Malaria Site: Pregnancy and Malaria

Malaria in pregnancy is a obstetric, social and medical problem requiring multidisciplinary and multidimensional solution. Pregnant women constitute the main adult risk group for malaria and 80% of deaths due to malaria in Africa occur in pregnant women and children below 5 years. In Africa, perinatal mortality due to malaria is at about 1500/day. In areas where malaria is endemic, 20-40% of all babies born may have a low birth weight. Malaria in pregnancy is a Priority Area in Roll Back Malaria strategy.

Malaria and pregnancy are mutually aggravating conditions. The physiological changes of pregnancy and the pathological changes due to malaria have a synergistic effect on the course of each other, thus making the life difficult for the mother, the child and the treating physician. P. falciparum malaria can run a turbulent and dramatic course in pregnant women. The non- immune, primi gravidae are usually the most affected. In pregnant women the morbidity due to malaria includes anemia, fever illness, hypoglycemia, cerebral malaria, pulmonary edema, puerperal sepsis and mortality can occur from severe malaria and haemorrhage. The problems in the new born include low birth weight, prematurity, IUGR, malaria illness and mortality.

More common	Malaria is more common in pregnancy compared to the general population. Immuno suppression and loss of acquired immunity to malaria could be the causes.
More atypical	In pregnancy, malaria tends to be more atypical in presentation. This could be due to the hormonal, immunological and hematological changes of pregnancy.
More severe	Due to the hormonal and immunological changes, the parasitemia tends to be 10 times higher and as a result, all the complications of falciparum malaria are more common in pregnancy compared to the non-pregnant population.
More fatal	P. falciparum malaria in pregnancy being more severe, the mortality is also double (13 %) compared to the non-pregnant population (6.5%).
Selective treatment	Some anti malarials are contra indicated in pregnancy and some may cause severe adverse effects. Therefore the treatment may become difficult, particularly in cases of severe P. falciparum malaria.
Other problems	Management of complications of malaria may be difficult due to the various physiological changes of pregnancy. Careful attention has to be paid towards fluid management, temperature control, etc. Also decisions regarding induction of labour may be difficult and complex. Foetal loss, IUGR, and premature labour are common.

The pathophysiology of malaria in pregnancy is greatly due to the altered immunity and availability of a new organ called placenta in pregnancy. A dramatic breakdown of acquired immunity occurs in pregnancy, especially in primigravidae. (Paradoxically, fully effective antimalaria immunity is transferred to the child!) Various hypotheses have been put forth to explain the pathophysiology of malaria in pregnancy.

Hypothesis - 1: Loss of antimalarial immunity is consistent with the general immunosupression of pregnancy viz; reduced lymphoproliferative response, sustained by elevated levels of serum cortisol. This is designed to prevent the fetal rejection but renders the pregnant woman susceptible to infection. However, this does not explain the diminished susceptibility to malaria experienced by multigravid women.

Hypothesis - 2: What is lost is cell mediated immunity, but what is transferred is the passive antibody mediated immunity and therefore the pregnant mother suffers.

Hypothesis - 3: Placenta is a new organ in the primigravidae and allows the parasites to by-pass the existing host immunity or allows placenta specific phenotypes of P. falciparum to multiply. Development of placenta specific immunity may thus explain the decreased susceptibility in multigravidae.

Recently, it has been discovered that multigravid women can form strain-independent antibodies against CSA-specific parasites, and they demonstrate greatly diminished parasite load. The unique susceptibility of primigravids to placental infection can be explained by their immune inexperience with the parasite subpopulation.

Hypothesis - 4: Pregnant women display a bias towards type- 2 cytokines and are therefore susceptible to diseases requiring type 1 responses for protection like TB, malaria, leishmaniasis etc. However, in infected pregnant women a change of balance of the local placental environment from TH2 to TH1 has been observed, consistent with large number of monocytes in infected placenta. IL-10 levels are decreased, while IFN-g , IL-2, and TNF-α levels-hallmarks of a type-1 cytokine response-are elevated. These pro-inflammatory cytokines account for the pathology of maternal malaria: Elevated levels of TNF- α are associated with severe maternal anemia; symptomatology of malaria and localized cytokine elevation contributes to adverse pregnancy outcomes.

