Acta Tropica 121 (2012) 55–70

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Acta Tropica
journal homepage: www.elsevier.com/locate/actatropica

Review

Congenital parasitic infections: A review

Yves Carlier a,b,∗ , Carine Truyens a , Philippe Deloron c , François Peyron d
a
Laboratoire de Parasitologie, Faculté de Médecine, Université Libre de Bruxelles (ULB), CP 616, Route de Lennik 808, 1070 Brussels, Belgium
b
Department of Tropical Medicine, School of Public Health and Tropical Medicine, Tulane University, Suite 2210, 1440 Canal Street, New Orleans, LA 70112-2797, USA
c
UMR 216, Institut de Recherche pour le Développement (IRD), Faculté de Pharmacie, Université Paris Descartes, 4 Avenue de l’observatoire, 75006 Paris, France
d
Service de Parasitologie, Hôpital de la Croix-Rousse, 93 Grande Rue de la Croix-Rousse, 69317 Lyon, France

a r t i c l e i n f o a b s t r a c t

Article history: This review defines the concepts of maternal–fetal (congenital) and vertical transmissions (mother-
Received 31 May 2011 to-child) of pathogens and specifies the human parasites susceptible to be congenitally transferred. It
Received in revised form 27 October 2011 highlights the epidemiological features of this transmission mode for the three main congenital parasitic
Accepted 29 October 2011
infections due to Toxoplasma gondii, Trypanosoma cruzi and Plasmodium sp. Information on the possi-
Available online 7 November 2011
ble maternal–fetal routes of transmission, the placental responses to infection and timing of parasite
transmission are synthesized and compared. The factors susceptible to be involved in parasite trans-
Keywords:
mission and development of congenital parasitic diseases, such as the parasite genotypes, the maternal
Congenital toxoplasmosis
Congenital Chagas disease
co-infections and parasitic load, the immunological features of pregnant women and the capacity of some
Congenital malaria fetuses/neonates to overcome their immunological immaturity to mount an immune response against the
Placenta transmitted parasites are also discussed and compared. Analysis of clinical data indicates that parasitic
Immune responses congenital infections are often asymptomatic, whereas symptomatic newborns generally display non-
specific symptoms. The long-term consequences of congenital infections are also mentioned, such as the
imprinting of neonatal immune system and the possible trans-generational transmission. The detection
of infection in pregnant women is mainly based on standard serological or parasitological investigations.
Amniocentesis and cordocentesis can be used for the detection of some fetal infections. The neonatal
infection can be assessed using parasitological, molecular or immunological methods; the place of PCR
in such neonatal diagnosis is discussed. When such laboratory diagnosis is not possible at birth or in the
first weeks of life, standard serological investigations can also be performed 8–10 months after birth,
to avoid detection of maternal transmitted antibodies. The specific aspects of treatment of T. gondii, T.
cruzi and Plasmodium congenital infections are mentioned. The possibilities of primary and secondary
prophylaxes, as well as the available WHO corresponding recommendations are also presented.
© 2011 Elsevier B.V. All rights reserved.

Contents

1. What is a congenital parasitic infection? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56

2. What are the parasites involved in human congenital infections? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
2.1. Congenital toxoplasmosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
2.2. Congenital Chagas disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
2.3. Congenital malaria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
2.4. Congenital infections with other parasites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
2.4.1. Congenital African trypanosomiasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
2.4.2. Congenital visceral leishmaniasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
2.4.3. Congenital infection with Trichomonas vaginalis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
2.4.4. Congenital transmission of helminths . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57

∗ Corresponding author at: Laboratoire de Parasitologie, Faculté de Médecine, Université Libre de Bruxelles (ULB), CP 616, Route de Lennik 808, 1070 Brussels, Belgium.
Tel.: +32 02 555 6255; fax: +32 02 555 6128.
E-mail addresses: ycarlier@ulb.ac.be (Y. Carlier), ctruyens@ulb.ac.be (C. Truyens), philippe.deloron@ird.fr (P. Deloron), francois.peyron@chu-lyon.fr (F. Peyron).

0001-706X/$ – see front matter © 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.actatropica.2011.10.018
56 Y. Carlier et al. / Acta Tropica 121 (2012) 55–70

3. What are the routes of maternal–fetal transmission of parasites? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58

3.1. The haematogenous transplacental route . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
3.1.1. Parasite invasion of trophoblast . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
3.1.2. Parasite invasion of placental areas deprived from trophoblast . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
3.1.3. Parasite transmission through placental breaches/tears . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
3.1.4. Parasite transmission through the mesenchymal/stromal tissues of placenta toward fetal vessels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
3.2. Other routes of maternal–fetal transmission of parasites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
4. How the placenta responds to parasite invasion? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
4.1. Parasite invasion and placental innate immune response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
4.2. Parasite invasion and pathology of placenta . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
5. When maternal–fetal transmission of parasites occurs? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
6. What factors are involved in transplacental transmission and development of parasitic infections in newborns? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
6.1. Parasite genotypes and congenital infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
6.2. Maternal parasitic load and congenital infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
6.3. Maternal immunity and other maternal factors in congenital infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
6.4. Maternal co-infection and congenital infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
6.5. Fetal/neonatal capacity of immune responses and other fetal factors in congenital infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
7. What are the clinical manifestations and long-term consequences of parasitic congenital infections? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
7.1. Clinical manifestations and mortality of congenital parasitic infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
7.2. Long-term consequences of congenital infection with parasites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
8. What are the laboratory tests to be used for detecting congenital parasitic infections? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
8.1. Detection of infection in pregnant women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
8.2. Detection of fetal infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
8.3. Detection of neonatal infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
8.4. Detection of late parasitic congenital infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
9. How to treat parasitic congenital infections? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
9.1. Treatment and other options for congenitally infected fetuses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
9.2. Treatment of congenitally infected neonates and infants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
10. How prevent or control parasitic congenital infections? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
10.1. Toxoplasmosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
10.2. Chagas disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
10.3. Malaria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
11. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66

