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.
Burden of Malaria in Pregnancy
According to the World Malaria Report 2020, in 2019, in 33 moderate to high transmission countries in the WHO African Region, there were an estimated 33 million pregnancies, of which 35% (12 million) were exposed to malaria infection during pregnancy. By WHO subregion, Central Africa had the highest prevalence of exposure to malaria during pregnancy (40%), closely followed by West Africa (39%), while prevalence was 24% in East and Southern Africa. It is estimated that malaria infection during pregnancy in these 33 countries resulted in 822 000 children with low birthweight. If up to 80% of pregnant women who reported using antenatal care (ANC) services once were to receive one dose of intermittent preventive treatment in pregnancy (IPTp), an additional 56 000 low birthweights would be averted in these 33 countries. [World Malaria Report 2020]
Pregnancy Increases Susceptibility
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.
In high transmission areas, such as some African countries, women having suffered repeated infections would have developed immunity that generally prevents severe disease, however, during pregnancy, this immunity to malaria somewhat wanes during pregnancy, leading to an increased risk malaria infection. In low transmission areas, women generally have developed no immunity to malaria malaria infection is more likely to result in severe malaria.
Pregnaancy provides an additional organ for the malarial parasites to bind, sequestrate and multiply, contributing to severe disease. During malaria in pregnancy, Plasmodium falciparum-infected erythrocytes express a unique variant surface antigen, VAR2CSA, that mediates sequestration in the placenta. This process may initiate a range of host responses that contribute to placental inflammation and dysregulated placental development, which affects placental vasculogenesis, angiogenesis and nutrient transport. Collectively, these result in the impairment of placental functions, affecting fetal development.[Chua CLL et al]
Malaria during pregnanacy in high transmisison areas is therefore more likely to contribute to maternal anemia and delivery of low birth-weight infants (<2500 g or <5.5 pounds), more so in women during first and second pregnancies, and in younger women, and women who are HIV-positive. In low transmission areas, malaria infection is more likely to result in severe malaria disease, maternal anemia, premature delivery, or fetal loss.[See CDC]
The precise mechanisms behind malaria associated preterm birth and small for gestational age remain unclear. P. falciparum infection can cause inflammation and potentially disrupt the fine immunological balance required to maintain pregnancy to term. On the other hand, small for gestational age is often linked to placental insufficiency and there is also substantial evidence to suggest dysregulated placental development in mothers with malaria in pregnancy. Preterm birth and small for gestational age do not commonly co-exist in malaria during preganancy, further highlighting the complexity of birth outcomes in malaria during preganancy.[Chua CLL et al]
Malaria during preganancy is estimated to cause approximately 900,000 low birth weight deliveries annually, with an estimated 100,000 infant deaths related to malaria during preganancy. Apart from high mortality risk, there is also increased morbidity in the surviving low birth weight infants, who are at elevated risk of poor cognitive and social development. Low birth weight due to fetal growth restriction, the cause of small for gestational age, is linked to increased incidence of adult diseases including type 2 diabetes and cardiovascular diseases. Hence, the prevention of low birth weight related to malaria during preganancy remains a priority in research.[Chua CLL et al]
Malaria in Pregnancy: Pathogenesis and Immunity
[Source: Chua CLL et al]
P. falciparum-infected erythrocytes adhere to endothelial and placental receptors, thereby sequester in the placenta, leading to placental infection and inflammation. Histological sections of P. falciparum-infected placentas reveal the presence of infected erythrocytes, particularly at the surface of the syncytiotrophoblast, which is the main site of exchange for nutrient, waste and other metabolites between maternal and fetal circulations. The binding is mediated by their expression of variant surface antigens (VSA). Placental-binding parasites express VAR2CSA, a major VSA that is mainly expressed during pregnancy, and they bind specifically to the placental receptor known as chondroitin sulfate A (CSA). Therefore, prior to pregnancy, antibodies against placental-binding infected erythrocytes are uncommon, predisposing primigravidas to the adverse effects of malaria. In subsequent pregnancies, the protective anti-VAR2CSA antibodies can be naturally acquired in a gravidity-dependent manner and have been demonstrated to be effective against malaria in pregnaancy and its consequences, thus preventing low birth weight. However, the specific antigenic targets and mechanisms of protection remain unclear. [Chua CLL et al]
Malaria in Pregnancy : Double Trouble
- Malaria is more common in pregnancy compared to the general population. Immuno suppression and loss of acquired immunity to malaria could be the causes.
- In pregnancy, malaria tends to be more atypical in presentation. This could be due to the hormonal, immunological and hematological changes of pregnancy.
- Due to the hormonal and immunological changes, the parasitemia tends to be 10 times higher and as a result, malaria tends to be more severe in pregnancy compared to the non-pregnant population.
