MALARIA in PREGNANCY

Prof.M.C.Bansal.Founder principal & Controller ;

Jhalawar Medical college And Hospital, Jhalawar.Ex. Principal & collenter;

Mahatma Gandhi Medical College And Hospital,Sitapura, Jaipur

INTRODUCTION

• Malaria is a protozoal disease transmitted by bite of infected female Anopheles mosquito.

• It is Most important parasitic infestation in humans with a transmission in 109 countries containing 3 billion people and responsible for 1 – 3 million deaths per year.

EPIDEMIOLOGY

There were an estimated 247 million malaria cases among 3.3 billion people at risk in 2006, causing nearly a million deaths, mostly of children under 5 years.

Nearly 2.48 million malaria cases are reported annually from South Asia of which 75% cases are contributed by India alone. . In Africa, perinatal mortality due to malaria is at about 1500/day.

Plasmodium vivax is the predominant malarial parasite in India accounting for 50.4- 56.4% cases in the last five years.

Falciparum malaria is the more severe variant of malaria in the region.

The states most affected in INDIA are UP, Bihar, Karnataka, Orissa, Rajasthan, Madhya Pradesh & Pondicherry

MALARIA

Malaria in pregnant women• >50 million pregnant women exposed to

malaria each year.• ~3.5 million pregnant women infected

Poor birth outcomesPoor maternal outcome.

• Pregnant women constitute the main adult

risk group for malaria.

Gravidity and malaria

• Primigravida have no pre-existing immunity to placental parasites and are highly susceptible.

• In high transmission areas, primigravida develop immunity to placental parasites and are protected in subsequent pregnancies.

• In low transmission areas, multigravida are unexposed and unprotected

ANOPHELES Mosquito

MALARIA

THE VECTOR…

ANOPHELES CULICIFACIES (RURAL)

ANOPHELES STEPHENSI (URBAN)

Life Cycle of Anopheles

They choose their victim by odor. Males are more frequently bitten. Most common time of bite is late evening to early

morning with peak at midnight. Stylets cut & proboscis probe for tiny blood vessels

in the skin. If it does not strike blood proboscis is withdrawn and struck again at different angle.

They can fly for few Km. Their life span is 2–3 weeks. Human blood is needed to lay eggs and nourish

eggs.

SOME FACTS ABOUT ANAPHELES…..

Transmission…

Bite of infected mosquito.

Congenitally acquired disease.

Blood transfusion.

Sharing of contaminated needles.

Organ transplantation.

CAUSATIVE ORGANISM…PlasmodiumApicomplexa group of protozoa, havespecialized complex of apical organellesinvolved in host cell invasion.

More than 120 species are present but only 4 are capable of causing HUMAN MALARIA.

p. Vivax

p. falciparum

p. Malariae

p. oval

LIFE CYCLE OF PLASMODIUM

• PRIMARY / DEFINITIVE HOST – MOSQUITO

• SECONDARY / INTERMEDIATE HOST - HUMAN

Malaria in Pregnancy : Double Trouble

• Malaria is more common in pregnancy compared to the general population.

• Malaria in pregnancy tends to be more atypical in presentation. This could be due to the hormonal, immunological and hematological changes of pregnancy.

• The parasiteamia tends to be 10 times higher.• P. falciparum malaria in pregnancy being more

severe, the mortality is also double (13 %) compared to the non-pregnant population (6.5%).

Pathogenesis of malaria in pregnancy

• During normal pregnancy, the cellular immune response (Th1) is suppressed to prevent fetal rejection.

• Malaria stimulates the Th1 response intrauterine growth retardation.

• Malaria stimulates expression of an HIV co-receptor (CCR5) in the placenta.

• Various hypotheses have been put forth to explain the pathophysiology of malaria in pregnancy.

The general immunosupression of pregnancy

Reduced lymph proliferative response

Elevated levels of serum cortisol

To prevent the fetal rejection

Renders the pregnant woman susceptible to infestations

(This does not explain the diminished susceptibility to malaria experienced by multigravid women.)

HYPOTHESIS -1

HYPOTHESIS - 2• Placenta is a new organ in the primigravida 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 multigravida.

• It has been discovered that multigravida women can form strain-independent antibodies against CSA-specific parasites, and they demonstrate greatly diminished parasite load.

Hypothesis - 3

• 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.

• 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.

Effects of malaria on pregnant women

MATERNAL EFFECTS:• Hyperpyrexia• Hemolytic anemia• Lactic acidosis• Folate deficiency• Bleeding disorders including DIC• Hypoglycemia• Acute renal failure• Acute pulmonary edema• Cerebral malaria:seizures,delirium• Jaundice• Hepatitis• Hepatic failure• Post partum haemorrhage• Circulatory collapse• Fluid and electrolyte imbalance• Blackwater fever• Yellow fever• Death

FETAL AND PERINATAL EFFECTS:

• High risk of abortion• Higher incidence of preterm delivery• Intrauterine growth retardation• Low birth weight• Intrauterine fetal demise• Congenital malaria• Failure to thrive• High perinatal morbidity and mortality

EFFECT OF PREGNANCY ON MALARIA

• Pregnancy is an immunocompromised state therefore the hazards of malaria increases.