1. What is a congenital parasitic infection? 2.1. Congenital toxoplasmosis

Congenital parasitic infection is an infection resulting from the Congenital toxoplasmosis generally results from the transmis-
transmission of live parasites from an infected pregnant woman to sion of T. gondii in women having acquired primary infection during
her fetus that persists after birth. Transmission can occur before pregnancy. It is rare in women having acquired toxoplasmosis
birth (in utero or “prenatal” transmission) or at the time of deliv- before pregnancy (chronic infection) (Silveira et al., 2003), except
ery (“perinatal” transmission), as indicated by its Latin etymology in the case of co-infection with HIV (see Section 6.4) (Montoya and
“cum” (with), and “genitus” (engendered). This definition excludes: Remington, 2008; Remington et al., 2006). Moreover, acute mater-
(i) postnatal transmission of parasites (mainly through maternal nal toxoplasmosis does not necessarily give rise to fetal infection.
milk by breast feeding); and (ii) transmission of dead parasites, Global estimates of maternal–fetal transmission are approximately
parasite DNA or other molecules released from parasites in the 20–33% of newly infected mothers. Important variations have also
mother and likely to be found in fetal blood. The term “vertical” been observed according to gestational age at the time of mater-
transmission has a broader connotation corresponding to mother- nal infection, with transmission rates below 6% when infection is
to-child transmission from one generation to the next, and includes acquired during the first trimester of pregnancy, and increasing
prenatal, perinatal, as well as postnatal routes of transmission. to approximately 22–40% in the second trimester and 58–72% in
This review concerns human congenital parasitic infections the third trimester, with the highest proportions in the last few
and does not cover the effects of parasitic infections on pregnant weeks before birth (Montoya and Remington, 2008; Rabilloud et al.,
women (inducing maternal or placental pathologies jeopardizing 2010). However, the greatest risk of severe fetal disease (of lower
the fetal/neonatal health) when there is no congenital transmission. frequency) is when maternal infection occurs earlier (see Section
5).
The reported incidence of congenital toxoplasmosis from dif-
ferent areas of the world varies widely, ranging from less than
2. What are the parasites involved in human congenital 1 per 10,000 live births in Austria (Aspock and Pollak, 1992),
infections? Norway (Jenum et al., 1998), Sweden (Evengard et al., 2001), USA
(Guerina et al., 1994); 1–3 per 10,000 in Denmark (Roser et al.,
Parasites known to be congenitally transmitted from infected 2010), Switzerland (Signorell et al., 2006), UK (Gilbert and Peckham,
pregnant women to their fetuses are mainly protozoa (Toxoplasma 2002); and 3–10 per 10,000 in Belgium (Naessens, 2003), Brazil
gondii, Trypanosoma cruzi and Plasmodium spp., and occasionally, (Lago et al., 2007), France (Villena et al., 2010), Italy (Stagni et al.,
Trichomonas vaginalis, African trypanosomes, and agents of vis- 2009), Poland (Paul et al., 2001). A decreasing trend in the preva-
ceral leishmaniasis), whereas the transmission of helminths rarely lence of T. gondii infection has been noted in Europe and USA, with a
occurs in humans. subsequent reduction in the incidence of congenital toxoplasmosis
 Y. Carlier et al. / Acta Tropica 121 (2012) 55–70
(Pappas et al., 2009). This could be related to a higher consumption
of frozen meat which effectively eliminates an important source of
viable contaminating parasites (Cook et al., 2000).
2.2. Congenital Chagas disease
In contrast with toxoplasmosis, congenital transmission of T.
cruzi can occur in both acute and chronic phases of infection.
However, most cases of congenital infection derive from chron-
ically infected mothers, having been infected by insect vectors
since childhood by residing in endemic areas of Latin America
(reviewed in Carlier and Truyens, 2010). Approximately 2 millions
women in fertile age are estimated to be infected with T. cruzi in
the Americas (OPS, 2006). Maternal–fetal transmission of T. cruzi
varies widely according to geographic regions, from less than 0.1%
in Brazil (Luquetti et al., 2005) to 2–12% in Argentina (Gurtler et al.,
2003; Sanchez et al., 2005; De Rissio et al., 2010), Bolivia (Carlier
and Torrico, 2003; Torrico et al., 2004; Brutus et al., 2007; Bern
et al., 2009), Chile (Apt et al., 2010; Jercic et al., 2010) and Paraguay
(Russomando et al., 2005). Migration of Latin American women,
particularly during this last decade, has also spread the risk of con-
genital transmission into non-endemic areas, particularly in the
United States, Canada, Australia, Japan and Europe (Buekens et al.,
2008; Yadon and Schmunis, 2009). Cases of congenital Chagas dis-
ease have been reported in the US (Leiby et al., 1999) and more
recently, in Spain (Munoz et al., 2009) and Switzerland (Jackson
et al., 2009).
Development of national programs for vector control and
screening of blood donors in many endemic countries has lim-
ited the occurrence of new cases of infection. Consequently, the
prevalence of infection in pregnant women is decreasing, as well
as the incidence of congenital transmission. However, the pos-
sibilities of repeating congenital transmission at each pregnancy
in the pool of currently infected women, and from one genera-
tion to another (Sanchez et al., 2005), suggest a long-term risk of
mother-to-offspring transmission even in the absence of vector-
borne transmission, in endemic as well as in non-endemic areas
(Raimundo et al., 2010).
2.3. Congenital malaria
Malaria during pregnancy is characterized by the sequestration
of Plasmodium falciparum-infected erythrocytes in the intervil-
lous spaces of the placenta. Together with localized inflammatory
responses, sequestered parasites induce an impairment of placen-
tal transport resulting in severe adverse perinatal outcomes (i.e.
stillbirths, perinatal mortality, low birth weight, and premature
delivery) (Uneke, 2007b; Desai et al., 2007). Such effects are beyond
the scope of this review.
A lesser known consequence of malaria in pregnancy is
maternal–fetal transmission of infected erythrocytes, resulting in
congenital malaria which could also jeopardize perinatal outcomes
(reviewed in Menendez and Mayor, 2007). However, the reported
incidences of congenital malaria in endemic areas of Africa and Asia
are highly variable. Such differences seem related to the fact that
microscopic examination or PCR studies are conducted on umbilical
cord blood or infant peripheral blood. Indeed, most reported rates
of maternal–fetal malaria transmission of more than 30% and till
55% derive from investigations of parasites in cord blood (Falade
et al., 2007; Malhotra et al., 2006; Menendez and Mayor, 2007;
Oduwole et al., 2011; Uneke, 2007a), whereas the observed low
rates, till less than 0.5% (Mwaniki et al., 2010), derive from studies
of infant peripheral blood, suggesting a rapid elimination of trans-
mitted parasite-infected erythrocytes. The possible reasons of such
self-cure of malaria congenital infection are mentioned in Section
6.5.
57
Primigravid and secundigravid women with placental malaria
are particularly at risk for congenital infection (Malhotra et al.,
2006). P. falciparum, and also Plasmodium vivax, Plasmodium malar-
iae and Plasmodium ovale to a lesser degree, have been detected in
blood of newborns of infected mothers, and therefore considered
as potential agents of congenital malaria (Singh et al., 2003; Tobian
et al., 2000). Cases of congenital malaria from African or Asiatic
migrant women have been also reported in USA and Europe (Del
Punta et al., 2010; Lesko et al., 2007; Vottier et al., 2008).
2.4. Congenital infections with other parasites
2.4.1. Congenital African trypanosomiasis
Occasional reports of individual cases of African trypanosomi-
asis demonstrate the undisputable occurrence of maternal–fetal
transmission of Trypanosoma brucei gambiense and Trypanosoma
brucei rhodesiense in infected pregnant women (Pepin et al., 1989;
Rocha et al., 2004; Traub et al., 1978; Triolo et al., 1985). Such
transmission likely occurs in the first lymphatic phase of the
human African trypanosomiasis (HAT), since endocrine abnormali-
ties occurring in the second severe neurological phase of the disease
result in amenorrhoea and sterility. Familial clustering of HAT
cases (Khonde et al., 1997), high frequencies of spontaneous abor-
tions in infected pregnant women, and severe neurological HAT
infections in neonates, with newborns presenting hydrocephalia
(Burke, 2000; Triolo et al., 1985) are observed in endemic areas
of Africa. Such observations argue in favour of a greater frequency
of congenital transmission of African trypanosomes than originally
expected. However, no systematic studies have been carried out
in endemic areas, thus the actual frequency of such transmission
remains unknown (Lindner and Priotto, 2010).
2.4.2. Congenital visceral leishmaniasis
There have been no systematic studies on maternal–fetal trans-
mission of visceral leishmaniasis in endemic areas, and congenital
visceral leishmaniasis would seem to be rare (Eltoum et al., 1992;
Figueiro-Filho et al., 2004; Pagliano et al., 2005). Most confirmed
case reports relate to infected and symptomatic infants born
to infected mothers in non-endemic countries (Boehme et al.,
2006; Bogdan et al., 2001; Figueiro-Filho et al., 2004; Zinchuk and
Nadraga, 2010).
