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Summary Table

Category	Details
Risk Factors	Pregnant women living in or traveling to endemic areas (Papua, Sumba, East Kalimantan in Indonesia); primigravida (first pregnancy) at highest risk due to lack of pregnancy-associated placental immunity; HIV coinfection; adolescent mothers
Etiology	Plasmodium falciparum (most dangerous, causes placental sequestration), P. vivax (causes maternal anemia, relapse risk from hypnozoites). Transmitted via Anopheles mosquito bite.
Patient Presentation	Fever or history of fever, anemia out of proportion to gestational age, splenomegaly. May present with preterm labor, intrauterine growth restriction, or stillbirth.
Classic Physical Exam	Fever (paroxysmal or continuous), pallor (conjunctival/palmar), splenomegaly, hepatomegaly, jaundice. In severe cases: altered consciousness, respiratory distress, hypoglycemia.
Key Diagnostic Results	Peripheral blood smear (thick and thin film) showing parasitemia with species identification; RDT positive for HRP-2 or pLDH; anemia on CBC; thrombocytopenia
Management	All trimesters: DHP (Dihydroartemisinin-Piperaquine) for 3 days. No primaquine. No doxycycline. No tetracycline. Artesunate IV for severe malaria. Iron supplementation continued. Insecticide-treated bed nets.
Keywords	"Pregnant woman from endemic area with fever and anemia," "placental sequestration," "low birth weight," "no primaquine in pregnancy," "artesunate IV for severe malaria in pregnancy"

1. Pathophysiology

Malaria in pregnancy represents a unique pathophysiological state because the placenta creates a new immunological niche that P. falciparum exploits. Infected erythrocytes express VAR2CSA, a variant of Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) that binds to chondroitin sulfate A (CSA) on the syncytiotrophoblast surface. This allows parasitized red blood cells to accumulate in the intervillous space of the placenta, a process called placental sequestration. Because of this, peripheral blood parasitemia may underestimate the true parasite burden, as a large proportion of the parasites are hidden in the placenta rather than circulating.

Placental sequestration triggers a local inflammatory response with monocyte and macrophage infiltration into the intervillous space, leading to chronic intervillositis. This inflammatory infiltrate, combined with fibrin deposits and parasitized erythrocyte accumulation, physically impairs nutrient and oxygen transfer across the placenta. The result is intrauterine growth restriction (IUGR) and low birth weight (LBW), which are the primary mechanisms by which malaria increases neonatal mortality.

Maternal anemia in malaria in pregnancy results from multiple converging mechanisms: direct hemolysis of parasitized erythrocytes, bystander destruction of uninfected erythrocytes (which are altered and tagged for splenic clearance), dyserythropoiesis from bone marrow suppression by inflammatory cytokines (TNF-alpha, IFN-gamma), and splenic sequestration. This anemia compounds the physiological hemodilution of pregnancy, making pregnant women especially vulnerable to severe anemia (Hb <7 g/dL).

Primigravidae are disproportionately affected because they lack antibodies against VAR2CSA. In subsequent pregnancies, women develop anti-VAR2CSA IgG that partially blocks placental binding, making multigravidae relatively protected. This is why the exam will often present a first pregnancy in the vignette as a risk factor clue.

Hypoglycemia is more common and more dangerous in pregnant women with malaria than in non-pregnant adults because of the combined effect of increased glucose consumption by the parasite, quinine-induced hyperinsulinemia (if quinine is used), and the increased metabolic demand of pregnancy itself. This makes glucose monitoring a non-negotiable part of managing severe malaria in pregnancy.

P. vivax in pregnancy, while generally less severe, still causes meaningful maternal anemia and is associated with preterm birth and LBW. The relapse risk from hepatic hypnozoites poses a unique challenge because primaquine is contraindicated in pregnancy, so radical cure must be deferred until after delivery and breastfeeding (if breastfeeding an infant <6 months).