• Frequency of infection is high during advanced pregnancy.

• Severity of infection is higher in primigravida.• Higher morbidity because of complications

following malaria during pregnancy.

Role of Placenta, the NEW ORGAN of pregnancy:

• Incidence of placental involvement during pregnancy in women living in endemic areas varies between 16 to 60%.

• P. falciparum has the unique ability of cytoadhesion.• Chondroitin sulfate A and hyaluronic acid have been identified as the

adhesion molecules for parasite attachment to placental cells.• 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.

• 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.

Placental malaria

CLINICALMICROSCOPY

IMMUNOLOGY

MOLECULAR

SEROLOGY

DIAGNOSIS OF

MALARIA

PROGNOSTIC PARAMETERS

• Parasitemia >5%• Packed cell volume <30%• Hemoglobin <7.1 gm%• Hypoglycemia :blood glucose <40 mg%• Low levels of glucose in cerebrospinal fluid• Raised venous lactic acid >60 m.mol/L• Low level of antithrombin 3• Peripheral schizontemia• Increased plasma S-nucleotides• Serum creatinine >3.0mg%• Blood urea >60.0mg%

CLINICAL FEATURE• Atypical manifestations of malaria are more common in

pregnancy, particularly in the 2nd half of pregnancy.

• Severity of the disease depends on the species of invading Plasmodium parasite ,the intensity of parasitemia , the extent of host resistance & the speed of diagnosis and implement of effective therapy.

• The three stages. The cold stage The hot stage The sweating stageIt is followed by another similar attack in 24-48 hours.

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

• Anemia: Most common feature of malaria in pregnancy.

• Splenomegaly: Enlargement of the spleen may be variable. It may be absent or small in 2nd half of pregnancy.

• Other symptoms besides fever with rigors include headache,malaise,nausea and vomiting,delirium,hemolytic jaundice,cachexia.

MICROSCOPIC DIAGNOSISLight microscopy of thick and thin films by a skilled microscopist – gold standered

Thick film- diagnosis of malaria, more sensitiveThin film- species identification

Sample can be collected any time irrespective of fever but before administration of antimalarials

For best results film should be made soon after collection and in case of anticoagulant within 2 hrs

Smear should be examined with 100x oil immersion objective lense 3 times before concluding it negative

BENEFITS OF MICROSCOPY

1) Skilled microscopist pick up 5-10 parasite/ml of blood.

2) species identification along with stage of parasite.

3) determines parasite density.

4) Malarial pigment in neutrophil & monocytes (in profound anemia).

DISADVANTAGES OF MICROSCOPY

1) Time consuming .

2) Skilled technician & infrastructure required.

3) Deep sequestered parasite not deleted.

4) In mixed infection often one species suppresses.

other making detection of suppressed one difficult.

RAPID DIAGNOSTIC TESTS ( RDTs )Immunochromatographic tests to detect plasmodium specific antigens in blood

Employ monoclonal antibodies directed against targeted parasite antigens

Currently available rapid Diagnostic Tests are as follows –

Histidine rich protein ii ( HRP-II ) : asexual stages and young gametocytes of p.Falciparum

Parasite lactate dehydrogenase (pLDH) : p.Vivex , p.Falciparum , all 4 plasmodiaPlasmodium aldolase – all 4 plasmodia

Performance characteristic of RDTs Sensitivity

WHO- A MINIMUM STANDARD OF 95% SENSITIVITY FOR P.FALCIPARUM DENSITIES OF 100 PARASITES/L OF BLOOD AND A SPECIFICITY OF 95%

HRP-II with parasite density 100/ml of blood -90% - with 10/ml -75%

HRP-II remain positive for 1-3wk.

p LDH remain positive for 5 days.

BENEFITS OF RDTs

NOT MUCH TRAINING REQUIRED

EASY TO INTERPRIT

DOES NOT NEED ELECTRICITY

RAPID RESULT

GOOD FOR FAR REACH HEALTH CARE FACILITIES WHERE MICROSCOPIC DIAGNOSIS IS NOT POSSIBLE

IN SEVERE COMPLICATED MALARIA WITH NEGATIVE PERIPHERAL PARASITAEMIA DUE TO SEQUESTRATION

DISADVANTAGES OF RDTs1)Cannot distinguish new infection from old

2) Do not quantify parasite load .

3) Detection threshold 40-60 parasites/ml.