2.4.3. Congenital infection with Trichomonas vaginalis
Some rare cases of vaginal, urinary tract, nasal and respira-
tory, infections with T. vaginalis have been reported in newborns
of mothers infected with this parasite (Schwandt et al., 2008;
Temesvari and Kerekes, 2004).
2.4.4. Congenital transmission of helminths
Although helminth larvae and schistosome ova have been occa-
sionally found in the placenta (Altshuler et al., 1975), congenital
transmission of human helminths is not common. Few cases
of transplacental passage of microfilariae of Onchocerca volvulus
(Anosike and Onwuliri, 1993) and Wuchereria bancrofti (Agarwal
et al., 1986; Chaturvedi et al., 1991; Fonticiella et al., 1995) have
been reported. Congenital transmission of Schistosoma spp. has
been also reported but the validity of these cases has proved diffi-
cult to verify (Pereira et al., 1972). A more recent study failed to
confirm the existence of congenital transmission of Schistosoma
japonicum in humans (Shi et al., 2001). It has to be noted that such
transmissions are limited to the considered parasite stages which
will not evolve into adult stages or multiply in the fetus/newborn.
58 Y. Carlier et al. / Acta Tropica 121 (2012) 55–70
Fig. 1. Possible routes of maternal–fetal transmission of parasites.
Modified from Benirschke et al. (2006) with permission.
3. What are the routes of maternal–fetal transmission of
parasites?
Maternal–fetal transmission of human parasites occurs mainly
by the haematogenous transplacental route, and much less fre-
quently by other routes (Fig. 1).
3.1. The haematogenous transplacental route
The transplacental route is the mandatory mode for transmis-
sion of parasites having a parasitemic phase that are present in
maternal blood which bathes the placental intervillous space. Such
a route requires parasites to cross and survive, or escape the tro-
phoblastic barrier (first placental line of defence) before traversing
mesenchymal tissues surrounding the fetal vessels (second pla-
cental line of defence), and finally gaining access to such vessels
(Fig. 2).
3.1.1. Parasite invasion of trophoblast
Invasion of the trophoblast is one of the modalities for con-
genital transmission of parasites infecting cells and resisting to
trophoblastic defences (see Section 4.1). Villi of the human placenta
are covered by two layers of trophoblast: an outer layer (mater-
nal side) called syncytiotrophoblast; and an inner layer termed
cytotrophoblast (Langhans cells), set upon a basement membrane.
An extravillous trophoblast also covers non-villous structures, e.g.
the chorionic plate. The internal cytotrophoblast layer is discontin-
uous, with its cell number decreasing during the gestation period
(Benirschke et al., 2006) (see Section 5). To a great degree, only
the syncytiotrophoblast is interposed between maternal blood and
fetal tissues, preventing intercellular penetration (structural bar-
rier). In order to invade the trophoblast, parasites are likely to be
recognized by receptors expressed at its surface (see Section 4.1).
In vitro studies and histopathologic analyses of placental tissue
from congenital toxoplasmosis cases indicate that T. gondii can
infect and multiply as bradyzoites within villous trophoblastic
cells to release new tachyzoites on the opposing side of the
trophoblast layer, i.e. in stroma of the villi (Abbasi et al., 2003;
Benirschke et al., 2006; Remington et al., 2006). This has also been
observed in placentas of stillborns highly infected with T. cruzi
(Altemani et al., 2000; Bittencourt, 1976), and in in vitro studies
when high numbers of blood trypomastigotes are in contact with
the trophoblast (Duaso et al., 2010; Shippey et al., 2005). However,
this seems to be uncommon in most placentas of chronically T.
cruzi-infected mothers having delivered live congenitally infected
neonates, since parasites are rarely found in villous trophoblasts
(Azogue et al., 1985; Carlier, 2005; Carlier and Truyens, 2010;
Fernandez-Aguilar et al., 2005; Moya et al., 1979).
3.1.2. Parasite invasion of placental areas deprived from
trophoblast
Parasites can also use an alternate path through placental tissues
deprived of trophoblastic defences. It is the case of the marginal
zone of the placenta joining the membranes to the chorionic and
basal plates, known to be constituted with smooth muscle cells only
covered by a maternal epithelium (Nanaev et al., 2000). This route
seems to be particularly important for congenital transmission of T.
cruzi from chronically infected mothers, since comparisons of serial
sections of placental biopsies from infected live newborns showed
a particularly high density of parasites at the level of marginal
zone, with gradually decreasing densities in the chorionic plate
and distant membranes in the absence of trophoblast invasion
(Carlier, 2005; Carlier and Truyens, 2010; Fernandez-Aguilar et al.,
2005). T. cruzi can easily infect and replicate in such muscle and
epithelium cells, likewise facilitating placental invasion. Another
hypothetical mode for parasites crossing trophoblast-free placental
areas might be through the acellular fibrinoid matrix (constituted
with fibronectin, collagen, laminin), known to progressively replace
the degenerating syncitiotrophoblast over the course of gestation
(Benirschke et al., 2006). It is not known if T. cruzi, expressing
receptors for fibronectin (Ouaissi et al., 1984) uses such a possi-
bility.
3.1.3. Parasite transmission through placental breaches/tears
Placental breaches/tears can facilitate congenital transmis-
sion of parasites from maternal blood. Such fissures can result
from damages induced by placental inflammatory responses (see
Section 4.2), and also appear naturally close to the pregnancy
 Y. Carlier et al. / Acta Tropica 121 (2012) 55–70
Fig. 2. Haematogenous transplacental route of parasite transmission.
Modified from Benirschke et al. (2006) with permission.
term, particularly during labour (contraction-mediated damages)
(Benirschke et al., 2006) (see Section 5). Transplacental microtrans-
fusions of maternal blood account for intrapartum maternal–fetal
transmission of HIV, explaining the ability of elective caesarean sec-
tion to prevent such transmission (Biggar et al., 2008; Parazzini,
1999). Such mechanism of transmission is likely relevant for extra-
cellular parasites, as well as for cells infected with parasites. Its
importance depends on the numbers of parasites in maternal blood
bathing the placental intervillous space near the time of delivery.
Such a route would be typical for transfer of Plasmodium-infected
erythrocytes since: (i) natural transmission of maternal erythro-
cytes into the fetal circulation occurs (Zarou et al., 1964) despite
the fact that the prevailing pressure differential favours movement
of blood in the opposite direction (fetal toward maternal); (ii) P.
falciparum-infected erythrocytes are sequestered in the placental
intervillous space at the end of pregnancy, especially in primi-
gravid women (Rogerson et al., 2007); and (iii) the presence of
infected erythrocytes in cord blood correlates with the severity of
placental intervillous inflammation (Ismail et al., 2000) (see Sec-
tion 4.2). The higher rate of congenital toxoplasmosis observed
when acute maternal infection occurs in the third trimester of
pregnancy (see Section 2.1) might also be explained by increased
parasite transmission via this breaches/tears route. The latter route
might also contribute to the transmission of African trypanosomes,
deprived of ability to infect cells and therefore susceptible to easy
elimination by trophoblastic defences. Circulating infected leuko-
cytes harbouring T. cruzi- or Leishmania-amastigotes, or T. gondii
bradyzoites might also be transmitted in this manner, since recent
studies indicate the natural high frequency of maternal–fetal cell
microchimerism in cord blood (Jonsson et al., 2008). Furthermore,
it is also conceivable that nematode larvae employ this mode of
transmission early in pregnancy by inducing placental breaches by
active migration.
59
3.1.4. Parasite transmission through the mesenchymal/stromal
tissues of placenta toward fetal vessels
Except for the microtransfusions through placental breaches
mentioned above, parasites having crossed or avoided the tro-
phoblastic barrier, are into the mesenchymal/stromal tissues of
the villi, and/or chorionic plate, constituted by a mixture of
fixed connective tissue fibres containing cells, such as fibroblasts,
myofibroblasts and macrophages (Hofbauer cells) surrounding
the embedded fetal vessels (Benirschke et al., 2006). Parasites as
T. gondii tachyzoites or T. cruzi trypomastigotes, that have not
been destroyed by the mesenchymal phagocytic cells (see Section
4.1) can undergo further multiplication cycles within such cells,
releasing new extracellular parasites. The latter are susceptible to
sequential infection of other cells, finally infecting endothelial cells
lining fetal vessels embedded in the villous chorion, the chorionic
plate or the umbilical cord, and gain access to the fetal circulation
(Carlier, 2005; Carlier and Truyens, 2010; Fernandez-Aguilar et al.,
2005).
3.2. Other routes of maternal–fetal transmission of parasites
Parasites can be released into the amniotic fluid (AF) follow-
ing a placental derived infection of the amniotic membranes (see
Section 4.2). These parasites might be responsible for complemen-
tary oral or pulmonary in utero contamination of fetuses bathing
in AF and continuously absorbing it. Though T. cruzi-infected still-
borns can exceptionally display massive lung infection (Bittencourt