- Malaria in pregnancy being more severe, also turns out to be more fatal, the mortality being double (13 %) in pregnant compared to the non-pregnant population (6.5%).
- 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.
- 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.
Role of Placenta, the NEW ORGAN of pregnancy:
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.
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
Atypical manifestations of malaria are more common in pregnancy, particularly in the 2nd half of pregnancy.
Fever: Patient may have different patterns of fever – from afebrile to continuous fever, low grade to hyper pyrexia. In 2nd 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 2nd 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.
Complications of malaria in pregnancy:
Anemia: Malaria can cause or aggravate anemia. It could be due to the following causes:
- Hemolysis of parasitised red blood cells.
- Increased demands of pregnancy.
- Profound hemolysis can aggravate folate deficiency.
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:
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 2nd and 3rd 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.
It is aggravated by pre existing anemia and hemodynamic changes of pregnancy.
Acute pulmonary oedema carries a very high mortality.
This is another complication of malaria that is peculiarly more common in pregnancy. The following factors contribute to hypoglycemia:
- Increased demands of hypercatabolic state and infecting parasites.
- Hypoglycemic response to starvation.
- Increased response of pancreatic islets to secretory stimuli (like quinine) leads to hyperinsulinemia and 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.
Risks for the foetus:
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: Congenital malaria due to transplacental or peripartal infection of the fetus is being increasingly reported in has been reported in 8–33% of pregnancies from both malaria-endemic and nonendemic areas.[9-15] It has been reported following maternal infections with all four species of human plasmodium, althighu most cases are reported following P. falciparum or P. vivax malaria.[5,16,17] In nonendemic countries, P. malariae may cause a disproportionately higher number of congenital malaria cases due to its longer persistence in the host. [Also See]
In endemic areas symptomatic malaria in the neonate is rare, despite a high incidence of maternal parasitemia and placental malaria, as maternally derived IgG and the high proportion of fetal hemoglobin inhibit parasite development.[16,17] In endemic areas a high prevalence of neonatal parasitemia has been reported, with majority of the parasitemic newborns being asymptomatic; however, the mortality was found to be higher in the parasitemic newborns compared with the aparasitemic and in the symptomatic compared with the asymptomatic.[11-15] On the other, infants born to nonimmune mothers with malaria at the time of labour may develop parasitemia and illness in the first few weeks of life. Congenital malaria usually manifests between the second and eighth weeks of life (as early as 1 day or delayed by weeks or months) with symptoms such as fever, anorexia, lethargy, anemia, and hepatosplenomegaly etc. Features suggestive of neonatal sepsis such as irritability, poor feeding, regurgitation, loose stools, jaundice, and occasionally drowsiness, restlessness, and cyanosis, may also be seen. However, complications seen in nonimmune adults have not been reported in congenital malaria.
The diagnosis of congenital malaria 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.
P. vivax malaria in pregnancy:
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:
Management of malaria in pregnancy involves the following three aspects and equal importance should be attached to all the three.
- Treatment of malaria
- Management of complications
- Management of labour
Treatment of malaria: [See Treatment of Malaria in Pregnancy]
Treatment of malaria in pregnancy should be energetic, anticipatory and careful.
- Don’t waste any time.
- It is better to admit all cases of P. falciparum malaria.
- Assess severity- General condition, pallor, jaundice, BP, temperature, hemoglobin, Parasite count, SGPT, S. bilirubin, S. creatinine, Blood sugar.
Anticipatory: Malaria in pregnancy can cause sudden and dramatic complications. Therefore, one should always be looking for any complications by regular monitoring.
- Monitor maternal and fetal vital parameters 2 hourly.
- RBS 4-6 hourly; hemoglobin and parasite count 12 hourly; S. creatinine; S. bilirubin and Intake / Output chart daily.
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.
- Choose drugs according to severity of the disease/ sensitivity pattern in the locality.
- Avoid drugs that are contra indicated
- Avoid over / under dosing of drugs
- Avoid fluid overload / dehydration
- Maintain adequate intake of calories.
Anti malarials in pregnancy:
All trimesters: Chloroquine; Quinine
2nd trimester: Mefloquine; Pyrimethamine / sulfadoxine; Artesunate / Artemether / Arteether
3rd trimester: Mefloquine; ?Pyrimethamine / sulfadoxine; Artesunate / Artemether / Arteether
Contra indicated: Primaquine; Tetracycline; Doxycycline; Halofantrine
Management of complications:
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.
Anemia: Packed cells should be transfused if hemoglobin is <5g%.
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 3rd generation 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).
Management of labour:
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 2ndstage by forceps or vacuum extraction. If needed, even caesarian section must be considered.
In pregnancy, use of primaquine is contraindicated. 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 delivery. At that point, a complete treatment with full therapeutic dose of chloroquine and primaquine should be administered.
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
Also see Chemoprophylaxis
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