P. falciparum has the unique ability of cytoadhesion and adhesion molecules such as CD36 and intercellular adhesion molecule-1 may be involved in the development of severe malaria in children and non-pregnant adults. Chondroitin sulfate A and hyaluronic acid have been identified as the adhesion molecules for parasite attachment to placental cells. The putative ligand expressed by the parasite is PfCSA-L and it has been found to be antigenically conserved among global cases of maternal malaria, suggesting a unique subpopulation of P. falciparum that do not bind to CD36. The parasites sequester along the surface of the placental membrane, specifically the trophoblastic villi, extravillous trophoblasts, and syncytial bridges. Intervillous spaces are filled with parasites and macrophages, interfering with oxygen and nutrient transport to the foetus. Villous hypertrophy and fibrinoid necrosis of villi (complete or partial) have been observed. All the placental tissues exhibit malarial pigments (with or even without parasites). These changes impede oxygen-nutrient transfer and can cause general hemorrhaging. These changes contribute to the complications experienced by both mother and child.

Atypical manifestations of malaria are more common in pregnancy, particularly in the 2^nd half of pregnancy.

Fever: Patient may have different patterns of fever - from afebrile to continuous fever, low grade to hyper pyrexia. In 2^nd half of pregnancy, there may be more frequent paroxysms due to immunosuppression.

Anemia: In developing countries, where malaria is most common, anemia is a common feature of pregnancy. Malnutrition and helminthiasis are the commonest causes of anemia. In such a situation, malaria will compound the problem. Anemia may even be the presenting feature of malaria and therefore all cases of anemia should be tested for MP. Anemia as a presenting feature is more common in partially immune multigravidae living in hyperendemic areas.

Splenomegaly: Enlargement of the spleen may be variable. It may be absent or small in 2^nd half of pregnancy. A preexisting enlarged spleen may regress in size in pregnancy.

Complications: Complications tend to be more common and more severe in pregnancy. A patient may present with complications of malaria or they may develop suddenly. Acute pulmonary edema, hypoglycemia and anemia are more common in pregnancy. Jaundice, convulsions, altered sensorium, coma, vomiting / diarrhoea and other complications may be seen.

Anemia: Malaria can cause or aggravate anemia. It could be due to the following causes:

Anemia due to malaria is more common and severe between 16-29 weeks. It can develop suddenly, in case of severe malaria with high grades of parasitemia. Pre existing iron and folate deficiency can exacerbate the anemia of malaria and vice versa.

Anemia increases perinatal mortality and maternal morbidity and mortality. It also increases the risk of pulmonary oedema. Risk of post-partum haemorrhage is also higher.

Significant anemia (Hemoglobin <7-8 g%) may have to be treated with blood transfusion. In view of the increased fluid volume in pregnancy, it is better to transfuse packed cells than whole blood. Rapid transfusion, particularly whole blood, may cause pulmonary oedema.

Acute pulmonary oedema is also a more common complication of malaria in pregnancy compared to the non-pregnant population. It may be the presenting feature or can develop suddenly after several days. It is more common in 2^nd and 3^rd trimesters.

It can develop suddenly in immediate post-partum period due to auto transfusion of placental blood with high proportion of parasitised RBC’s and sudden increase in peripheral vascular resistance after delivery.

This is another complication of malaria that is peculiarly more common in pregnancy. The following factors contribute to hypoglycemia:

Hypoglycemia in these patients can remain asymptomatic and may not be detected. This is because, all the symptoms of hypoglycemia are also caused by malaria viz. tachycardia, sweating, giddiness etc. Some patients may have abnormal behaviour, convulsions, altered sensorium, sudden loss of consciousness etc. These symptoms of hypoglycemia may be easily confused with cerebral malaria. Therefore, in all pregnant women with falciparum malaria, particularly those receiving quinine, blood sugar should be monitored every 4-6 hours. Hypoglycemia can be recurrent and therefore constant monitoring is needed.

In some, it can be associated with lactic acidosis and in such cases mortality is very high. Maternal hypoglycemia can cause fetal distress without any signs.

Immunosuppression in pregnancy poses special problems. It makes malaria more common and more severe. And to add to the woes, malaria itself suppresses immune response.