et al., 1981), parasites are rarely found in AF (Virreira et al., 2006b).
The relative importance of such potential additional route of fetal
contamination remains to be determined for T. gondii which is fre-
quently detected in AF (see Sections 4.2 and 8.2).
Congenital infections with T. vaginalis result from local contam-
ination of the birth canal at delivery, since this parasite usually
60 Y. Carlier et al. / Acta Tropica 121 (2012) 55–70
colonizes the vagina and the cervix of the female genital tract
(Schwandt et al., 2008; Temesvari and Kerekes, 2004).
The trans-uterine route applies to pathogens present within
the peritoneal cavity (following a peritonitis-complicating preg-
nancy) that reach the fetus directly through the uterine wall. The
human parasite having strong histolytic capacities enabling use
of this transmission route could be Entamoeba histolytica, but this
possibility has not been confirmed (Czeizel et al., 1966). The pos-
sibility of fetal/placental invasion from the uterine wall containing
T. gondii or T. cruzi parasites remains to be determined. The other
possible retrograde route from the peritoneal cavity through the
fallopian tubes is not relevant to parasites.
4. How the placenta responds to parasite invasion?
4.1. Parasite invasion and placental innate immune response
It is now clear that the placenta is able to serve as a
microbial sensor during pregnancy. Recent studies have shown
that 10 members of the Toll-Like Receptors (TLR) family are
expressed by trophoblast and syncytiotrophoblast, in addition to
several populations of underlying fibroblasts (including perivascu-
lar myofibroblasts), Hofbauer phagocytic cells (macrophages), and
endothelial cells (reviewed in Koga and Mor, 2010; Abrahams and
Mor, 2005).
TLR-2 and TLR-4 recognize pathogen-associated membrane pat-
terns of T. gondii, T. cruzi, and P. falciparum (Egan et al., 2009;
McCall et al., 2007; Tarleton, 2007; Truyens and Carlier, 2010). Such
TLR expression is strongly enhanced during placental infection
(Hartgers et al., 2008). The well-known trophoblastic FcRn, besides
its function of maternal transfer of antibodies to the fetus (Simister,
2003), might also help to phagocytize parasites opsonized by such
antibodies.
Placental sensing through specific intracellular pathways
promotes an innate immune response with the release into mater-
nal blood of pro-inflammatory cytokines (Yang et al., 1993),
chemokines and endothelial adhesion molecules (Abrahams and
Mor, 2005), reactive oxygen and nitrogen intermediates (Myatt
and Cui, 2004; Rutherford et al., 1995), as well as activation of
indoleamine-2,3-dioxygenase (inducing tryptophan degradation)
(Kudo et al., 2004). Altogether, these innate effector mechanisms
activated in placenta might fight infections, avoiding or limiting
maternal–fetal transmission of parasites. Such activation seems
active against T. cruzi by limiting trophoblastic infection (Altemani
et al., 2000; Lujan et al., 2004). However, its protective role against
T. gondii in placenta remains controversial (Oliveira et al., 2006;
Pfaff et al., 2005b) and it has not been demonstrated in placental
malaria.
4.2. Parasite invasion and pathology of placenta
Maternal infection is often associated with pronounced placen-
tal inflammation with infiltration of neutrophils and lymphocytes
(placentitis) that can induce apoptosis in placental cells, and finally
a rupture of the trophoblastic barrier (Garcia-Lloret et al., 2000;
Redline, 2006). This has been observed both in infections with T.
gondii and T. cruzi (mainly in placentas of highly infected still-
borns) (Bittencourt, 1976; Yavuz et al., 2006). The over-expression
of ICAM-1 on trophoblast and other factors favouring adhesion of
monocytes infected with T. gondii (Ferro et al., 2008; Juliano et al.,
2006; Pfaff et al., 2005a), as well as free T. gondii tachyzoites (Ferro
et al., 2008), can enhance transmission of parasites to the fetus (see
Section 3.1). This phenomenon can also be observed in T. cruzi-
associated villitis (i.e. in case of massive infection) (Juliano et al.,
2006). Adhesion of P. falciparum-infected erythrocytes also induces
diffuse villitis/intervillitis which is especially severe during the first
pregnancy (Ismail et al., 2000).
Invasion and multiplication of parasites in placental tissues can
also induce necrosis and lysis of the chorionic plate (chorionitis)
and umbilical cord (funisitis). A result of the presence of parasites
into the placental chorion is secondary infection of the contigu-
ous layer of amniotic cells (chorioamnionitis). This is frequently
observed in placentas of asymptomatic or mildly symptomatic
neonates congenitally infected with T. cruzi (Carlier, 2005; Carlier
and Truyens, 2010; Fernandez-Aguilar et al., 2005). Dissemination
of parasites to membranes surrounding the fetus induces their frag-
ilization and their premature rupture, as frequently observed in
case of congenital infection with T. cruzi (Torrico et al., 2004). Inter-
estingly, this parasitic amnionitis derives from placental infection,
and not, as seen with other pathogens such as bacteria, mycoplasma
or fungi (mainly Candida sp.), from an ascending infection of the
female genital tract (see Section 3.2) (Benirschke et al., 2006;
Melis et al., 2007; Redline, 2006). As mentioned above (see Sec-
tion 3.2), release of parasites into AF can follow infection of the
amniotic membranes. Persistence of viable parasites in AF depends
on their resistance to antimicrobial peptides normally contained in
AF (Akinbi et al., 2004).
Inflammatory mediators, such as reactive oxygen species,
nitric oxide, peroxynitrite and activated components from the
complement cascade can have deleterious effects on placental vas-
cularization (Conroy et al., 2011; Myatt and Cui, 2004) inducing
long-term fetal damage and worsening the clinical outcome of con-
genital infection. A release of cytokines into the umbilical/fetal
circulation may also induce a fetal inflammatory response syn-
drome affecting the developing fetus (Romero et al., 2007). In
addition, such placentitis can reduce the transfer of protective anti-
bodies from mother to fetus, as shown in malaria (Cumberland
et al., 2007), although this has not been observed in Chagas disease
(Dauby et al., 2009).
5. When maternal–fetal transmission of parasites occurs?
The transplacental transmission of blood parasites does not
occur throughout pregnancy. There is likely little transmission dur-
ing the first trimester of pregnancy, since the placental intervillous
space is not open due to endovascular trophoblast plugging of the
spiral arteries. Maternal blood supply becomes continuous and dif-
fuse in the entire placenta only after the 12th week of gestation
(Jauniaux et al., 2003). The absence of developmental malforma-
tions in newborns congenitally infected with parasites (see Section
7.1) also suggests there is no transmission and detrimental interac-
tion of parasites at the early stages of organogenesis in the embryo.
Transmission of blood parasites probably occurs most fre-
quently during the second and especially the third trimesters of
pregnancy (prenatal transmission), and even during labour (perina-
tal transmission). Indeed, the placenta progressively evolves from
a haemodichorial structure in the first trimester to a haemomono-
chorial structure during the later stages of pregnancy, facilitating
parasite trophoblast crossing. Placental breaches/tears also appear
closer to delivery and during labour (see Section 3.1) (Benirschke
et al., 2006). This is in line with epidemiological observations in tox-
oplasmosis, showing congenital infection much more frequently
when maternal infection occurs during the third trimester of preg-
nancy (see Section 2.1). However, the greatest risk of significant
fetal disease (of lower frequency) is when maternal infection occurs
earlier, probably because the mechanisms of infection control have
still not been well developed by the infected fetus (see Section
6.4). In addition, the differential expression of TLRs and pattern
of responses upon TLR engagement along pregnancy likely also
contributes to differentially modulate the parasite passage early
 Y. Carlier et al. / Acta Tropica 121 (2012) 55–70
or later during pregnancy (see Section 4.1; Koga and Mor, 2010).
Except in the rare reported cases of acute T. cruzi infection during
pregnancy (Moretti et al., 2005), it is generally impossible to pin-
point the timing of maternal–fetal transmission of T. cruzi, since
most pregnant women are in the chronic phase of Chagas disease,
with infection having been acquired a long time before pregnancy
(see Section 2.2).
The rare prenatal transmission of nematode larvae through the
placenta might occur earlier in pregnancy due to their active capac-
ity of migration (see Sections 2.4 and 3.1). Congenital infection with
T. vaginalis is considered a result of perinatal transmission within
the birth canal (see Section 2.4).
6. What factors are involved in transplacental transmission
and development of parasitic infections in newborns?
The main factors that permit occurrence and development of
a congenital infection are the parasite itself and the maternal and
fetal capacities of response to parasitic invasion.
6.1. Parasite genotypes and congenital infection
Protozoan parasites are heterogeneous complexes of genetic
lineages. Such phylogenetic differences might have relevant con-
sequences on parasitic virulence, congenital transmission and
pathology (Conway, 2007; Macedo and Segatto, 2010; Sibley et al.,
2009).
All three of the known lineages of T. gondi have been identified
