continued the children who had congenital toxoplas-
malities relative to toxoplasmosis. An same treatment, whereas patients in the mosis although the amniocentesis result
amniocentesis was later performed in 131 PS group had a shorter duration of was a negative PCR, 2/15 (13.3%; 95% CI,
cases. The proportion of positive PCR for treatment with PS. 1.7e40) in the S group and 4/16 (25%;
T gondii was 7/67 (10.4%) in the PS 95% CI, 7.3e52) in the PS group. The
group vs 13/64 (20.3%, P ¼.147) in the S Congenital toxoplasmosis median time between maternal serocon-
group. The National Reference Center in The diagnosis of congenital toxoplasmosis version and amniocentesis in these cases
Reims confirmed the results. After a was established in 30 children (29 certain, was 48.8 days (range 29e67). The diag-
positive amniocentesis, all but 1 patient 1 probable), excluded in 95 children (75 nosis of congenital toxoplasmosis was

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Perinatal outcomes were unremark-

FIGURE 2
able, except for the 2 cases of termina-
Transmission rate according to treatment and gestational age
tions of pregnancy (Table 2). The
median gestational age was 40.1 weeks
and birthweight 3375 g, with no differ-
ence between the 2 treatment groups.

Comment
This is the first randomized controlled
trial to be performed regarding the pre-
vention of congenital toxoplasmosis
following maternal seroconversion. The
transmission rate was 2-fold lower when
using PS, vs S. The difference was in line
with our initial hypotheses, but did not
reach statistical significance, probably
for lack of statistical power. Our results
are consistent with some observational
data. In a retrospective study that
accounted partially for gestational age,
Prusa et al23 reported a lower trans-
Predicted risk of mother-to-child transmission of Toxoplasma gondii by gestational age at maternal
mission rate when the PS-based “Aus-
seroconversion, for each treatment group.
trian treatment scheme” was used, in
Mandelbrot et al. Congenital toxoplasmosis prevention. Am J Obstet Gynecol 2018.
comparison with the small minority of
pregnancies in which other regimens or
no therapy were used. Hotop et al13 re-
made at birth except for 1 child in the PS in the S group (8.6%), vs none in the PS ported that the rate of vertical trans-
group with a delayed diagnosis at 5 group (P ¼ .012). These abnormal find- mission in Germany using intermittent
months despite regular follow-up. ings were associated with severe congen- PS prophylaxis >16 weeks’ gestation was
As expected, the mother-to-child ital toxoplasmosis leading to termination lower than expected when taking into
transmission rate increased significantly of pregnancy in 2 cases and were cerebral account gestational age, although there
with the gestational age at seroconversion hyperechogenic foci in 4 cases. was no reference group. In a retrospec-
(odds ratio [OR], 1.17 for each additional tive study, Valentini et al24 compared
week higher; 95% CI, 1.08e1.27) Tolerance transmission rates from mothers with
(Figure 2). A total of 26 severe adverse events (SAE) primary Toxoplasma infection according
The transmission rate was 12/65 in the were reported, 12 in the S group and 14 in to whether they received S/cotrimox-
PS group (18.5%; 95% CI, 9.9e30.0), vs the PS group. They were analyzed blindly azole, PS, or S alone; S alone appeared
18/60 in the S group (30%; 95% CI, by the scientific committee. Two were the least effective to prevent transmission.
18.8e43.2) but this difference did not terminations of pregnancy for fetal The Syrocot study8 showed no difference
reach statistical significance (P ¼ .147). toxoplasmosis. Twenty SAEs were unre- in transmission according to whether S
The effect of prenatal treatment did not lated to the study drugs or toxoplasmosis. or PS were used, but prescriptions
differ after adjustment for gestational age Two women in the PS group developed differed according to gestational age.
at seroconversion: unadjusted OR, 0.53 maculopapular rashes, 1 associated with In our study, the efficacy of PS vs S
(corresponding to the difference above) liver function abnormalities, which tended to be stronger when therapy was
and adjusted OR, 0.47 (P ¼ .12), resolved after discontinuation. A third started within 3 weeks of seroconversion,
respectively. The effect of prenatal case declared as SAE was actually mod- and although this did not attain statisti-
treatment was modified according to the erate; the patient had nausea and vomit- cal significance, the interaction term was
timing of initiation (P for interaction ¼ ing, which transiently improved with significant. This is indirect evidence that
.03). It varied significantly with an OR metoclopramide, then reappeared, again there is a window of opportunity to
for PS vs S of 1.20 (95% CI, 0.35e4.14) improved for 10 days when treatment was prevent fetal infection after maternal
when initiated >3 weeks and an OR of fractioned, and finally switched to S; infection, before the tachyzoites cross the
0.03 (95% CI, 0.00e1.63) when initiated although the nausea improved, the pa- placenta, although the time between
within 3 weeks of the estimated maternal tient had to continue metoclopramide. primary infection and fetal infection
infection. Finally, another case of rash, associated may be variable. Experimental data show
During follow-up, abnormal ultra- with fever, disappeared spontaneously that placental infection by T gondii pre-
sound findings appeared in 6 of 70 fetuses without changing the study drug. cedes the passage of the parasite to the

