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Eur J Clin Microbiol Infect Dis (2009) 28:297300

DOI 10.1007/s10096-008-0612-5

BRIEF REPORT

Role of spiramycin/cotrimoxazole association


in the mother-to-child transmission of toxoplasmosis
infection in pregnancy
P. Valentini & M. L. Annunziata & D. F. Angelone &
L. Masini & M. De Santis & A. Testa & R. L. Grillo &
D. Speziale & O. Ranno

Received: 17 February 2008 / Accepted: 25 July 2008 / Published online: 21 August 2008
# Springer-Verlag 2008

Abstract The purpose of this report is to evaluate the


efficacy and safety of spiramycin/cotrimoxazole in the
mother-to-child transmission of Toxoplasma gondii infection. We retrospectively analysed 76 infants born to
mothers with toxoplasmosis during pregnancy and estimated the risk of mother-to-child transmission considering the
gestational age at the time of infection. Seventy-six mothers
were given spiramycin, cotrimoxazole and folinic acid;
only two babies (2.6%) were infected by Toxoplasma and
none of them showed signs or symptoms of congenital
infection or interference of sulphamid on tetrahydrofolate
reductase (THFR) either at birth or during follow-up.
Treatment did not need to be stopped in any mother
because of adverse drug effects. Our results seem to
encourage the use of spiramycin/cotrimoxazole in women
with toxoplasmosis during pregnancy.

P. Valentini (*) : M. L. Annunziata : D. F. Angelone : A. Testa :


O. Ranno
Department of Pediatrics, Pediatric Infectious Diseases Unit,
Catholic University of the Sacred Heart,
L.go A. Gemelli, 8,
00168 Rome, Italy
e-mail: pvalentini@rm.unicatt.it
L. Masini : M. De Santis
Department of Obstetrics and Gynecology,
Catholic University of the Sacred Heart,
Rome, Italy
R. L. Grillo : D. Speziale
Institute of Microbiology, Catholic University of the Sacred Heart,
Rome, Italy

Introduction
Toxoplasmosis during pregnancy can cause a severe foetal
infection with possible central nervous system (CNS) and
eye damage. In recent years, there has been increasing
controversy surrounding the efficacy of treatment of the
mother during gestation to prevent congenital transmission,
as well as regarding the cost benefit of such treatment.
The standard therapy of toxoplasmosis is pyrimethamine + sulphadiazine, but the most often used antibiotic
in pregnant women is spiramycin, because of the potential
teratogenic effects of pyrimethamine. The pyrimethamine/
sulphadiazine association is used in the presence of prenatal
infection diagnosis [1, 2].
Cotrimoxazole is not usually used for the prevention of
congenital toxoplasmosis because the anti-Toxoplasma
activity of trimethoprim is lower than that of pyrimethamine. However, experimental and clinical studies provide
evidence of the efficacy of cotrimoxazole and its potential
use in the prevention of congenital toxoplasmosis [3, 4].
The purpose of this study is to evaluate the efficacy and
safety of spiramycin/cotrimoxazole association in the
mother-to-child transmission of Toxoplasma gondii infection.

Materials and methods


At the Pediatric Infectious Diseases Unit of A. Gemelli
hospital, a retrospective study on a group of 212 newborns
born to mothers infected with Toxoplasma gondii during
pregnancy was undertaken, following informed consent in
accordance with an institutionally approved protocol. All of
the children born to mothers treated during pregnancy with
spiramycin/cotrimoxazole were considered to be eligible for

298

the study. The exclusion criteria were: (a) infants in which


it was not possible to establish the gestational age (GA) of
maternal infection; (b) infants born to mothers not treated
or treated with protocols different from the spiramycin/
cotrimoxazole association.
Infected newborns were defined according to the Italian
Congenital Toxoplasmosis Study Group Criteria [5]; in
particular, to make the diagnosis of congenital infection,
one of the following was needed: (1) seropositivity for
specific IgM and/or IgA in the first 6 months of age; (2)
increase of specific IgG in the first 12 months of age, with
or without clinical signs; (3) persistence of specific IgG
antibodies beyond 7 months of age, until 12 months; (4)
clinical signs of infection (cerebral calcifications, chorioretinitis, obstructive hydrocephalus, hepatosplenomegaly,
petechiae, jaundice). Non-infected children were diagnosed
on the basis of undetectable specific IgG beyond 12 months
of age without treatment.
All of the women who were Toxoplasma-seronegative
admitted to the Department of Obstetrics and Gynecology
of our hospital undertook serological tests every 3 weeks
and were treated within 4 weeks from seroconversion with
spiramycin, 3106 IU (3106 International Unit=3.480 g)
4 times a day, and cotrimoxazole, 960 mg (sulphamethoxazole 800 mg plus trimethoprim 160 mg) twice a day, plus
folinic acid, 4 mg/day. Women seroconverting in the 1st
trimester of pregnancy were treated first with spiramycin;
cotrimoxazole was added beginning at the 14th week. In all
women, cotrimoxazole was discontinued 2 weeks before
the expected delivery date. Spiramycin was continued until
delivery.
Neonates with infection at birth were prescribed pyrimethamine (1 mg/Kg/day) and sulphadiazine (100 mg/Kg/day)
for 1 year, and were followed up with retinal examination
yearly.