in human cases of congenital toxoplasmosis. However, if the lin-
eage II is more frequently found in Europe and North America, the
genotypes I and III, as well as recombinant genotypes I/II and I/III
have been found in South American and African cases (Ajzenberg
et al., 2002; Boughattas et al., 2010; Fuentes et al., 2001; Kieffer
et al., 2011; Nowakowska et al., 2006; Peyron et al., 2006). It is not
known if such predominance reflects differences in geographical
distribution of lineages or a real differential capacity for congenital
transmission. Reinfection during pregnancy of previously infected
women with another strain harbouring a different genotype for
which there is no cross immunity might explain the rare cases of
congenital transmission in chronically infected women (see Section
2.1; Elbez-Rubinstein et al., 2009).
The T. cruzi intra-specific nomenclature considers six main
genotypes (some of them being hybrids) (Zingales et al., 2009).
Genotypes TcI, TcII, TcV and TcVI have been identified in congenital
Chagas disease (Burgos et al., 2007; Corrales et al., 2009; Falla et al.,
2009; Pavia et al., 2009; Virreira et al., 2006a, 2007). The TcV geno-
type predominates in Bolivia and Argentina, with a distribution of
frequencies similar to that observed in the infected local population
(Burgos et al., 2007; Corrales et al., 2009; Virreira et al., 2006a). A
congenital case of co-infection with TcI and TcII genotypes has been
reported (Pavia et al., 2009) and the genotypes detected in moth-
ers are generally found in infected newborns (Burgos et al., 2007;
Virreira et al., 2007).
In endemic areas of malaria, infections with multiple genotypes
of P. falciparum are common in peripheral maternal, placental and
cord blood samples. Quantitative measurement of parasite alle-
les present in each of these compartments demonstrated 80–95%
of them being identical (Jafari-Guemouri et al., 2005; Kamwendo
et al., 2002; Kassberger et al., 2002; Mayengue et al., 2004).
So, at this time, there is no clear evidence of a relationship
between T. gondii, T. cruzi or P. falciparum genotypes and congenital
infection.
61
6.2. Maternal parasitic load and congenital infection
Parasitemias in pregnant women seems to be an important
factor contributing to congenital transmission of T. gondii and T.
cruzi. Indeed, congenital toxoplasmosis mainly occurs during the
parasitemic phases of newly acquired acute infection or reacti-
vated infection associated with HIV, but rarely in chronic infection
where circulating tachyzoïtes are hardly detectable (Remington
et al., 2006; see Section 2.1). In Chagas disease for reasons men-
tioned above (see Section 2.2), congenital transmission is mainly
observed in chronically infected women, during which blood par-
asites are hardly detectable using standard parasitological tests.
However, estimation of maternal parasitemia by more sensitive
assays indicates that congenital T. cruzi infection occurs more fre-
quently in mothers displaying higher parasitemias (Brutus et al.,
2010; Hermann et al., 2004; Virreira et al., 2007). For malaria,
the sequestration of P. falciparum-infected erythrocytes in placenta
makes that there is a constant high maternal parasitic load in case
of congenital malaria (see Sections 2.3 and 8.3). These data allow to
postulate that significant maternal parasitemia in the intervillous
space is necessary to cope with the endogenous placental defences
(eliminating one part of parasites present in maternal blood) and
to successfully encounter an optimal route of transmission (see
Section 3.1).
6.3. Maternal immunity and other maternal factors in congenital
infection
Maternal immunity might be a limiting factor for both trans-
mission and development of infections in the fetus/neonate (see
Section 6.5). Maternal IgG antibodies play a protective role in
mothers by contributing to reduce parasitemia in the placenta,
by enhancing the uptake of opsonized parasites by the placen-
tal reticuloendothelial system, and in fetuses when antibodies are
transferred through the placenta (Redline, 2006) in response to
T. gondii, T. cruzi, and Plasmodium infections (Correa et al., 2007;
Hafalla et al., 2011; Truyens and Carlier, 2010).
Activation of innate defences is observed in T. cruzi-infected
mothers and their uninfected newborns, suggesting a protec-
tive role of such maternal defences probably by elimination of
opsonised parasites by activated monocytes and/or other cells
(Vekemans et al., 2000). Mothers transmitting T. cruzi to their
fetuses display lower T cell-mediated immune responses to par-
asites and produce less IFN-␥, which probably contributes to an
increase in parasitemia (Hermann et al., 2004) (see Section 6.2). Per-
sistence of this reduced capacity of T cell-mediated response after
pregnancy, as well as the familial clustering of cases of congenital
infection with T. cruzi (Hermann et al., 2004; Sanchez et al., 2005),
suggest that some mothers might be predisposed to repeated trans-
mission of parasites, which raises the question of a possible role for
genetic factors that favour parasite transmission.
Maternal immunity is also an important factor for congenital
malaria. Infected women with a low level of immunity are more
prone to clinical attacks and congenital malaria (Amaratunga et al.,
2011; Menendez and Mayor, 2007; Rogerson et al., 2007). T cell-
mediated immunity to T. gondii has been investigated in pregnant
women with primary toxoplasmosis (Prigione et al., 2006), but its
impact on neonatal infection has not been determined.
Other maternal factors such as young age and/or primiparity of
mothers, and/or exposure to vectorial re-infections during the time
of pregnancy (contributing to increased maternal parasitemia; see
Section 6.2), and/or malnutrition and poverty also favour the con-
genital transmission of T. cruzi (Bittencourt, 1992; Torrico et al.,
2004, 2006) and malaria (Malhotra et al., 2006; Okafor et al., 2006).
Maternal anaemia appears to be another factor that could increase
62 Y. Carlier et al. / Acta Tropica 121 (2012) 55–70
the risk of congenital malaria by inducing a reorganization of pla-
cental architecture and angiogenesis (Menendez and Mayor, 2007).
6.4. Maternal co-infection and congenital infection
Women co-infected with T. gondii and HIV are at risk of reacti-
vating their T. gondii infection and of transmitting the parasite to
their fetuses, though surprisingly, such transmission appears to be
rare (Montoya and Remington, 2008; Remington et al., 2006) (see
Section 2.1).
Maternal co-infection with T. cruzi and HIV results in increasing
frequency and severity of congenital Chagas disease (Freilij et al.,
1995; Nisida et al., 1999; Sartori et al., 2007; Scapellato et al., 2009),
highlighting the important role of maternal immune-depression
in favouring parasite transmission to the fetus (see Section 6.3).
Interestingly, recent data have indicated a reduced HIV replication
in in vitro cultures of human placenta infected with T. cruzi (Dolcini
et al., 2008).
The role of malaria in increasing the risk of fetal infection with
HIV is well known (Mwapasa et al., 2004). A study also indicates
a higher prevalence of congenital malaria in newborns of women
co-infected with P. falciparum and HIV, associated with increased
placental parasite density (Perrault et al., 2009).
A recent interesting survey performed in a Bolivian area
endemic for both T. cruzi and P. vivax infections indicates that cha-
gasic pregnant women displaying positive thick blood smears for P.
vivax present higher T. cruzi parasitemia and rate of T. cruzi congen-
ital transmission than mothers infected only with T. cruzi (L. Brutus,
personal communication).
6.5. Fetal/neonatal capacity of immune responses and other fetal
factors in congenital infection
A crucial factor to stop, limit or release the development
of fetal/neonatal parasitic infection relates to the capacity of
fetus/neonate to mount innate and/or specific immune response(s)
against parasites transmitted from their mothers. Immune
responses in early life are considered of limited effectiveness owing
to the relative immaturity of the human immune system (Levy,
2007; PrabhuDas et al., 2011). The immune system is initially polar-
ized toward a Th2 immune environment which appears essential
for survival of the fetus (Wilczynski, 2005). Indeed, both dendritic
cells and T cells present quantitative and qualitative defects dur-
ing the neonatal period, limiting the development of CD4+ Th1
cell responses essential for the control of intracellular pathogens
(Marchant and Goldman, 2005; Willems et al., 2009; Zaghouani
et al., 2009) as well as for the production of antibodies (Siegrist,
2007).
While the first studies in neonates with congenital toxo-
plasmosis indicated an impaired Toxoplasma-specific immune
response (McLeod et al., 1990; Remington et al., 2006), further
works reported that newborns as well as young children are able
to develop specific Th1 responses that progressively evolve to be
similar to that of infected adults (Chapey et al., 2010; Ciardelli et al.,
2008; Fatoohi et al., 2003; Guglietta et al., 2007). We have also
demonstrated that neonates congenitally infected with T. cruzi can
overcome the immature nature of their immune system. Indeed,
such infected newborns are able to mount an adult-like CD8T
cell-specific immune response producing IFN-␥ (Hermann et al.,
2002), a critical cytokine for controlling T. cruzi infection (Truyens
and Carlier, 2010). Newborns with a compromised capacity to pro-
duce IFN-␥ display the highest parasitemias and the more severe
