This review of protozoan and helminth infections in pregnancy focuses on the impact on the immune response in the newborn infant to maternal infection. Studies of protozoan and helminth infections in pregnant women and in their offspring have shown that children exposed to antigens or microorganisms during pregnancy often have a reduced immune response to these infections. The most common finding is a reduced IFNγ response to specific antigens regardless of specific infection studied. In some studies the impaired immune response disappeared before the age of one year, while in other studies the impaired immune response was present as much as two decades after birth. Data from chronic viral infections like Rubella, cytomegalovirus and hepatitis B also show that congenital or perinatal infections may result in a life-long inability to control the infections. Studies of both helminth and protozoan infections show that children exposed to antigens during gestation have a microorganism-specific impaired immune response which is characterized by reduced IFN-γ and stimulation of responses to specific antigens.

P. falciparum malaria severely affects pregnant women and children. Despite immunity through lifelong exposure to malaria, pregnant women become susceptible to infections causing anaemia, abortions and low birth weight. They experience massive accumulation of infected erythrocytes (IEs) in the placenta. Adhesion of IEs to host endothelial receptors is mediated by members of a large diverse protein family called P. falciparum erythrocyte membrane protein 1 (PfEMP1). Pregnancy malaria is generally associated with the emergence of a distinct subset of parasites expressing a unique PfEMP1 that binds to the host-receptor chondroitin sulfate A (CSA). Resistance to pregnancy malaria is associated with the acquisition of antibodies that block IEs binding to placental CSA. The absence (or rare occurrence) of CSA-binding parasites in malaria patients (children, men and non-pregnant women) suggests that these parasites become virulent only during pregnancy. The molecular mechanisms used by P. falciparum to achieve the timely expression of the Pf-CSA ligand in pregnant women remain puzzling. In this review we will discuss two hypothetical mechanisms by which CSA-binding parasites may arise during pregnancy. The first, a selection process by the placenta of a distinct sub-population of P. falciparum expressing a particular PfEMP1. The second, an induction mechanism that facilitates the expression of a particular PfEMP1 protein by specific host factor(s) present only during pregnancy.

People living in areas with stable transmission of P. falciparum parasites acquire protective immunity to malaria over a number of years and following multiple disease episodes. Immunity acquired this way is mediated by IgG with specificity for parasite-encoded, clonally variant surface antigens (VSA) on the surface of infected erythrocytes (IEs). However, women in endemic areas become susceptible to P. falciparum infection when they become pregnant, particularly for the first time, regardless of previously acquired protective immunity. This conundrum was resolved when it was observed that the selective placental accumulation of IEs that characterizes pregnancy-associated malaria (PAM) is caused by an immunologically and functionally unique subset of VSA (VSAPAM) that is only expressed by parasites infecting pregnant women, and that protective immunity to PAM is mediated by IgG with specificity for VSAPAM. In this review we summarize the research leading to the identification of the distinctly structured PfEMP1 variant VAR2CSA as the dominant PAM-type VSA and as the clinically most important target of the protective immune response to placental P. falciparum infection.

The epidemiology of pregnancy malaria infection and disease is complex but reflects underlying interactions between the Plasmodium falciparum parasite, the mother, and the foetus. Parasites sequester in the human placenta by binding to chondroitin sulfate A (CSA), a novel receptor that does not commonly support binding of other parasites. Women become resistant to P. falciparum malaria over successive pregnancies as they acquire antibodies against the CSA-binding placental parasite forms. Due to acquired immunity, placental malaria is briefer and less inflammatory in multigravid women than primigravid women, and these parity differences may account for the different outcomes these women and their offspring experience. Commonly recognized sequelae of malaria-like maternal anaemia and low birth weight primarily occur in first and second pregnancies. Hypertension may result from maternal-foetal conflict over the inflammatory response to placental malaria, and occurs in young, first-time mothers. Placental malaria can either increase or decrease parasitaemia risk in the offspring, depending on the mother's parity. The burden of disease due to pregnancy malaria, and the benefits of an effective vaccine, may be much greater than is currently appreciated.

Malaria infection during pregnancy is associated with poor maternal and foetal outcomes including low birth weight. In malaria-endemic areas, low birth weight is primarily a consequence of foetal growth restriction. Little is known on the pathogenesis of foetal growth restriction and our understanding of the relationship between epidemiological observations and the pathogenesis or consequences of disease is incomplete. In this review, we describe these gaps in our knowledge and also try to identify goals for future research into malaria in pregnancy. Foetal growth restriction results from a complex four-dimensional interaction between the foetus, the mother and the malaria parasite over gestation, and research into its pathogenesis may be advanced by combining longitudinal studies with techniques and approaches new to the field of malaria in pregnancy. Such approaches would greatly increase our knowledge on the pathogenesis of this disease and may provide new avenues for intervention strategies.

Toxoplasma gondii is one of the few pathogens that can cross the placenta. Frequency and severity of transmission vary with gestational age. While the control of acquired toxoplasmosis is already well explored, the control of materno-foetal transmission of the parasite remains almost unknown. This is partly due to the lack of an animal model to study this process. This review summarises the studies which have been undertaken and shows that the mouse is a valuable model despite obvious differences to the human case. The paramount role of the cellular immune response has been shown by several experiments. However, IFN-γ has a dual role in this process. While its beneficial effects in the control of toxoplasmosis are well known, it also seems to have transmission-enhancing effects and can also directly harm the developing foetus. The ultimate goal of these studies is to develop a vaccine which protects both mother and foetus. Therefore, it is useful to study the mechanisms of natural resistance against transmission during a secondary infection. In this setting, the process is more complicated, involving both cellular and also humoral components of the immune system. In summary, even if the whole process is far from being elucidated, important insights have been gained so far which will help us to undertake rational vaccine research.

The protozoan parasite Neospora caninum is an important cause of reproductive disease in cattle worldwide. The dog is a definitive host for the parasite and the oocyst stage, shed in the faeces, is a source of infection for cattle through consumption of contaminated feed or water. In addition, transplacental transmission of N. caninum is a very efficient means of the parasite infecting a new host and this can occur in successive pregnancies and over several generations. Neospora parasites may cause disease during pregnancy resulting in death of the foetus or birth of live congenitally infected calves that may show some neurological clinical signs at birth. The stage of pregnancy at which infection/parasitaemia occurs is an important factor in determining disease severity. Neospora infection in the first trimester of pregnancy may have more severe consequences for the foetus compared with infection occurring in the final trimester. The host-parasite relationship during pregnancy is a fascinating interaction and research in this area will improve understanding of disease pathogenesis and the various consequences of the host immune response, being host-protective, parasite protective and contributing to disease pathology. Pregnancy poses an interesting problem for the immune system of the dam as she is essentially carrying a semi-allogeneic tissue graft (the foetus) without immunological rejection taking place. To facilitate the pregnancy the cytokine environment in the placenta favours the regulatory Th-2-type cytokines, whose role is to counteract the pro-inflammatory Th1-type immune responses. Protective immunity to N. caninum, similar to many other intracellular parasites, involves Th1-type immune responses, which may pose problems for the dam trying to control a Neospora infection during pregnancy.

This paper will discuss the host-parasite relationship at different stages of gestation in pregnant cattle and review the implications of this research for our understanding of disease pathogenesis, parasite transmission and host protection.