2. Classification and Clinical Manifestation

Maternal Complications

Complication	Mechanism	Clinical Feature
Severe anemia	Hemolysis + dyserythropoiesis + splenic sequestration	Pallor, tachycardia, fatigue, high-output cardiac failure in extreme cases
Hypoglycemia	Parasite glucose consumption + pregnancy metabolic demand + quinine-induced insulin secretion	Altered consciousness, seizures, diaphoresis (may be mistaken for cerebral malaria)
Cerebral malaria	Sequestration of parasitized RBCs in cerebral microvasculature	GCS <11, seizures, coma
Pulmonary edema/ARDS	Increased vascular permeability from systemic inflammation + iatrogenic fluid overload	Dyspnea, SpO2 <92%, bilateral infiltrates
Acute kidney injury	Hemoglobinuria, reduced renal perfusion, tubular necrosis	Oliguria, elevated creatinine (>3 mg/dL)
Splenic rupture	Splenomegaly from chronic parasitemia + physical trauma	Acute abdomen, hemodynamic instability (rare but lethal)

Fetal/Neonatal Complications

Complication	Mechanism
Low birth weight	Placental insufficiency from sequestration and intervillositis
Intrauterine growth restriction	Impaired placental nutrient/oxygen transfer
Preterm delivery	Systemic inflammation triggering prostaglandin release and uterine contractions
Stillbirth	Severe placental dysfunction, maternal hyperpyrexia, severe anemia
Congenital malaria	Transplacental passage of parasitized erythrocytes (uncommon but recognized)
Spontaneous abortion	Especially in first trimester with high parasitemia

Classification by Severity

Category	Definition	Key Criteria
Uncomplicated malaria in pregnancy	Positive blood smear or RDT, symptomatic, no signs of severity, able to take oral medication	Fever, anemia (Hb ≥7 g/dL), no organ dysfunction
Severe malaria in pregnancy	Positive blood smear with at least one WHO severity criterion	GCS <11, severe anemia (Hb <7 g/dL), hypoglycemia (<40 mg/dL), jaundice (bilirubin >3 mg/dL with parasitemia >100,000/uL), AKI (creatinine >3 mg/dL), pulmonary edema, hyperparasitemia, metabolic acidosis (bicarb <15 mmol/L), shock (SBP <80 mmHg)

3. Diagnostic Workup

Test	Role	Key Finding
Thick blood smear	Best initial test for detection	Presence of parasites (higher sensitivity for low parasitemia)
Thin blood smear	Species identification and staging	Identifies P. falciparum vs. P. vivax, quantifies parasitemia (%)
RDT (HRP-2 / pLDH)	Point-of-care screening when microscopy is unavailable	Positive for P. falciparum antigen; note that HRP-2 can remain positive up to 28 days after treatment, so it cannot be used for treatment evaluation
CBC	Baseline and monitoring	Anemia (low Hb/Hct), thrombocytopenia
Blood glucose	Rule out hypoglycemia (critical in pregnancy)	<40 mg/dL defines hypoglycemia in severe malaria
Renal function (BUN/Creatinine)	Assess for AKI	Creatinine >3 mg/dL or urea >20 mmol/L
Liver function (SGOT/SGPT, bilirubin)	Assess for hepatic involvement/jaundice	Elevated bilirubin >3 mg/dL with high parasitemia suggests severe malaria
Lactate	Severity marker	>5 mmol/L indicates severe disease
Blood gas	Assess metabolic acidosis	Bicarb <15 mmol/L
PCR	Confirmatory for species (especially P. knowlesi)	Gold standard for species differentiation, but not routinely available

Microscopy (thick and thin film) remains the gold standard for malaria diagnosis. The thick film is used for detection because it concentrates parasites across a larger blood volume, while the thin film allows species identification and parasitemia quantification. In pregnancy, serial blood films are important because placental sequestration can make peripheral parasitemia falsely low in P. falciparum infection.

RDT is used when microscopy is not available or when rapid results are needed for emergency treatment. The key limitation for exam purposes: RDT detects circulating antigens (HRP-2 for P. falciparum), and these antigens persist in the blood up to 28 days after successful treatment. Maka, RDT cannot be used to evaluate treatment response. Only microscopy can confirm parasite clearance.

In daerah endemis, the Buku Saku recommends screening all pregnant women with microscopy or RDT as early as possible. This is a test-writer favorite: the concept that pregnant women in endemic areas should be screened even if asymptomatic, because semi-immune individuals may harbor subclinical parasitemia that still causes placental damage.