forms of congenital Chagas disease, suggesting the protective role
of such T cell-mediated responses (Carlier, 2005; Mayer et al.,
2010). Most newborns with congenital malaria are able to control
and clear the infection without receiving specific treatment. The
mechanisms leading to such favourable issue are poorly known.
They may involve neonatal immune responses toward parasite,
as well as maternally transmitted antibodies (see Section 6.3) and
the presence of high levels of fetal haemoglobin (Amaratunga
et al., 2011; Falade et al., 2007; Menendez and Mayor, 2007; Shear
et al., 1998). Self-cure of congenital malaria (see above), T. cruzi
infection or toxoplasmosis in newborns having been able to mount
an efficient protective immune response could have important
consequences both in interpreting neonatal results of laboratory
diagnosis, as well as in public health control programs related to
congenital parasitic diseases (see Sections 8 and 10).
As for mothers (see Section 6.3), the familial clustering of con-
genital T. cruzi infections (Sanchez et al., 2005) suggests that some
neonates might be predisposed to a lower capacity of immune
responses, raising the question of a possible role of genetic fac-
tors in the susceptibility to congenital infection. Fetal sex does not
seem to be a risk factor for congenital malaria, or for T. cruzi and T.
gondii infections (Bittencourt, 1992; Menendez and Mayor, 2007;
Torrico et al., 2004; Remington et al., 2006).
7. What are the clinical manifestations and long-term
consequences of parasitic congenital infections?
7.1. Clinical manifestations and mortality of congenital parasitic
infections
Congenital parasitic infections are acute infections frequently
asymptomatic at birth. This is true for approximately 85–90% of
congenital toxoplasmosis (mainly when maternal infection occurs
during the third trimester of pregnancy; (Remington et al., 2006);
see Section 2.1), 55–90% of congenital T. cruzi infections (Carlier and
Torrico, 2003; Freilij and Altcheh, 1995; Schijman, 2007; Torrico
et al., 2004) and most congenital malaria in endemic countries
(Menendez and Mayor, 2007). This is in agreement with the prob-
able higher frequency of late transmission of maternal parasites
during pregnancy (see Section 5), reducing the time period for
parasite multiplication in fetuses/neonates and the induction of
clinically evident damages. Nevertheless, clinical manifestations
can appear within days or weeks after birth, or even later, in
congenital toxoplasmosis, Chagas disease, and malaria, thereby
delaying clinical diagnosis. This highlights the mandatory need for
sensitive diagnostic tools to detect such infections closer to birth
(see Section 8).
Signs and symptoms of parasitic congenital infections are gen-
erally similar to those of other common congenital infections, such
as those due, e.g. to cytomegalovirus and Herpes simplex virus. T.
gondii, T. cruzi or Plasmodium-infected newborns frequently exhibit
fever, low birth weight (<2500 g), prematurity (gestational age < 37
weeks), hepatosplenomegaly, jaundice, and pneumonitis (Carlier
and Torrico, 2003; Freeman et al., 2005; Menendez and Mayor,
2007; Remington et al., 2006; Torrico et al., 2004). Signs of growth
retardation can be associated with a multi-systemic diffusion of
pathogens in fetus, in addition to being a consequence of placenti-
tis (see Section 4.2). Premature rupture of membranes (see Section
4.2) can result in the birth of premature newborns with insufficient
pulmonary function worsening pneumonitis susceptible to evolve
into a respiratory distress syndrome (Torrico et al., 2004). No mal-
formations are detected in infected newborns, arguing for parasite
transmission after the embryonic period, as mentioned above (see
Section 5).
Progressive haemolytic anaemia is observed in congenital
malaria, whereas thrombocytopenia and purpura can be observed
in all of these congenital parasitic diseases (Menendez and Mayor,
2007; Remington et al., 2006; Torrico et al., 2004). More severe
symptoms may be involved in the clinical picture. Brain is often
 Y. Carlier et al. / Acta Tropica 121 (2012) 55–70
affected in congenital toxoplasmosis and Chagas disease, causing
meningoencephalitis and convulsions (Freilij and Altcheh, 1995;
Remington et al., 2006; Torrico et al., 2004). Brain calcifications
and hydrocephaly (inflammatory dilatation of cerebral ventricles,
often detectable in utero using ultrasound echography), leading to
psychomotor retardation, are especially observed in congenital tox-
oplasmosis (Remington et al., 2006). Heart can be also affected,
particularly in congenital Chagas disease with acute myocarditis
resulting in alterations of cardiac rhythm and cardiomegaly (severe
myocarditis and meningoencephalitis in congenital Chagas disease
are more frequently observed in case of co-infection with HIV; see
Section 6.4). Eye is also an organ frequently altered in congenital
toxoplasmosis leading to a choroidoretinitis (Melamed et al., 2010;
Remington et al., 2006). Most of these signs (except the toxoplasmic
choroidoretinitis) are non-specific, highlighting the need of labo-
ratory diagnostic tools for identifying such an infection (see above
and Section 8).
Mortality can occur in the days after birth in untreated con-
genital toxoplasmosis, Chagas disease, and malaria (Menendez and
Mayor, 2007; Remington et al., 2006; Torrico et al., 2004). Fre-
quencies of abortion and stillbirths seem rare, but remain to be
determined in such congenital parasitic diseases.
7.2. Long-term consequences of congenital infection with
parasites
Untreated congenital toxoplasmosis and Chagas disease, what-
ever the neonatal morbidity, can develop into chronic disease years
after birth. Cases of apparently asymptomatic congenital toxoplas-
mosis at birth can lead to delayed severe forms of choroidoretinitis
decades after birth (Melamed et al., 2010; Remington et al., 2006;
Wallon et al., 2004). Congenital T. cruzi infections can lead to chronic
chagasic myocardiopathy or digestive megaviscera 25–35 years
later (Carlier et al., 2002; Rassi et al., 2010), though such evolution
of infection might be less frequent in subjects infected congenitally
as compared with those infected by vectors or blood transfusion
(Storino et al., 2002). Congenital malaria may be related to an
increased risk of anaemia in infancy (Menendez and Mayor, 2007).
A trans-generational transmission of parasites, from an infected
mother to her daughter who in turn transmits parasites to her own
infants, is also a potential long-term consequence of congenital
Chagas disease (Sanchez et al., 2005). Though, generally, this does
not occur in congenital toxoplasmosis since maternal–fetal trans-
mission of T. gondii is mainly active in mothers suffering an acute
(recent) infection, such trans-generational transmission might be
suggested in case of reactivation of chronic infection (see Section
2; Garweg et al., 2005). The short life-time of P. falciparum does not
allow such forms of vertical transmission of congenital malaria.
Another unexpected effect of parasitic congenital infections is
the imprinting of the fetal/neonatal immune system which is sus-
ceptible to long-term consequences on later immune responses.
Besides the direct effects on priming parasite-specific immune
responses or inducing parasite-specific immune tolerance (see Sec-
tion 6.5), fetal exposure to parasites and/or parasitic antigens may
increase resistance or susceptibility to subsequent homologous
re-infection (Carlier and Truyens, 1995; Petersen, 2007; Soulard
et al., 2011). Moreover, such imprinting can also affect heterologous
immune responses. Studies by our team showed that infants suf-
fering congenital T. cruzi infection developed strong type 1 immune
responses to hepatitis B, diphtheria and tetanus vaccines, as well
as an enhanced antibody production to Hepatitis B vaccine (Dauby
et al., 2009).
63
8. What are the laboratory tests to be used for detecting
congenital parasitic infections?
Laboratory diagnosis of congenital parasitic infections involves,
first, the detection of infection in pregnant women; and second, the
confirmation of infection in newborns of positive mothers.
8.1. Detection of infection in pregnant women
Detection of a primary (acute) toxoplasmosis during pregnancy
is based on the results of specific serological tests detecting IgG, and
IgM or IgA antibodies, or measuring the avidity of IgG antibodies
(Candolfi et al., 2007; Montoya and Remington, 2008; Remington
et al., 2006).
Positive results of standard serology that detects the presence of
T. cruzi antibodies are sufficient for confirming a chronic infection
in pregnant women. Detection of such infections has to be per-
formed as soon as the diagnosis of pregnancy has been made, or if
not possible, at any time during pregnancy, including at the time
of delivery (Carlier and Torrico, 2003).
Standard thick blood smears are generally used to detect malaria
infection during pregnancy, allowing to detect only mothers with
patent parasitemias (Menendez and Mayor, 2007).
8.2. Detection of fetal infection
Amniotic fluid can be collected by amniocentesis from the 14th
gestational week forwards (18 weeks of gestation is optimal time)
and can be used to determine the presence of parasites or parasitic
DNA (see Section 4.2). Although protocols remain to be standard-
ized and validated, PCR is detecting 64–100% of fetal/neonatal
toxoplasmosis cases, depending on the gestational age at mater-
nal infection (Montoya and Remington, 2008; Wallon et al., 2010).
