Malaria in Pregnancy

This review summarizes the epidemiology, clinical course, and diagnosis of malaria. The influence of infection during pregnancy upon maternal and neonatal anemia, stillbirth, preterm labor, low birth weight, and congenital malaria is discussed. Options for treatment and prophylaxis during pregnancy are presented.

The female Anopheles ingests gameocytes during a blood meal, MOSQUITO Sporogenic Cycle: In the mosquito, the gametocytes initiate sexual reproduction resulting in the formation of sporozoites, Once formed, sporozoites moee into the salieary glands of the female mosquito, Some merozoites dev el op into male and female gametocytes, Eryhrocytic Cycle: Merozoites ie red blood cells to form schizos hich mure and release more merozoites to perpue the cy cl e, HUMAN Plasmoclial sporozoites are njectecl into the human bloodstream by an infected female Anophel es mosquito, Exo-Erythroctic Cycle: S porozoites nv ade hepatocytes and deeelop into schizonts that release merozoites into the bloodstream, have increased susceptibility to malaria when com- pared to multigravid women.This vulnerability oc- curs even in areas where malaria is endemic. 5he reason for the increased susceptibility in pregnancy has long been a topic of research.Postulated mechanisms include alterations in hormonal factors as well as changes in cell-mediated and humoral antibody responses.Recently, several investigators have found that a placental protein, chondroitin sulfate A (CSA), may play a role. 6,7Ma- laria-infected red blood cells produce surface pro- teins that allow them to bind to particular tissues.Fried and Duffy s have isolated red blood cells in- fected with P. falciparum from human placentas.These cells bind only to CSA and not to other known infected red blood cell receptors.These cells also bind to uninfected placentas in the same distribution as in naturally infected placentas.The authors propose that a woman becomes highly sus- ceptible to malarial infection during her initial pregnancy when she first provides the placental substrate CSA.This exposure selects CSA-binding parasites for growth.With subsequent pregnancies, the woman develops increasing immunity to the selected subpopulation, reducing the frequency and severity of infection.

COMPLICATIONS OF MALARIA IN PREGNANCY
A wide variety of complications can arise from ma- larial infection.Anemia is very common and occurs even in endemic regions.Abortion and premature delivery can occur in women without immunity.Intrauterine growth restriction, congenital malaria, and pcrinatal death are also risks.

Anemia
The prevalence of anemia is highest between 16 and 28 weeks' gestation, following the peak preva- lence of parasitemia. 9'1 Non-immune women will develop significant anemia with malarial infection.
The mechanism for the anemia is multifaceted.Immune-mediated hemolysis occurs in the peripheral circulation.In addition, red cells coated with immune complexes are cleared from the circulation by the spleen.Sequestration of infected erythrocytes in the spleen, liver, bone marrow, and placenta also decreases the hematocrit.The degree of splenomcgaly has been correlated with the severity of anemia in a study by Brabin et al. 3 Nutritional deficiencies further compound the anemia.Iron stores may be decreased by repeated pregnancies as well as inadequate diet.Folate de- ficiency with resulting megaloblasts occurs when the diet is unable to supply the increased demands of erythropoiesis.
Dyserythropoiesis is yet another potential con- tributor to the anemia observed in infected patients.This abnormal bone marrow response to anemia has been observed in children 11 and in- cludes erythroblast multinuclearity, karyorrhexis, incomplete and unequal amitotic nuclear division, and cytoplasmic bridging.
In addition to maternal anemia, malaria is also associated with fetal anemia.Brabin lz compared maternal and cord hemoglobin values in malaria- endemic and non-endemic regions.The range of maternal values in the population of pregnant women not exposed to malaria was 4.7-14.2g/dl.
The lowest cord value in this series of reports was 12.6 g/dl for a severely iron-deficient group of women (Hgb 4.7 g/dl).In contrast, in pregnant populations from malaria-endemic regions, cord hemoglobin values less than 13 were not uncom- mon and values as low as 7.4 g/dl were found in certain populations.Thus, it appears that exposure to malaria produces a degree of fetal anemia which seems greater than would be expected as a result of maternal iron deficiency alone.

Stillbirth
Malaria is associated with an increased risk of still- birth.While data to determine the precise mecha- nism of fetal death are lacking, several risk factors have been identified.Primigravidity is associated with stillbirth rates in excess of 10% in rural Gambia where malaria is endemic.For multigravidas, rates range from 0.9 to 6.9% in malaria-endemic areas.Other associated factors are hyperpyrexia, 14 severe anemia, placental parasitemia, and hypoglycemia.14 When placental infection occurs early in gestation, spontaneous abortion can result.

Preterm Labor
There is currently little data demonstrating a causal relationship between malaria and preterm labor.Studies from sub-Saharan Africa are often limited by imprecise estimates of gestational age.