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observational studies using PS in preg-

TABLE 2
nancy showed few adverse events. Hotop
Perinatal outcomes
et al13 reported no hematological adverse
Pyrimethamine þ event and only 1 allergic reaction in 119
Spiramycin group sulfadiazine group pregnancies (0.8%), however, nausea and/
N % N % or vomiting were frequent. Prusa et al29
reported a single case of allergic reaction
Pregnancy outcome
with shortness of breath and swollen
Liveborn 68 97.1% 73 100.0% tongue after taking PS. Of note, the PS
TOP 2 2.9% regimens differed from the Toxogest trial.
Infant sex a Tolerance is generally good in the fetus
and neonate,13,18,30,31 with rare excep-
Male 32 47.1% 37 50.7%
tions.32 It is recommended to avoid
Female 35 51.5% 36 49.3% exposure during the first 2 months of
Not available 1 1.5% gestation if possible. Pyrimethamine is a
Birthweight, g a dihydrofolate reductase inhibitor, leading
to bone-marrow toxicity, thus requiring
n (dm) 62 (8) 67 (6)
administration of folinic acid and weekly
Median (IQR) 3460 (3180; 3720) 3340 (3060; 3630) blood cell counts. Among the other mol-
Length, cma ecules of the same class, only trimetho-
n (dm) 48 (22) 54 (19) prim is effective and without significant
hematological toxicity, but its antiparasitic
Median (IQR) 50 (48; 52) 50 (49; 51)
activity is 10e100 times lower than that of
a
Head circumference, cm pyrimethamine. Sulfonamides are con-
n (dm) 48 (22) 47 (26) traindicated in case of allergies to sulfon-
Median (IQR) 34.8 (33.8; 35.5) 34.8 (33.5; 35.0) amides or G6PD deficiency. In case of
a
oliguria and low urinary pH, sulfadiazine
Gestational age at delivery can precipitate in the urine and lead to
n (dm) 48 (22) 47 (26) crystalluria.33
Median (IQR) 40.1 (38.9; 41.0) 40.3 (39.3; 41.1) Regarding S, its tolerance is usually
dm, data missing; IQR, interquartile range (Quartile1; Quartile 3); TOP, terminations of pregnancy.
excellent, and there was no SAE in the S
a
Not including TOP.
group that could be drug-related. Other
Mandelbrot et al. Congenital toxoplasmosis prevention. Am J Obstet Gynecol 2018. options may be considered for further
studies, but lack pregnancy data.34,35
Macrolides or related molecules such as
azithromycin, roxithromycin, and clari-
fetus,25 and clinical cases have been re- starting PS very early may be beneficial for thromycin have a comparable mode of
ported of placental infection without fetuses with congenital toxoplasmosis, as action, and atovaquone could have the
fetal infection.16 In large observational has been reported from retrospective advantage of being effective (experimen-
studies, shorter intervals between cohort data.19,27 There has not yet been a tally) on cysts, but has poor bioavailability.
maternal infection and the initiation of randomized controlled trial to evaluate Another important issue in using PS
antiparasitic therapy were associated prenatal toxoplasmosis therapy. To for prophylaxis is the risk of reducing the
with significantly lower transmission.8,26 confirm whether antenatal therapy with sensitivity of prenatal diagnosis. In our
Delayed transmission may explain cases PS is effective, long-term follow-up for the experience, 6 cases with a negative
of congenital toxoplasmosis despite a infants would be required, which was not amniocentesis turned out to have
negative PCR at the time of amniocen- available in our trial. congenital toxoplasmosis, including 1
tesis. Since the sensitivity of current PCR with delayed diagnosis until 5 months
techniques is high, these cases are likely Safety after birth. The proportion tended to be
to be due to transmission in the weeks or We observed 2 rashes requiring hospital- higher after PS (4 cases) than S (2 cases),
months following the amniocentesis. ization related to PS, 1 associated with although the difference did not reach
We also observed that the incidence of liver enzyme elevation. We observed no statistical significance due to small
prenatal cerebral signs of toxoplasmosis hematologic toxicity in the 72 patients, all numbers. The sensitivity of PCR for pre-
following prophylactic therapy was of whom received folinic acid. In a litera- natal diagnosis on amniotic fluid has been
significantly lower in the PS than in the S ture review of studies mostly in nonpreg- reported to be as high as 95%,36,37 due to
group, in fact all of the cerebral signs nant patients, a high rate of treatment technical improvements that are not
appeared in the S group. This suggests that discontinuation was reported.28 However, routinely available wordwide38; however,