However, this is not the case for congenital Chagas disease since
T. cruzi parasites are rarely found in amniotic fluid (Virreira et al.,
2006b). Examination of amniotic fluid has no diagnostic applica-
tions for congenital malaria.
Fetal blood sampling (cordocentesis) can be performed after 20
weeks of gestation by experienced clinical practitioners. Collected
blood can be submitted to standard parasitological, molecular or
serological testing for IgA and/or IgM antibodies. This has been
applied mainly in suspected cases of congenital toxoplasmosis
that permits detection of 30–40% of cases (Foulon et al., 1999a).
However, cordocentesis has been replaced in clinical practice by
amniocentesis because of inherently lower risk and higher sensi-
tivity (Montoya and Remington, 2008). It has been rarely used for
congenital T. cruzi infections (Okumura et al., 2004) and is not used
in congenital malaria.
8.3. Detection of neonatal infection
Blood samples can be collected at birth, either from the umbili-
cal cord (the most easiest to collect, without trauma for newborns
and mothers) or peripheral venipuncture in neonates (from heel,
arm or finger). In case of symptoms suggesting meningoencephali-
tis, cerebrospinal fluid can also be collected for such diagnosis in
neonates.
Parasitological tests include direct examination of fresh blood
samples (T. cruzi) or fixed blood smears (T. cruzi, Plasmodium
sp.). If results are negative, concentration techniques can also
be employed, such as the thick smear or blood centrifugation in
heparinized capillary tubes allowing examination of parasites by
light or fluorescence microscopy (T. cruzi, Plasmodium sp.). Blood
cultures are also useful for detecting low parasitemias in congen-
ital toxoplasmosis and Chagas disease (Carlier and Torrico, 2003;
Carlier and Truyens, 2010; Menendez and Mayor, 2007; Mora et al.,
64 Y. Carlier et al. / Acta Tropica 121 (2012) 55–70
2005; Remington et al., 2006). Inoculation of mice with biological
fluids is mainly used in the diagnosis of congenital toxoplasmosis
(Remington et al., 2006). Detection of parasites in blood/CSF defini-
tively confirms congenital infection. In case of negative results
at birth, examination of another biological sample of the same
neonate week(s) or month(s) after birth is desirable (this increases
the sensitivity of detection when congenital transmission occurs
later in pregnancy).
PCR assays on blood samples can detect low amounts of T. cruzi
DNA, but standardization and validation of protocols and primers
to be used are in their early phases of development (Burgos et al.,
2009; Diez et al., 2008; Svoboda et al., 2011; Virreira et al., 2003).
Critical information is still lacking on the stability of parasite DNA in
maternal and umbilical cord blood. This complicates the interpre-
tation of PCR results showing low intensity amplicons in umbilical
cord, since trace amounts of parasite DNA transmitted from the
mother might be detected instead of live parasites. PCR tests on
subsequent samples of such positive neonates have to be repeated.
Quantitative (Real Time) PCR that estimates parasite DNA levels
would be useful in validating equivocal PCR results (Kasper et al.,
2009; Virreira et al., 2007).
Comparison of IgG antibodies present in maternal and neona-
tal blood by western blot assay is a useful tool for the diagnosis
of congenital toxoplasmposis by identifying antibodies produced
by the neonate and not transferred from the mother (Magi and
Migliorini, 2011; Robert-Gangneux et al., 1999). Detection of IgM
and IgA antibodies, not transferred by mothers, in cord or neonatal
blood and/or CSF is generally considered strongly suggestive of con-
genital infection. This can be useful for the diagnosis of congenital
toxoplasmosis (Machado et al., 2010; Montoya, 2002), but not for
congenital T. cruzi infection in which such antibody isotypes are also
detected in uninfected newborns of infected mothers (likely related
to maternal–fetal transfer of parasitic circulating antigens) and are
not present in all parasitologically positive newborns (Carlier and
Torrico, 2003; Carlier and Truyens, 2010; Truyens et al., 2005). Such
testing is not routinely carried out for the detection of congenital
malaria.
Histopathological and PCR analyses or in vitro cultures of placen-
tal biopsies have been considered for the diagnosis of congenital
toxoplasmosis, T. cruzi infection or malaria. However, discordant
results have been reported for congenital T. cruzi and T. gondii infec-
tions (Azogue et al., 1985; Bittencourt, 1976; Fernandez-Aguilar
et al., 2005; Filisetti et al., 2010; Fricker-Hidalgo et al., 2007;
Remington et al., 2006; Robert-Gangneux et al., 2010) Indeed, the
presence of parasites in the placenta does not confirm compulso-
rily such congenital infections, since the placental and/or neonatal
defences are able to contend parasitic infection before it occurs in
neonates (see Sections 4.1 and 6.5). For malaria, the prevalence of
placental infection is much higher than that of congenital infection
(Falade et al., 2007), since P. falciparum-infected erythrocytes are
sequestered in the placenta (see Section 2.3).
8.4. Detection of late parasitic congenital infections
If newborns of mothers infected with T. gondii or T. cruzi display
negative results with the above mentioned tests, detection of spe-
cific antibodies using standard serological assays (as for laboratory
diagnosis in mothers; see Section 8.1) can be carried out in infants
when antibodies transferred from the mothers have been elimi-
nated, i.e. 8–10 months after birth (Carlier and Torrico, 2003; Carlier
and Truyens, 2010; Remington et al., 2006). A positive serological
result at this time indicates that the infant is currently infected.
The congenital origin of the contamination in case of T. cruzi infec-
tion can be established in areas where possibilities of vector or
other transmission routes have been ruled out (i.e. in non-endemic
areas or in areas previously endemic but having developed vector
or blood bank control programs) (Carlier and Torrico, 2003; Carlier
and Truyens, 2010).
9. How to treat parasitic congenital infections?
There is no controlled drug trials for congenital toxoplasmosis,
congenital Chagas disease or congenital malaria, and the treatment
protocols mentioned below derive from the experience of expert
panels.
9.1. Treatment and other options for congenitally infected fetuses
Practically, the prenatal detection of infection is possible only
in toxoplasmosis (see Section 8.2). Treatment of in utero infec-
tion implies administration of drugs to pregnant women that can
cross the placenta. The combination of sulfadiazine 3 g daily (in 3
divided doses), plus pyrimethamine in a single dose of 50 mg daily,
plus folinic acid, is generally recommended in Europe and US for
congenital toxoplasmosis. This treatment has to be given after 18
weeks of gestation since pyrimethamine is potentially teratogenic.
Treatment must be continued until delivery. Such treatment has
been shown to limit the morbidity and mortality of fetal infection
(Montoya and Remington, 2008; McLeod et al., 2009).
In case of confirmed fetal infection associated with obvious
central nervous system pathology (confirmed encephalitic tox-
oplamosis; see Section 7.1), termination of pregnancy can be
discussed (Montoya and Remington, 2008; Remington et al., 2006).
9.2. Treatment of congenitally infected neonates and infants
All congenital T. gondii, T. cruzi and Plasmodium infections
detected in newborns or infants must be treated with specific stan-
dard drugs at doses adapted according to age. If complete cure of
infected newborn/infant cannot be achieved, it can be expected that
such treatment limits the morbidity and mortality of acute infec-
tion and the development of further chronic disease at adult age
(see Section 7.2).
Neonates infected with Toxoplasma will receive sulfadi-
azine 50–100 mg/kg per os (po) daily (in 2 divided doses),
plus pyrimethamine 1 mg/kg po daily (single dose), plus
folinic acid supplement. Alternative treatments consider
also the association pyrimethamine/sulfadoxine (Fansidar® )
or trimethoprime/sulfamethoxazole (cotrimoxazole) or
pyrimethamine/clindamycine. Such treatment will be contin-
ued for 1 year to avoid the appearance of delayed clinical forms of
toxoplasmosis (see Section 7.2; reviewed in McLeod et al., 2009). If
it improves the clinical outcome of congenital toxoplasmosis and
does not affect the long-term quality of life of treated individuals
(Peyron et al., 2011), it seems having a limited effect on prevention
of ocular lesions (Phan et al., 2008).
Congenital T. cruzi infection can be treated with ben-
znidazole (7–10 mg/kg/day po for 1–2 months) or nifurtimox
(10–15 mg/kg/day po for 2–3 months) (Carlier et al., 2011;
Russomando et al., 1998; Schijman et al., 2003; Torrico et al., 2004).
Such a prolonged treatment regimen with doses adapted to increas-
ing body weight is not easy to carry out since pediatric formulations
of these drugs are still unavailable despite of the fact they have been
urgently requested (Carlier and Torrico, 2003; Sosa-Estani et al.,
2005). Full adherence of mothers to scheduled treatment requires
a firm relationship between the pediatrician and affected families.
Negative serology is required to confirm cure, though this result
frequently needs some months to ascertain (Chippaux et al., 2010).
Side effects are rare in newborns and therapeutic efficacy is around
90–100% in most studies if treatment is applied before one year
of age (Altcheh et al., 2011; Blanco et al., 2000; Carlier and Torrico,