Hormonal changes of pregnancy, reduced synthesis of immunoglobulins, reduced function of reticulo endothelial system are the causes for immunosuppression in pregnancy. This results in loss of acquired immunity to malaria, making the pregnant more prone for malaria. Malaria is more severe with higher parasitemia. Patient may have more frequent paroxysms of fever and frequent relapses.

Secondary infections (UTI and pneumonias) and algid malaria (septicaemic shock) are more common in pregnancy due to immunosuppression.

Malaria in pregnancy is detrimental to the foetus. High grades of fever, placental insufficiency, hypoglycemia, anemia and other complications can all adversely affect the foetus. Both P. vivax and P. falciparum malaria can pose problems for the foetus, with the latter being more serious. The prenatal and neonatal mortality may vary from 15 to 70%. In one study, mortality due to P. vivax malaria during pregnancy was 15.7% while that due to P. falciparum was 33%. Spontaneous abortion, pre mature birth, still birth, placental insufficiency and IUGR (temporary / chronic), low birth weight, fetal distress are the different problems observed in the growing foetus. Transplacental spread of the infection to the foetus can result in congenital malaria.

Congenital malaria: It is very rare and occurs in < 5% of affected pregnancies. Placental barrier and matenal Ig G antibodies which cross the placenta may protect the foetus to some extent. However, it is much more common in non-immune population and the incidence goes up during epidemics of malaria. Fetal plasma quinine and chloroquine levels are about one third of simultaneous maternal levels and this subtherapeutic drug level does not cure the infection in the foetus. All four species can cause congenital malaria, but it is proportionately more with P. malariae. The new born child can manifest with fever, irritability, feeding problems, hepato splenomegaly, anemia, jaundice etc. The diagnosis can be confirmed by a smear for MP from cord blood or heel prick, anytime within a week after birth (or even later if post-partum, mosquito-borne infection is not likely). Differential diagnoses include Rh. incompatibility, infections with CMV, Herpes, Rubella, Toxoplasmosis, and syphilis.

Pregnancy-malaria and intensity of transmission: Clinical presentation and severity of malaria in pregnancy differ in areas of high transmission and low transmission due to differences in the level of immunity. In high endemic areas, acquired immunity is high, mortality is less common, asymptomatic and incidental parasitemia are not uncommon. Sequestration of MP in the placenta and long standing placental malaria occur and peripheral blood may be negative for MP. Higher parasitemia, particularly in II and III trimester; anemia and altered placental integrity result in less nutritional support leading to LBW, abortion, stillbirth, premature birth and low birth weight, and excess infant mortality/morbidity. These problems are more common in first and second pregnancies as the parasitemia level decreases with increasing number of pregnancy. HIV infection extends this to all pregnancies and makes it worse. The strategy for management of malaria in pregnant population in areas of high transmission include intermittent treatment and use of insecticide treated bednets.

In areas of low transmission, the problems are dramatically different. The risk of malaria infection during pregnancy is greater and can result in maternal death and spontaneous abortion in up to 60% of cases. Low birth weight can occur even in cases of treated malaria; however, silent malaria rather rare. The strategy involves measures to avoid malaria by ITMs/chemoprophylaxis and early diagnosis and prompt treatment of cases.

Table: Comparison of occurrence of complications in areas of high and low transmission

There are very few documented studies on P. vivax malaria in pregnancy. It appears to be more common in primigravidae than multigravidae. Parasite densities are similar in pregnant and non-pregnant states. It may be associated with mild anaemia and increased risk of low birth weight and not associated with abortion, stillbirth or a reduction of the duration of pregnancy. Benefit of chemoprophylaxis has not been established.

Management of malaria in pregnancy involves the following three aspects and equal importance should be attached to all the three.

Treatment of malaria in pregnancy should be energetic, anticipatory and careful.

Anticipatory: Malaria in pregnancy can cause sudden and dramatic complications. Therefore, one should always be looking for any complications by regular monitoring.

Careful: The physiologic changes of pregnancy pose special problems in management of malaria. In addition, certain drugs are contra indicated in pregnancy or may cause more severe adverse effects. All these factors should be taken into consideration while treating these patients.