Low Birth Weight
The prevalence of low birth weight (<2,500 g) in- fants in malaria-endemic areas ranges from 15 to INFECTIOUS DISEASES IN OBSTETRICS AND GYNECOLOGY 47 30%. 17,18Diverse factors are associated with the delivery of these small infants including environ- mental and demographic characteristics.Several studies have demonstrated that the prevalence of low birth weight infants is higher among primigravidas than multigravidas. 17,19aternal complications of Plasmodium infection such as anemia are also associated with low birth weight.Both the multifactorial nature of the problem and difficulty in accurate assessment of gesta- tional age make determination of the direct effect of malaria on birth weight elusive.
Contributions to abnormal growth by circulating malaria parasites, malaria-associated placental le- sions, and maternal anemia were evaluated by Meuris and colleagues. 17The prevalence of low birth weight was 15% in the total population; how- ever, in women without these factors, only 6.4% of infants had low birth weight.When both circulat- ing parasites and placental lesions were found at birth, the percentage of low birth weight was 25.9%, and rose to 29.2% when maternal anemia (Hgb < 10) was also present.
One theoretical explanation for the association between infection and fetal growth abnormalities is placental damage.Malaria infection causes a thick- ening of the trophoblastic basement mem- brane, e-ee Placental sinusoids are closely packed with parasitized red blood cells.This, together with an excess of intervillous macrophages and perivil- lous fibrin deposition, may be expected to cause microcirculatory obstruction and a reduction in nu- trients supplied to the fetus.

Congenital Malaria
Congenital malaria is defined as clinical malaria with peripheral parasitemia within 2 weeks of birth.It is important to note that this infection can be acquired by the fetus during the pregnancy (congenital) or during labor (perinatally).e3 The in- cidence of congenital malaria in infants of immune mothers in endemic areas is 0.3%, compared with 1-10% in infants of non-immune mothers in the 14 same area.
Symptoms include anorexia, irritability, nausea, vomiting, and jaundice, z3 Splenomegaly and asso- ciated thrombocytopenia are very common.The characteristics of congenital malaria can be modi- fied by maternal antibody status.Transplacental passage of maternal immunoglobulin in the third trimester can potentially prevent or result in milder or delayed disease in the neonate.The gradual dis- appearance of the antibodies allows for the acquisition of mosquito-transmitted disease by the in- fant in endemic areas.
Cerebral dysfunction is the most common se- vere manifestation of (P.falciparum) malaria in man.Symptoms can be gradual in onset or coma can follow a generalized convulsion.Other symptoms include delirium and focal "fits" without loss of consciousness, es Several hypotheses have been put forth to explain the disease process including sludging or obstruction of the cerebral vessels, as well as a breakdown of the vascular endothelium leading to cerebral edema.
Other complications of severe malaria infection include renal failure, adult respiratory distress syn- drome, and intravascular hemolysis.P. falciparum is usually the etiologic agent; other species rarely cause severe disease.
Fever and chills occur at the time of rupture of erythrocytes containing merozoites, z6 Cytokines, e.g., tumor necrosis factor-alpha (TNF-ot) and in- terleukin-1, are both thought to play a role in the systemic manifestations of the illness.Cytoadherence also plays a role in the establishment of severe disease.
Both acute infection with malaria and its therapy are associated with hypoglycemia, ls'16 Pregnancy is associated with an increased sensitivity of the pan- creatic 13 cells to stimulants for insulin release.
Therefore, pregnant patients are particularly sus- ceptible to hyperinsulinemia caused by quinine and quinidine.

Diagnosis
A fresh sample of blood should be obtained for both thin and thick smear preparations.For thin smears, Wright stains alone are not satisfactory; the addition of 3% Giemsa or Giemsa alone improves the parasite yield.In inexperienced hands, the thin smear may be easier to read.The thick smear, how- ever, provides the experienced technician higher sensitivity due to higher concentration of the para- sites.Several smears may be necessary to establish the diagnosis in women with low parasite density, e TREATMENT There are three basic principles which guide therapy: the infecting species, parasite density, and clinical status of the patient, z Early identification of the species is important because the illness caused by P. falciparum can progress rapidly.Pregnant women are at especially high risk; therefore, early and aggressive therapy is critical.In addition to giving a drug which rapidly kills the parasites, sup- portive therapy is very important.Fluid status and serum glucose need to be monitored.Daily blood smears should be obtained until negative.
Infections caused by P. vivax, P. ovale, and P. malariae should be treated with chloroquine.P. vivax and P. ovale both have dormant forms, re- ferred to as hypnozoites, which are asymptomatic.These forms are not susceptible to chloroquine and, therefore, in non-pregnant individuals a course of primaquine is added at the completion of the initial therapy.Prior to treatment with prima- quine, individuals at risk for glucose-6-phosphate deficiency should be evaluated.Those patients with <10% residual enzyme activity should not be treated due to the risk of hemolytic disease.
Primaquine can cause hemolytic disease in the fetus, so it is not recommended in pregnancy.Rather, the gravida should be maintained on pro- phylactic doses of chloroquine until delivery in an effort to prevent relapse during gestation.She can then be treated with primaquine in the postpartum period, e When infection is caused by P. falciparum, it is important to know if the infection was acquired in an area with reported chloroquine resistance.If the infection was acquired in an area without reported resistance, treatment with oral chloroquine is ad- equate.For infections thought to be caused by re-