Results
Out of 212 newborn infants, 76 (35.8%) were considered to
be eligible for the study because they were born to mothers
treated with spiramycin/cotrimoxazole/folinic acid, 86
(40.6%) were from women treated with different protocols,
28 (13.2%) from untreated women and 22 (10.4%) from
mothers in which it was not possible to evaluate the time of
infection.
Of the 76 eligible cases, 2/76 (2.6%) children acquired
the infection in utero. The infected children, a male and a
female, were born at term (40 and 38 weeks GA,
respectively) and their growth parameters were normal:
weight 3,580 g (75th centile) and 2,920 g (25th centile);
head circumference 37 cm (90th centile) and 34 cm (50th
centile). They were asymptomatic at birth, were given

Eur J Clin Microbiol Infect Dis (2009) 28:297300

pyrimethamine plus sulphadiazine and did not show signs


or symptoms that were related to toxoplasmosis or to the
interference of sulphamid on tetrahydrofolate reductase
(THFR), either at birth or during the 7-years of follow-up.
Of the 74 non-infected children, 67 (90.5%) were born at
term and seven (9.5%) were preterm. All of them had no
therapy.
The rate of congenital infection was 0% during the first
14 weeks GA, 4.7% between the 14th and 26th week, and
100% after the 26th week (Table 1).
Maternal Toxoplasma therapy was well tolerated. Only
three women presented an erythematous and maculopapular
rash; in two cases, the rash was related to spiramycin
administration, in one case to cotrimoxazole. These women
successfully underwent a rush tolerance induction to drugs
during pregnancy. They continued the therapy until the end
of pregnancy without side effects and delivered three
healthy newborns [6].

Discussion
The usual treatment protocols of toxoplasmosis during
pregnancy include spiramycin started immediately after the
confirmation of maternal infection and pyrimethamine/
sulphadiazine following the diagnosis of foetal infection. In
some centres, pyrimethamine/sulphadiazine is prescribed
immediately if maternal infection occurs in the 3rd trimester.
Desmonts and Couvreur demonstrated that, using spiramycin precociously, the mother-to-child transmission
crude risk of infection was reduced from 56 to 24% [1].
Several studies could not show any significant difference
in the incidence of congenital infection between treated and
non-treated groups. However, metanalysis suggest that the
efficacy of prenatal treatment could not be ruled out
completely, because many of the studies were not carried
on in the appropriate way. These studies do not exclude a
possible clinical effect of the prenatal treatment.
A recent systematic review shows that the estimated rate
of mother-to-child transmission by gestational age at
seroconversion is 15% at 13 weeks, 44% at 26 weeks and
71% at 36 weeks. The odds of transmission increases by

Table 1 Mother-to-child transmission according to maternal gestational age (GA) at the time of infection
Time of maternal
infection (weeks)