Acute Pulmonary Oedema: Careful fluid management; back rest; oxygen; diuretics; ventilation if needed.

Hypoglycemia: 25-50% Dextrose, 50-100 ml I.V., followed by 10% dextrose continuous infusion. If fluid overload is a problem, then Inj. Glucagon 0.5-1 mg can be given intra muscularly. Blood sugar should be monitored every 4-6 hours for recurrent hypoglycemia.

Renal failure: Renal failure could be pre-renal due to unrecognised dehydration or renal due to severe parasitemia. Treatment involves careful fluid management, diuretics, and dialysis if needed.

Septicaemic shock: Secondary bacterial infections like urinary tract infection, pneumonia etc. are more common in pregnancy associated with malaria. Some of these patients may develop septicaemic shock, the so called 'algid malaria'. Treatment involves administration of 3^rdgeneration cephalosporins, fluid replacement, monitoring of vital parameters and intake and output.

Exchange transfusion: Exchange transfusion is indicated in cases of severe falciparum malaria to reduce the parasite load. Patient’s blood is removed and it is replaced with packed cells. It is especially useful in cases of very high parasitemia (helps in clearing) and impending pulmonary oedema (helps to reduce fluid load).

Anemia, hypoglycemia, pulmonary oedema, and secondary infections due to malaria in full term pregnancy lead to problems for both the mother and the foetus. Severe falciparum malaria in full term pregnancy carries a very high mortality. Maternal and fetal distress may go unrecognised in these patients. Therefore, careful monitoring of maternal and foetal parameters is extremely important and pregnant women with severe malaria are better managed in an intensive care unit.

Falciparum malaria induces uterine contractions, resulting in premature labour. The frequency and intensity of contractions appear to be related to the height of the fever. Fetal distress is common and often unrecognised. Therefore only monitoring of uterine contractions and fetal heart rate may reveal asymptomatic labour and foetal tachycardia, bradycardia or late deceleration in relation to uterine contractions, indicating fetal distress. All efforts should be made to rapidly bring the temperature under control, by cold sponging, anti pyretics like paracetamol etc.

Careful fluid management is also very important. Dehydration as well as fluid overload should be avoided, because both could be detrimental to the mother and/or the foetus. In cases of very high parasitemia, exchange transfusion may have to be carried out.

If the situation demands, induction of labour may have to be considered. Once the patient is in labour, foetal or maternal distress may indicate the need to shorten the 2^nd stage by forceps or vacuum extraction. If needed, even caesarian section must be considered.

In pregnancy, use of primaquine is contraindicated. Primaquine is also contraindicated in lactating mothers. Therefore to prevent the relapse of vivax malaria from reactivation of hypnozoites in the liver, suppressive chemoprophylaxis with chloroquine is recommended. Tablet Chloroquine 500 mg weekly should be administered to all such patients until stoppage of lactation. At that point, a complete treatment with full therapeutic dose of chloroquine and primaquine should be administered.

Malaria being potentially fatal to both the mother and the foetus, all pregnant women, who remain in the malarious area during their pregnancy, should be protected with chemoprophylaxis against malaria. This is a most important part of antenatal care in areas of high transmission of malaria.

Choice of anti malarials for chemoprophylaxis: Chloroquine being the safest drug in pregnancy, it should be the first choice. 500 mg of chloroquine should be administered once every week. However, use of chloroquine may be restricted due to the wide spread resistance to this drug. In areas with known resistance to chloroquine, pyrimethamine/ sulphadoxine or mefloquine can be used. But these drugs should be started in early 2^nd trimester. Dose of mefloquine may have to be increased in the last trimester, in view of the accelerated clearance of the drug.

Vaccine against malaria in pregnancy: Although a general malaria vaccine appears to be a distant possibility, there is much hope for a vaccine against placental malaria. The administration of excessive soluble CSA to pregnant women has proven to drastically reduce parasite adhesion; however, in excess levels, this soluble protein is severely nephrotoxic. Studies have demonstrated that the administration of chondroitinase AC can effectively reduce parasite adhesion by 95%. This preliminary data is being further tested in combination with therapeutic use of monoclonal antibodies to CSA