Pregnancy-associated malaria


Pregnancy-associated malaria or placental malaria is a presentation of the common illness that is particularly life-threatening to both mother and developing fetus. PAM is caused primarily by infection with Plasmodium falciparum, the most dangerous of the four species of malaria-causing parasites that infect humans. During pregnancy, a woman faces a much higher risk of contracting malaria and of associated complications. Prevention and treatment of malaria are essential components of prenatal care in areas where the parasite is endemic.
While the average adult citizen of an endemic region possesses some immunity to the parasite, pregnancy causes complications that leave the woman and fetus extremely vulnerable. The parasite interferes with transmission of vital substances through the fetal placenta, often resulting in stillbirth, spontaneous abortion, or dangerously low birth weight. The tragedy of malaria in developing countries receives abundant attention from the international health community, but until recently PAM and its unique complications were not adequately addressed.

Cause

Transmission of malaria occurs when humans get bitten by infected mosquitos carrying the parasite known as Plasmodium falciparum. The saliva from the mosquito transfers the P. falciparum into the blood which then travels to the liver where it is converted to the merozite form and further replicated. After undergoing these changes in the liver, the parasite is then able to infect erythrocytes in the bloodstream. It can take 7 to 30 days after being bitten by a mosquito before symptoms start to arise. It is believed that pregnant women are more susceptible to malaria infection due to being immunocompromised and because infected erythrocytes tend to congregate around the placenta.
The disease results from the aggregation of erythrocytes infected by Plasmodium falciparum which have been shown to adhere to chondroitin sulfate A on placental proteoglycans causing them to accumulate in the intervillous spaces of the placenta, blocking the crucial flow of nutrients from mother to embryo. Infected erythrocytes express the VAR2CSA variant of P. falciparum Erythrocyte Membrane Protein 1 which allows them to bind to CSA on the placenta. In areas of high malaria transmission such as Africa, primigravidae have the highest risk of infection compared to in lower transmission areas where gravidity has less of an effect on infection rates. This is because women who are pregnant for the first time generally lack antibodies to VAR2CSA on erythrocytes that have been infected by the parasite. Women are most susceptible to malaria infection early on in the first trimester but the risk of infection decreases in the second trimester due to the development of antibodies to the infectious agent over time following the initial exposure. The infection risk also decreases after successive pregnancies.

Mechanism

P. falciparum expresses proteins on the surface of parasite-infected erythrocytes helping them bind to an unusually low-sulfated form of chondroitin sulfate A in the placental intervillous space. By this process, the parasite avoids being filtered through the spleen where it would be cleared from the bloodstream and killed. When selected in vitro for CSA-binding, the only upregulated gene expressed in the P. falciparum parasites was the var2csa gene. Parasite clones where the var2csa gene was disrupted lost the ability to adhere to CSA by blocking the binding of IE. Its protein, VAR2CSA, belongs to the Plasmodium falciparum erythrocyte membrane protein 1 family and contains six Duffy binding-like domains. The regions that mediate binding to CSA have not been defined, but DBL2, DBL3, and DBL6 have shown the highest affinity for CSA binding when testing with recombinant single-domains.
A unique var gene encodes this particular PfEMP1, which is differently regulated than other genes from the var family. It is also only expressed as protein in pregnant women, even though the transcript is present in children, men and non-pregnant women. It has a unique regulatory region, a uORF located upstream from the ORF that codes for the VAR2CSA protein. The expression of a protein named PTEF has been described to be necessary for the translation machinery to overcome the uORF and produce VAR2CSA protein, but the mechanism behind it remains to be elucidated.

Signs and Symptoms

Women experiencing PAM may exhibit normal symptoms of malaria, but may also be asymptomatic or present with more mild symptoms, including a lack of the characteristic fever. This may prevent a woman from seeking treatment despite the danger to herself and her unborn child. Some initial symptoms of malaria include feeling unwell, experiencing headaches and fatigue, and having muscle aches and abdominal pain. This can eventually progress to a fever. Other common symptoms consist of nausea, vomiting, and orthostatic hypertension. Malaria can also lead to seizures which may precede going into a comatose state.

Maternal and Fetal Outcomes

In general, women with PAM have a higher likelihood of premature birth and low birthweight of their infant. In examination of possible malarial immunity, some studies have shown that the presence of P. falciparum antibodies may decrease the likelihood of low birthweight in the infants of women who have had pregnancy-associated malaria, but these findings do not specifically correlate to malarial immunity during pregnancy. However, the relationship between many P. falciparum antibodies during pregnancy and maternal and birth outcomes remains variable.
Children of women with PAM are also more likely to contract clinical malaria and P. falciparum parasitaemia, although the reasoning for this is uncertain.

Prevention and Treatment

Prevention

Prevention of pregnancy-associated malaria can be done with the use of various antimalarial drugs that are given before or during pregnancy to susceptible populations. Some of the antimalarial drugs used include Chloroquine, Mefloquine, and Sulfadoxine/pyrimethamine since they are safe for use during pregnancy. For regions of moderate or high malaria risk, preventative measures include insecticide-treated nets and intermittent preventive treatment in pregnancy. Because IPTp plays a role in altering the immune response that the infant can display, the World Health Organization recommends starting IPTp as soon as possible during the 2nd trimester. These treatments are with doses of Sulfadoxine/pyrimethamine and are given at each antenatal visit, as long as the visits are one month apart.

Treatment

Epidemiology

Globally, an estimated 125 million or more pregnant women per year risk contracting PAM. Pregnancy-related malaria causes around 100,000 infant deaths each year, due in large part to low birth weight.
Due to the nature of disease transmission and life cycle of the parasite, malaria is prevalent in warm, humid climates, such as tropical and subtropical regions. Consistent with previous years, the incidence of malaria in general is greatest in African regions as defined by the World Health Organization, although there was a decline from 2010 to 2018. In the realm of pregnancy, individual immunity and level of transmission within the area play an important role in the malarial complications that manifest. For example, areas with high level of transmission are also associated with higher incidence of immunity. Therefore, infection from P. falciparum is usually associated with no symptoms in pregnant women. However, it is not to conclude that the presence of P. falciparum is completely benign, as it has been associated with maternal anaemia. Similarly to P. falciparum, Plasmodium vivax , another malarial pathogen found primarily in Asia and South America, has also been associated with maternal anaemia and low birthweight. On the contrary, women who live in areas with lower transmission are at a very high risk of adverse malarial outcomes despite their amount of pregnancies.

Current research

Each VAR2CSA domain has a potential affinity to CSA, but there are large areas not exposed to the immune system and appear to be buried in the quaternary structure. Data has indicated that these domains interact, forming a binding site that is specific for low-sulfated CSA found in the placenta. The binding of antibodies to one of these domains would prevent adhesion of parasitic IE in the placenta.
Moreover, studies have shown that women acquire immunity to PAM through antibody recognition of the VAR2CSA domain, also known as VSAPAM, after exposure during their first pregnancy. By measuring circulating levels of IgG antibodies that presumably target VAR2SCA, the study demonstrated that subsequent pregnancies confer progressively greater protection to PAM. Thus, PfEMP1 proteins such as the VAR2CSA domain could prove attractive as potential candidates for vaccine targets.
A vaccine to prevent a pregnancy-associated malaria called PAMVAC is currently undergoing clinical trials.