4) Storage problem.

5) cost.

6) Cross-reactions with autoantibodies

7) False positive & false Negative results

MOLECULAR METHODS

DNA PROBES .

DOT BLOT ASSAY .

PCR AMPLIFICATION.

MASS SPECTROMETRY

FLOW CYTOMETRY

SEROLOGICAL TEST INDIRECT IMMUNOFLUROSCENCE

(using quantitative buffy coat – QBC )

Detect I'm, Gig, IgA.

Indirect haem agglutination .

ELISA

RIA

Complications

• 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.• It 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:-

• It may be the presenting feature or can develop suddenly after several days.

• More common in 2nd and 3rdtrimesters.• 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.

• Aggravated by pre existing anemia and hemodynamic changes of pregnancy.

• It carries a very high mortality.

Hypoglycemia:

• It is also more common in pregnancy. • Contributing factors:

- Increased demands of hyper catabolic state and infecting parasites.- Hypoglycemic response to starvation.- Increased response of pancreatic islets to secretory stimuli (like quinine) leads to hyper insulinemia 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.

Immuno suppression:-• It makes malaria more common and more severe.• 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 many infection and also malaria.

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

Congenital malaria:

• It is due to transplacental or peripartal infection of the fetus is being increasingly reported in 8–33% of pregnancies from both malaria-endemic and non endemic areas.

• Most cases are following P. falciparum or P. vivax malaria.• Infants born to non immune 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.

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

• Certain drugs are contraindicated 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 contraindicated.• Avoid over / under dosing of drugs• Avoid fluid overload / dehydration• Maintain adequate intake of calories.

ANTIMALARIAL IN PREGNANCY

• All trimester –Chloroquine,Quinine,Artesunate,Artemether, Artether.

• Second trimester-Mefloquine,Sulfadoxin.• Third trimester-Mefloquine,Sulfadoxin.

• Contraindication-Primaquine,Tetracycline,Doxycycline, Maloprim,Paludrin,Mefloquine,Halofentrin, Artemesinine.

TREATMENT OF UNCOMPLICATED MALARIA

SEVERITY INDICATION DOSES

UNCOMPLICATED MALARIA

P.FALCIPARUM Oral quinine 600 mg 8hourly and oral Clindamycin 450 mg 8 hourly for 7 days (can be given together)

Or Atovaquone –Proguanil 4 tab daily for 3 days

• Chloroquine -10mg base /kg perorally followed by 10mg/kg at 24 hours and 5.0 mg base /kg at 48 hrs.

• For radical care Primaquine is prescribed after delivery .

• Alternatively,Quinine 10 mg/kg po every 8 hours for 7 days.

TREATMENT OF COMPLICATED MALARIA

SEVERITY INDICATION DOSESSEVERE OR COMPLICATED MALARIA

ANY PLASMODIUM ARTESUNATE iv 2.4mg/kg at 0,12,24 hr than daily artether when patient is well enough to take oral medication.She can be switched to oral artesunate 2mg/kg once a day plus clindamycin or quinine and clindamycin 450 mg TDS for 7 days.

ANY SPECIES QUININE iv 20mg/kg loading dose(no loading dose if patient took oral quinine or mefloquine)in 5%Dextrose over 4 hours than 10 mg/kg iv over 4 hours in every 8 hours and Clindamycin 450 mg in every 8 hours(max dose of quinine is 1.4 gms).When the patient is well enough to take orally switch on 600 mg oral quinine TDS to complete 5-7 days and oral clindamycin 450 mg TDS for 7 days.

TREATMENT OF COMPLICATED MALARIA

• Chloroquine -10mg base/kg iv over 8hrs,followed by 15 mg base/kg over 24 hours.

• Alternatively consider Quinine salt 20 mg/kg iv infusion over 4 hrs every 8 hrly until oral intake become permissible.

• Complete 7 days treatment in all.• Patient with severe anaemia(Hct <20)require

packed cell transfusions.

MANAGEMENT OF COMPLICATION

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• 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. • 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 2nd stage by forceps or vacuum extraction.

• If needed, even caesarian section must be considered

SUPPORTIVE MANAGEMENT

Household spraying

• Anophelies rest on walls and ceiling after blood meal

• DDT is best: – Affordable, effective, safe

• Requires too much infrastructure for poor countries

Insecticide Treated Nets• Bednets impregnated

with permethrin insecticide.– Need retreatment every 6

months– New “permanets” do not

need retreatment• Act as human-baited

mosquito traps and are better with high coverage

THANK YOU

Pathophysiology

• 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 ant malaria immunity is transferred to the child!) Various hypotheses have been put forth to explain the pathophysiology of malaria in pregnancy.

• Some anti malarial 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 labor may be difficult and complex. Fetal loss, IUGR, and premature labor are common.

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 bednests.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.