 Y. Carlier et al. / Acta Tropica 121 (2012) 55–70
2003; Schijman et al., 2003; Torrico et al., 2004). Obviously, the ben-
efit of treatment remains in effect if infants are not reintegrated in
endemic areas where vector transmission remains active.
Despite the lack of information regarding the clinical man-
agement of congenital malaria, quinine can be recommended
in P. falciparum-infected neonates born to non-immune women
(10 mg/kg orally every 8 h or the same dosage in IV infusion
until oral administration is possible). Use of alternative antimalar-
ial drugs, e.g. chloroquine or artemisinin derivatives, is limited
to local experiences. Sulfadoxine–pyrimethamine is not recom-
mended, according to the manufacturer, for use in the first 6 months
of life; there are no specific recommendations for the use of meflo-
quine and amodiaquine in neonates (Menendez and Mayor, 2007).
In the particular case of congenital P. vivax infections, treatment
is limited to oral chloroquine. Primaquine, usually used to prevent
the development of hepatic malaria, is not necessary since only
infected erythrocytes are released into the fetal circulation from
the maternal bloodstream. In endemic areas, treatment may not
be required as spontaneous parasite clearance before apparition of
clinical symptoms is very frequently observed (see Section 6.5).
10. How prevent or control parasitic congenital infections?
Prophylaxis of congenital infection consists of avoiding fetal
infection. Primary prophylaxis aims to prevent infection of preg-
nant women. Secondary prophylaxis aims to avoid maternal–fetal
parasite transmission from a previously infected pregnant woman
using anti-parasitic safe drugs. In cases where treatment of infected
pregnant women is not possible, detection and treatment of infec-
tion in the newborn/infant remain the only possible intervention
(control of congenital infection) to reduce short-term morbidity
and mortality, as well as long-term effects of congenital infections
(see Sections 7.1 and 7.2).
10.1. Toxoplasmosis
Primary prophylaxis of toxoplasmosis in pregnant women is
mainly based on health education and counseling on how to best
avoid contamination from the main possible routes of transmission,
e.g. eating well-cooked meat; thorough hand washing after contact
with raw meat; avoiding close contact with materials potentially
contaminated with cat feces (cat litter, gardening); and avoid-
ance of drinking water potentially contaminated with oocysts.
Large surveys have shown such counseling as particularly effec-
tive, reducing the incidence of acute toxoplasmosis in sero-negative
pregnant women by 63–92% (Breugelmans et al., 2004; Gollub et al.,
2008; Di Mario et al., 2009). Women chronically infected with T.
gondii and co-infected with HIV (at risk of reactivating their T.
gondii infection; see Sections 2.1 and 6.4) can receive spiramycin
(3 g/day in 3 divided doses) for the duration of their pregnancy;
or trimethoprim–sulfamethoxazole (80 mg/400 mg, respectively; 1
tablet per day) from the second trimester of gestation (not in the
first trimester because it is a folic acid antagonist) (Montoya and
Remington, 2008).
Secondary prophylaxis for toxoplasmosis consists of detecting
the occurrence of acute infection during pregnancy (by checking
specific serology in previously sero-negative women each month
or trimester) and treating positive cases as soon as possible with
spiramycin 3 g daily (divided into 3 doses) until delivery (spi-
ramycin concentrates mainly in placenta and AF but remains at
low levels in fetal tissues (Gratzl et al., 2002; Schoondermark-
Van de Ven et al., 1994); there is no evidence that spiramycin
is teratogenic). This type of treatment is generally recommended
in Europe and US with the idea of reducing the maternal para-
sitemia and potentially the risk of congenital infection (McLeod
65
et al., 2009; Montoya and Remington, 2008). Some European coun-
tries have developed prenatal screening programs (such as Austria,
France, Italy (Campania), Lithuania, Slovenia) (Benard et al., 2008;
Stagni et al., 2009). Studies indicate a positive cost/benefit ratio for
concerned populations (Berrebi et al., 2007; Foulon et al., 1999b;
Gras et al., 2005; Wallon et al., 1999). However, meta-analyses
of such strategies have questioned its effectiveness (Thiebaut
et al., 2007). It is unknown whether the application of such
large program of prenatal screening to countries of low endemic-
ity, e.g. USA, would significantly reduce the risk of congenital
toxoplasmosis (Thiebaut et al., 2007). Other European countries,
e.g. Germany and Italy, promote neonatal screening with treatment
of positive neonates instead of a prenatal intervention, as being
less expensive for preventing sequelae of congenital toxoplasmo-
sis (Benard et al., 2008). If such a program improves the clinical
outcome of congenital toxoplasmosis, it does not attempt to pre-
vent it (see Section 9.2; Gilbert and Dezateux, 2006; McLeod et al.,
2006, 2009; Montoya and Remington, 2008).
10.2. Chagas disease
Primary prophylaxis of congenital infection with T. cruzi can be
obtained by limiting the risk of vector/blood transfusion contam-
ination, and by treating infected girls before they enter into their
childbearing years (Sosa-Estani et al., 2009). However, in contrast
to malaria and toxoplasmosis, treatment of T. cruzi infection during
pregnancy (as secondary prophylaxis of congenital infection) is not
recommended. The potential teratogenic effects of both currently
used drugs, benznidazole and nifurtimox, are not known. More-
over, side effects, unacceptable during pregnancy, are frequent in
adults, and efficacy of such treatment is limited in the chronic phase
of infection presented by most infected pregnant women (Carlier
and Torrico, 2003; Viotti et al., 2009). There is presently an interna-
tional consensus to recommend neonatal screening (by detecting
congenital infection either at birth, close to birth, or by serology
8–10 months after birth; see Sections 8.3 and 8.4) with treatment
of positive neonates (see Section 9.2), as the best strategy for lim-
iting morbidity and mortality of acute infection, and preventing
long-term effects of Chagas disease (Carlier et al., 2011). A cost
effectiveness study of such a control program of congenital Cha-
gas disease in Bolivia clearly indicated it as being highly profitable
in economical as well as public health terms (Billot et al., 2005).
10.3. Malaria
In endemic areas of malaria, primary prophylaxis can be
obtained, as for T. cruzi infection, by limiting the risk of vector
contamination by appropriate measures (Coll et al., 2008; Gamble
et al., 2007). WHO recommends intermittent preventive treatment
(IPT) of pregnant women with sulfadoxine–pyrimethamine (Briand
et al., 2007; Coll et al., 2008; Deloron et al., 2010; Falade et al., 2007;
Garner and Gulmezoglu, 2006; Peters et al., 2007) in association
with the use of insecticide-treated bednets (Menendez et al., 2008).
Altogether these measures have been shown effective in reducing
the prevalence of pregnancy-associated severe malaria, anaemia
and low birth weight, as well as peripheral and placental infec-
tions, whereas a reduction in congenital infection remains to be
confirmed. However, given the current increase of parasite resis-
tance to sulfadoxine–pyrimethamine in almost all parts of Africa, it
is likely that this IPT will soon become ineffective, and alternative
drugs are urgently needed (Deloron et al., 2010). There is little evi-
dence on the safety and efficacy of new artemisinin-based combi-
nations for pregnancy, nor for atovaquone–proguanil (Malarone® ),
and the use of oral quinine is recommended (Adam et al., 2009; Coll
et al., 2008; Rogerson and Menendez, 2006). The efficacy of such
curative treatment for prevention of congenital malaria remains
66 Y. Carlier et al. / Acta Tropica 121 (2012) 55–70
to be determined (Orton and Omari, 2008). Neonatal screening for
detecting and treating congenital malaria in endemic areas remains
highly recommended. Pregnant women living in non-endemic
areas should be advised against travel into endemic regions.
11. Conclusions
T. gondii, T. cruzi and Plasmodium spp. are the prime parasites
able to induce congenital infections in humans. These infections
can have severe outcomes by compromising fetal/neonatal growth.
Congenital infections with T. gondii and T. cruzi parasites can
also lead to serious chronic infections later in adult life. Para-
sitic congenital infections can be found worldwide since congenital
transmission of tropical parasites (such as T. cruzi and Plasmodium
spp.) can occur in endemic, as well as non-endemic areas receiv-
ing immigrants from endemic regions. Often asymptomatic at birth
and remaining undetected, these congenital infections are more
frequent than expected, and neglected (mainly congenital Chagas
disease and congenital malaria). Such parasitic infections in early
life must be considered an important public health problem requir-
ing the development of reasonable prevention or control strategies.
Selecting, planning and implementing the best strategies require a
deeper understanding of mechanisms and multiple factors involved
in congenital transmission of parasites.
Acknowledgements
We are grateful to Drs. Mark James, Richard Oberhelman and
Pierre Buekens for their help in reviewing the manuscript. The kind
permission of Dr. Kurt Benirschke, Peter Kaufmann and Rebecca
N. Baergen and Springer Verlag for using their drawings is also
acknowledged.
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