For suspected severe malaria in pregnancy, the workup expands to include CBC, blood glucose, renal and liver function, lactate, blood gas, and chest X-ray if pulmonary edema is suspected.

4. Management and Treatment

Scenario	Treatment	Key Notes
Uncomplicated malaria, all trimesters	DHP (Dihydroartemisinin-Piperaquine) oral for 3 days, dose by body weight	No primaquine. No doxycycline. No tetracycline.
Severe malaria in pregnancy	Artesunate IV 2.4 mg/kg at 0, 12, 24 hours, then every 24 hours until oral intake is possible, then switch to DHP oral for 3 days	Same dosing as non-pregnant adults. Treat in ICU or high-dependency setting.
Pre-referral (no IV access/facility)	Artesunate IM or oral DHP single dose, then refer immediately	Do not delay referral; give the first dose and transfer
Vivax in pregnancy	DHP for 3 days. Defer primaquine until after delivery and cessation of breastfeeding (if infant <6 months)	Hypnozoites persist; relapse risk remains until primaquine can be given postpartum
Adjunctive	Continue iron/folate supplementation. Insecticide-treated bed nets.	Bed nets reduce re-infection risk

Uncomplicated Malaria

Per the Buku Saku Kemenkes 2023, the current Indonesian national policy treats pregnant women with DHP for all trimesters (trimester I through III). This is a notable update, as older guidelines restricted ACT use in the first trimester. The WHO 2022 guidelines also now support ACT use throughout pregnancy based on safety data.

The DHP dose is weight-based and follows the same dosing table as for non-pregnant adults. For example, a woman weighing 40-60 kg receives 3 tablets of DHP per day for 3 days (each tablet containing Dihydroartemisinin 40 mg + Piperaquine 320 mg).

Primaquine is absolutely contraindicated in pregnancy due to the risk of hemolytic anemia in a G6PD-deficient fetus. This is a high-yield exam point. Similarly, doxycycline and tetracycline are contraindicated because of fetal tooth discoloration and bone growth inhibition.

For P. vivax or P. ovale infections, DHP clears the erythrocytic-stage parasites, but hypnozoites in the liver cannot be eliminated during pregnancy. The patient must be counseled about relapse risk, and primaquine should be given postpartum once the infant is >6 months old or if the mother is no longer breastfeeding an infant <6 months.

Severe Malaria

Treatment is identical to non-pregnant adults: Artesunate IV at 2.4 mg/kg given at hours 0, 12, and 24, then every 24 hours until the patient can tolerate oral medication, at which point she is switched to oral DHP for 3 days. The minimum parenteral course is 3 doses (24 hours).

Critical supportive care considerations:

Hypoglycemia must be actively monitored. Blood glucose should be checked every 4-6 hours. If GDS <40 mg/dL with altered consciousness, administer Dextrose 40% 50 mL IV diluted 1:1, followed by Dextrose 5-10% maintenance drip. In children, use Dextrose 10% at 2 mL/kg bolus.

Fluid management follows the "keep slightly dry" principle. The recommended volume is NaCl 0.9% at 1-2 mL/kg/hour, with strict intake-output monitoring. Ringer Lactate is not recommended. Bolus fluids are contraindicated in malaria (both colloid and crystalloid) because of the high risk of pulmonary edema from capillary leak. If MAP <65 mmHg (shock), give NaCl 0.9% at 5 mL/kg as a cautious bolus with vasopressor support.

Anemia management: Transfuse PRC if Hb <7 g/dL with signs of hemodynamic compromise. Be careful of volume overload; give furosemide if there are signs of pulmonary edema.

Antibiotics can be considered in severe malaria with hyperparasitemia, AKI, acidosis, or shock, as co-infection with bacterial sepsis is common and difficult to distinguish clinically.

All antimalarial drugs should be taken after eating to reduce gastric irritation.