Intravenous
Quinidine gluconate 10 mg base/kg p.o. followed by 10 mg base/kg p.o. at 24 h and 5 mg base/kg p.o. at 48 h 650 mg salt p.o. q 8 h x 3-7 days 450 mg p.o. q 8 h x 3 days 15 mg base/kg in a single dose 10 mg/kg loading dose over I-2 h 0.02 mg/kg/min continuous maintenance infusion aCQ chloroquine prophylaxis.bAntimalarial drug doses can be expressed in terms of either the base or the salt of the drug.Because dosages differ for the different forms, clinicians must specify the form desired.
sistant organisms, quinine and clindamycin can be used.Mefloquine is another alternative that can be used in pregnancy (Table 1).Little information is currently available on the use of artemisinin deriva- tives in pregnancy, however, their use is recom- mended for the treatment of mefloquine-resistant, P. falciparum infections after the first trimester, e7 Indications for intravenous therapy include in- ability to tolerate oral therapy and parasite density exceeding 5%.e Intravenous quinidine is given to maintain levels of 3-7 mg/1 (Table 1).These pa- tients require central venous pressure monitoring as well as continuous cardiac monitoring for early detection of prolongation of the QT interval.The 3-day course of therapy can be completed orally when the parasite density falls below 1% and the patient can tolerate oral medication.A 7-day course is needed if the disease is acquired in Thailand.
Potential indications for exchange transfusion include parasite density >10% or severe complica- tions such as altered mental status, non-volume overload pulmonary edema, or renal disease.Intravenous quinidine is administered during the ex- change, e PREVENTION AND CHEMOPROPHYLAXIS Prevention Basic principles to improve the control of malaria include 1) protection of the human from the Anopheles mosquito, 2) reduction of the breeding and sur- vival of the mosquito, 3) aggressive and early treat- Pyrimethamine/ sulfadoxine Mefloquine 300 mg base p.o. q week 200 mg p.o. daily (may be combined with chloroquine) 75 mg/I,500 mg p.o. single dose, repeat at beginning of the third trimester 250 mg salt p.o. q week merit of the human disease, and 4) establishment of surveillance and education programs, zs Two newer devices for human protection in- clude insecticide-impregnated bed nets and cur- rains, z9 At the present time, studies of their effec- tiveness are small and financial factors may limit their usefulness.

Prophylaxis
Because prophylactic treatment can fail, it should be emphasized that the optimal method for pre- venting malarial infection in the non-immune gravida is to refrain from travel to malaria-endemic regions.When such travel is unavoidable, however, there are several prophylactic regimens safe for use in pregnancy (Table 2).The cost-effectiveness of these regimens for women living in endemic re- gions remains to be proven.
Mefloquine has been evaluated as prophylaxis for chloroquine-resistant malaria. 3In a double- blind, placebo-controlled study in Thailand, meflo- quine gave >86% protection against P. falciparum and complete protection against P. vivax.There was no difference in either the mean birth weight or the mean gestational age at delivery between the two groups.Mcfloquine is not recommended for use in the first trimester or in individuals with known neurologic or psychiatric disorders.The drug may provoke severe neuropsychiatric reac- tions.3a In Malawi, another area with chloroquine- resistant malaria, prophylaxis was evaluated in primi-and secundagravidas.3e Three regimens were compared: chloroquine treatment followed by chloroquine prophylaxis (CQ/CQ), sulfadoxine/ pyrimethamine treatment followed by chloroquine prophylaxis (SP/CQ), and sulfadoxine/ pyrimethamine treatment and prophylaxis (SP/SP).
Combined treatment and prophylaxis with sulfa- doxine/pyrimethamine resulted in a marked de- crease in maternal parasitemia (32% for CQ/CQ and 14% for SP/CQ vs 3% for SP/SP).Placental parasitemia was also significantly reduced (32%, 25%, and 9%, respectively, for CQ/CQ, SP/CQ, and SP/SP).Three percent of SP-treated infants devel- oped scleral icterus; all cases resolved without com- plications after phototherapy.The effect of proguanil, either alone or in com- bination with chloroquine, was evaluated by Mutabingwa et al. 3 Therapy was noted to reduce the rate of low birth weight infants, however, due to the small numbers of participants, the differences were not significant. 3Placental parasitemia was significantly reduced.In primigravidas, the preva- lence of severe anemia was also reduced.

SUMMARY
Malaria is caused by four species of P/asmodium.
Infections in pregnant women are associated with multiple complications including anemia, low birth weight, and stillbirth.A high index of suspicion for malaria in women emigrating from or traveling through endemic areas is vital.Prompt diagnosis and initiation of appropriate therapy may be life- saving.

Fig. I .
Fig. I. Plasmodium life cycle (adapted from Zucker and Campbell').

TABLE I .
Treatment options safe for use during pregnancy

TABLE 2 .
Prophylactic regimens safe for use in