Infected
newborns

Non-infected
newborns

Total

<14
1426
>26
Total

0
1
1
2

54
20
0
74

54
21
1
76

Eur J Clin Microbiol Infect Dis (2009) 28:297300

12% per week of maternal gestation at seroconversion; the


sooner prenatal treatment is started after seroconversion, the
lower the adjusted odds of mother-to-child transmission (OR
0.94 per week, 95% CI 0.900.98). The type of prenatal
treatment does not seem to have a significant effect [2].
In the literature, there are no large studies on the use of
cotrimoxazole in pregnancies complicated with toxoplasmosis, except for that in animal models; its use in pregnant
mice infected with Toxoplasma gondii revealed a higher
therapeutic efficacy than the use of spiramycin [7].
Cotrimoxazole has favourable pharmacokinetic because
of the combination of two drugs (trimethoprim and
sulphametoxazole) with a short half-life, and it is well
tolerated in non-AIDS patients. The risk of side effects
associated with short-term treatment seems to be very low,
similar to that of many other antibiotics. Clinical experiences in immunocompromised patients revealed the same
efficacy of cotrimoxazole in preventing and treating
cerebral toxoplasmosis, and a better tolerance compared
with pyrimethamine/sulphadiazine association [8].
Cotrimoxazole has also been suggested as a valid
alternative to pyrimethamine/sulphadiazine for the therapy
of ocular toxoplasmosis.
Recent studies estimated that the rate of exposure to
cotrimoxazole during pregnancy ranges between 0.542.1%
in the 1st trimester and 3.2% throughout gestation. It is
prescribed in particular for urinary tract infections and to
women with chronic health problems, of younger age and
lower socioeconomic status [9].
In consideration of these issues and because pyrimethamine and sulphadiazine are not readily available in Italy,
we decided to use the spiramycin/cotrimoxazole association
for the treatment of toxoplasmosis during pregnancy.
About the potential teratogenic effect of cotrimoxazole,
different casecontrol studies have been performed. A
protective effect of a high dose of folic acid has been
demonstrated for cotrimoxazole-associated congenital
anomalies; its potential teratogenic effect is neutralised in
cardiovascular malformations and reduced in multiple
malformations by the association with folic acid [10].
A recent review of the safety of cotrimoxazole used for
prophylaxis in HIV-infected pregnant women showed a
good tolerance and a low risk of bilirubin metabolism
alteration in newborns [11].
In our study, women seroconverting during the 1st
trimester of pregnancy were given cotrimoxazole in
association with folinic acid only after the 14th week.
After this period of time, in fact, there is no strong evidence
in the current literature for any teratogenic effect of this
drug in human subjects.
Maternal therapy was well tolerated; we recorded only
three cases of erythematous and maculopapular rash.
Treatment was not interrupted in any of the women.

299

We focussed on the mother-to-child transmission rate


and clinical sequellae following maternal therapeutic
regimen with spiramycin/cotrimoxazole.
The mother-to-child transmission crude rate observed in
76 enrolled children was 2.6% (2/76), similar to other
Italian studies [3]. The congenital infection cases occurred
in the 2nd and 3rd trimester of pregnancy, with a
transmission rate, respectively, of 4.6% and 100%. This
result seems to be promising in preventing mother-to-child
infection in case of seroconversion during the 2nd trimester
of pregnancy. During the 3rd trimester, the small number of
patients studied prevent statistical analysis from being
performed. Moreover, the presence of only one case of
maternal infection during the 3rd trimester may overestimate the crude risk of mother-to-child transmission after the
26th week of pregnancy, compared with the literature data.
Possibly, the short period of antibiotics therapy between
infection and delivery could poorly affect the mother-tochild transmission rate in the 3rd trimester of pregnancy;
moreover, cotrimoxazole was interrupted before delivery,
so only spiramycin was administrated for at least 2 weeks.
Regardless, in this period, organogenesis is completed and
the foetus is fully grown, so we could accept the low
efficacy of the therapy because the clinical sequellae of
congenital infection rarely happen.
Otherwise, the efficacy of the treatment during the 1st
and 2nd trimesters has a fundamental importance because
of the higher risk of clinical sequellae.
These results may reflect the different pharmacokinetic
and biological characteristics of spiramycin and cotrimoxazole. The former exerts much of its effects on the placental
infection, but is not capable of eradicating an already
existing foetal infection. The latter (being composed of two
drugs, trimethoprim and sulphamethoxazole, acting sinergically through succeeding steps on Toxoplasma folic acid
metabolism and across the placental barrier) can kill
parasites in the tissues, preventing organ lesions in a foetus
that is already infected.
The SYROCOT study group revealed that 19% of
infected infants presented at least one clinical manifestation, 14% had ocular lesions and 9% had intracranial
lesions. The odds of clinical manifestations during infancy
decreased with older gestational age at seroconversion. The
adjusted odds of any clinical manifestations did not
significantly differ between the infants of treated mothers
and those of untreated mothers (OR 1.11, p=0.74) [2].
Retinochoroiditis is the most frequent consequence of
congenital toxoplasmosis. In our study, the two congenitally
infected children were followed up for a median of 7 years
(range: 68 years); to date, no new retinochoroidal lesions
have occurred.
Treatment for 12 months initiated in infants in the first
few months of life seems to reduce, although not completely

300

prevent, ophthalmological and neurological sequellae [12].


Parents and elder children with congenital infection should
be informed that late-onset retinal lesions and relapse can
occur many years after birth, but that the overall ocular
prognosis of congenital toxoplasmosis is satisfactory when
infection is identified early and treated accordingly.
Though limited due being a retrospective study, our
results seem to encourage the use of the association of
spiramycin and cotrimoxazole in women with toxoplasmosis
during pregnancy either for its safety, effects on reducing the
mother-to-child transmission rate and on preventing the risk
of clinical sequellae.
More detailed information is required through cohort
studies and randomised controlled trials of treatment
regimens, but, as clearly underlined by the International
Ethical Guidelines for Biomedical Research Involving
Human Beings (Geneva 2002), it is not possible to carry
out a randomized controlled trial. In fact, a non-treatment
in case of seroconversion is considered to be ethically
unacceptable, subtracting the control group from treatments
whose efficacies are being shown.

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