5. Differential Diagnosis and Distractors

Differential	Why It Mimics Malaria in Pregnancy	Key Discriminator
Dengue fever	Fever, thrombocytopenia, headache, myalgia in endemic tropical area	Dengue: hemoconcentration (rising Hct), positive NS1/IgM serology, no parasitemia on blood smear, rash, retro-orbital pain. Malaria: parasites on smear, splenomegaly more prominent.
Typhoid fever	Prolonged fever, hepatosplenomegaly, travel to endemic area	Typhoid: stepladder fever pattern, relative bradycardia, rose spots, positive blood/stool culture (Salmonella typhi), Widal titer. No parasites on smear.
Leptospirosis	Fever, jaundice, thrombocytopenia, renal dysfunction	Leptospirosis: conjunctival suffusion, calf tenderness, exposure to contaminated water, positive leptospira serology. Jaundice in malaria requires high parasitemia (>100,000/uL).
Acute viral hepatitis	Fever, jaundice, elevated transaminases	Hepatitis: ALT/AST elevation typically much higher (>1000 IU/L), positive viral markers (HBsAg, anti-HAV IgM, anti-HCV), no parasitemia.
HELLP syndrome	Hemolysis, thrombocytopenia, elevated liver enzymes in pregnancy	HELLP: occurs in 3rd trimester, associated with hypertension/proteinuria (preeclampsia), schistocytes on peripheral smear, no parasites on blood film, LDH markedly elevated.
Preeclampsia/Eclampsia	Seizures and altered consciousness in pregnancy (mimics cerebral malaria)	Eclampsia: hypertension (BP ≥140/90), proteinuria, edema, seizures typically after 20 weeks. No parasitemia, no cyclical fever.
Sepsis	Fever, tachycardia, hypotension, altered consciousness, organ dysfunction	Sepsis: identifiable source of infection (UTI, pneumonia, chorioamnionitis), positive blood cultures, procalcitonin elevated, no parasitemia. Can coexist with severe malaria.

6. Traps and High-Yield Pearls

Trap 1: Primaquine in pregnancy. The most common error is selecting primaquine as part of the treatment regimen. Primaquine is contraindicated throughout pregnancy (risk of fetal hemolysis in G6PD deficiency), in breastfeeding mothers of infants <6 months, and in infants <6 months. For vivax or ovale infections in pregnancy, you treat with DHP only and defer radical cure with primaquine to the postpartum period.

Trap 2: Assuming first-trimester ACT restriction still applies. Older guidelines restricted artemisinin-based therapies in the first trimester due to limited safety data. The current WHO 2022 guidelines and the Indonesian Buku Saku 2023 both recommend DHP for all trimesters. If a question presents a first-trimester pregnant woman with confirmed malaria, the answer is DHP, not quinine.

Trap 3: Using RDT to evaluate treatment response. RDT detects circulating antigen (HRP-2), which persists up to 28 days after parasite clearance. A positive RDT after treatment does not mean treatment failure. Only microscopy can confirm whether parasites have been cleared.

Trap 4: Underestimating severity because peripheral parasitemia is low. In P. falciparum malaria in pregnancy, parasitized erythrocytes sequester in the placenta. A woman may have a seemingly low peripheral parasitemia but harbor a very high placental parasite burden. If the clinical picture suggests severe disease (altered consciousness, severe anemia, hypoglycemia), treat as severe malaria regardless of the peripheral parasite count.

Trap 5: Fluid bolus in severe malaria. Bolus IV fluids (both colloid and crystalloid) are contraindicated in malaria because of the high risk of precipitating pulmonary edema. The correct approach is cautious maintenance fluids at 1-2 mL/kg/hour with NaCl 0.9%. This is a frequently tested concept because it contradicts the standard sepsis resuscitation protocol.

Trap 6: Forgetting hypoglycemia. Pregnant women with severe malaria are at particularly high risk of hypoglycemia. If a pregnant patient with cerebral malaria does not respond to antimalarials, the next best step is to check blood glucose before assuming treatment failure. Hypoglycemia can mimic cerebral malaria and is immediately reversible with dextrose.

Core competency being tested: The exam tests your ability to (1) select the correct antimalarial that is safe in pregnancy while avoiding contraindicated drugs, (2) recognize severity criteria that mandate parenteral treatment and ICU-level care, (3) understand that placental sequestration makes peripheral smear an unreliable marker of true parasite burden, and (4) manage the unique complications of malaria in pregnancy (hypoglycemia, severe anemia, fluid restriction) without defaulting to standard non-pregnant adult protocols.

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