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ajog.org OBSTETRICS Original Research

in a nationwide survey in France the France over the last 40 years27 and also as 5. Thiebaut R, Leroy V, Alioum A, et al. Biases in
sensitivity in clinical practice in 2016 compared to the United States where observational studies of the effect of prenatal
treatment for congenital toxoplasmosis. Eur J
was 88% Centre National de Référence screening and treatment is not offered.1,30 Obstet Gynecol Reprod Biol 2006;124:3–9.
Toxoplasmose (CNR, unpublished data). 6. Foulon W, Villena I, Stray-Pedersen B, et al.
There are several possible explanations for Conclusion Treatment of toxoplasmosis during pregnancy:
the discordance between negative PCR on The difference in the incidence of a multicenter study of impact on fetal trans-
amniotic fluid and an infant with congenital toxoplasmosis between PS mission and children’s sequelae at age 1 year.
Am J Obstet Gynecol 1999;180:410–5.
congenital toxoplasmosis. This may be and S was in agreement with the ex- 7. Gilbert RE, Gras L, Wallon M, Peyron F,
due to delayed transmission from the pected difference, but did not reach sta- Ades AE, Dunn DT. Effect of prenatal treatment
placenta after the amniocentesis and in tistical significance, possibly because the on mother to child transmission of Toxoplasma
some cases after prophylaxis was stopped. trial was interrupted without reaching gondii: retrospective cohort study of 554
It may also be due to a large reduction in the planned sample size. Furthermore, mother-child pairs in Lyon, France. Int J Epi-
demiol 2001;30:1303–8.
parasite load following more effective there was a significant interaction with 8. SYROCOT (Systematic Review on Congenital
antiparasitic treatment. time to treatment initiation, where the Toxoplasmosis) Study Group, Thiebaut R,
The main limit of our study was lack difference between PS and S was larger Leproust S, Chene G, Gilbert R. Effectiveness of
of power because the trial was prema- when started within 3 weeks of sero- prenatal treatment for congenital toxoplasmosis:
turely interrupted before reaching the conversion. These promising findings a meta-analysis of individual patients’ data.
Lancet 2007;369:115–22.
targeted sample size due to slow call for further research. The lessons 9. Haute Autorité de Santé HAS Recommandation
recruitment and lack of funding to pro- learned with this first randomized clin- en santé publique: surveillance serologie toxo-
long the trial. Also, transmission in the S ical trial should help to design a new plasmose et rubéole durant la grossesse. Avail-
group was lower than expected, pre- international study, possibly involving able at: https://www.has-sante.fr/portail/jcms/c_
sumably because there were fewer third- alternative potent antiparasitic regimens 893585/fr/surveillance-serologique-et-prevention-
de-la-toxoplasmose-et-de-la-rubeole-au-cours-
trimester infections than anticipated. to optimize tolerance, to give a definitive de-la-grossesse-et-depistage-prenatal-de-l-
Such a trial is difficult to conduct answer to the question of the prevention hepatite-b-pertinence-des-modalites-de-
because the incidence of maternal sero- of the congenital toxoplasmosis. n realisation. Accessed June 16, 2018.
conversion is low39 and because cases are 10. Dunn D, Wallon M, Peyron F, Petersen E,
dispersed outside of reference centers. Acknowledgment Peckham C, Gilbert R. Mother-to-child trans-
mission of toxoplasmosis: risk estimates for
Furthermore, while infants with a diag- The promoter was the Assistance Publique-
clinical counseling. Lancet 1999;353:1829–33.
nosis of congenital toxoplasmosis were Hopitaux de Paris Delegation à la Recherche
11. Wallon M, Peyron F, Cornu C, et al.
Clinique et à l’Innovation. We thank the Unité de
followed up by specialists, those pre- Congenital toxoplasma infection: monthly pre-
Recherche Clinique Paris-Nord and the Assis-
sumed uninfected were referred to local tance Publique-Hopitaux de Paris Centre de
natal screening decreases transmission rate and
pediatricians or general practitioners, improves clinical outcome at age 3 years. Clin
Pharmaco-épidémiologie, Nessima Yelles, Sarra
Infect Dis 2013;56:1223–31.
who did not always pursue follow-up20 Pochon. and Amandine Terrasson for their role in
12. Daffos F, Forestier F, Capella-Pavlovsky M,
until documenting a negative serology. coordinating and conducting the study, the in-
et al. Prenatal management of 746 pregnancies
vestigators in the study sites, the Club Franco-
We did not conduct a placebo- at risk for congenital toxoplasmosis. N Engl J
phone de Médecine Foetale and the members of
controlled trial, because a survey the Centre National de Référence de la Toxo-
Med 1988;318:271–5.
showed that most investigators were 13. Hotop A, Hlobil H, Gross U. Efficacy of rapid
plasmose for their involvement, and above all, the
treatment initiation following primary Toxo-
convinced that this would be unaccept- patients who participated in the study.
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ajog.org OBSTETRICS Original Research

Marie-Pierre Brenier-Pinchart and Catherine Thong- Frederic Dalle, Centre Hospitalier Universitaire de Dijon; Supported by a grant from the French Ministry of
Vanh, Centre Hospitalier Universitaire de Grenoble; Marie Laure Dardé and Véronique Aubard, Centre Hos- Health, Program for Hospital Clinical Research (national
Laurent Mandelbrot and Corinne Floch, Hôpital Louis- pitalier Universitaire de Limoges; Camille Olivier, Centre AOM09182).
Mourier, Colombes; Lionel Carbillon and Eric Lachassine, Hospitalier de Chartres; Eric Verspyk and Loic Favennec, The authors report no conflict of interest.
Hôpital Jean-Verdier, Bondy; Aude Ricbourg, Hopital Centre Hospitalier Universitaire de Rouen. Corresponding author: Laurent Mandelbrot, MD.
Lariboisière, Paris; Luc Paris and Marc Dommergues, Received Jan. 16, 2018; revised May 15, 2018; laurent.mandelbrot@aphp.fr
Hôpital Pitié-Salpêtrière, Paris; Thierry Rousseau and accepted May 24, 2018.

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