Efficacy of chemoprophylaxis in preventing Plasmodium falciparum parasitaemia and placental infection in pregnant women in Malawi

520

TR.U-E.~CT~ONS OF THE ROYALSOCIETY OF TROPICALMEDICINE

Efficacy of chemoprophylaxis parasitaemia and placental

AND

HYGIENE (1988) 82, 520-523

in preventing Pfasmudium infection in pregnant women

falciparum in Malawi

Jack J. Wirima’, Alan P. Macheso’, Richard D. Wah14, Jeanne M. McDermott’, David L. Heyma&*, Richard W. Steketee3 and Carlos C. Campbell3 ‘Combatting Childhood Communicable Diseases Project, Ministry of Health, Malawi; zInternational Health Program Office, and 3Malaria Branch, Centers for Disease Control, Atlanta, Georgia, USA; 4Armed Forces Institute of Pathology, Department of the Army, Washington, DE., USA

Abstract 73 pregnant women in Malawi were given weekly antimalarial chemoprophylaxis under observation and were monitored for Piasmodium falcipurum parasitaemia and placental infection. 3 of 19 women (16%) who were parasitaemic at the time they began chemomonhvlaxis were infected with chloroquineresista& k.- fulciparum. After clearance of initial infections. 25% of the 73 women became varasiraemic while &g prophylaxis and 56% had-evidence of active or past placental infection at the time of delivery. None of the women who were parasitaemic at the time of enrohnent, and only 11% of those who had breakthrough parasitaemiaswhile taking prophylaxis, had a bisrorY of fever and signs or symptoms that ihey recogniz&d as malaria. Altliough the density of P. falciponan infection and rates of placental infection adpeared to be lower among women taking regular chioroquine prophylaxis, this drug did not infection among pregnant prevent P. falciparum women. Introduction In Malawi. chloroouine (CQ) mophvlaxis for meanant women’ in a d&e of’ 300 mdwiek or apbroximately 5 mgfltg body weight (CQS) is recommended by the Ministry of Health, and CQ tablets for this purpose are provided through the government and private antenatal clinic systemsin a voluntary chemoDroDhYlaxis programme. Women with signs and/or &nip
1986; ARCHIBALD,

19561. and abortion and stillbirth in areas of low -‘:

m&a

endemicity

(MCGREGOR, 1984).

Chloroquine-resistant P. f4Zc@4rum has been present in Malawi since the early 1980s and exists throughout the country (KHOR&ANA et al., 1986). However, CQ remains the first line of therapy because of its successin decreasing the densities of most P.

Addressc&n~unications to Richard W. Steketee,Malaria Branch, DPD, CID, Centersfor DiseaseControl, Adan& GA 30333,USA.

falciparum infections and in producing a favourable

clinicat response (Pappaioanou, unpublished data). Amodiaauine (A01 and Dvrimethamine-sulfadoxine have beeh iden’&& as eff&ve drugs for the therapy of chloroquine treatment failures (HEYMANN et al., 1987), as has quinine (Wirima, unpublished data). Of these drugs, only AQ is used for treatment of chloroquine-resistant infections among pregnant women. The present study was undertaken to compare the effectiveness of CQ and AQ in preventing P. falciparurn parasitaemia and placental infections when used weekly by pregnant women during the second and third trimester of pregnancy, but after the report of apparent toxicity of AQ (NEFTEL er al., 1986) its administration was stopped and the aim of the study was changed to an evaluation of the effectiveness of prophylaxis with either drug. Methods Prenatul study

Pregnant women at 18-26 weeks gestation, estimated by the date of last menstrual period or fundal height, or both, were enrolled in the study during their first antenataf clinic visit at the Kamuzu Central Hospital, Lilongwe. Enrolrnent was at the end of the 6 month dry season, the low point of malaria transmission. After informed consent, women were alternatively assigned to CQ or AQ prophylaxis groups. Fingerstick blood was obtained for haematocrit determination and a thick smear for malaria parasites. CQ or AQ basewas then given under observation in a doseof 5 mg/kg body weight (CQS or AQ5). Blood smears were stained with Giemsa and examined under oil immersion for malaria parasites. Asexual parasites and white blood cells were counted in 100 oil immersion fields and the parasite density per cubic millimeter (mm3) of blood-was calculated, based on a standard of 6000 white blood cells oer mm3. AU women were visited in their homes each week until delivery. During these visits, CQS or AQ5 was given under observation and women were questioned regarding any history of fever in the previous week. Whole Mood for haematocrit determination was collected at 4-week intervals. Thick blood smears were made at 2-week intervals. Women who had parasitaemia detected by thick smear were treated at the next visit with CO25. and a thick blood smearwas repeated one week la<&. -If the repeat thick smearwas not parasite-free, women were treated wih AQ25 and

521 the thick smear was repeated one week later. A blood smear was obtained from women with a history of fever or symptoms suggestive of malaria during the preceding 7 d and they were treated with CQ25. All women received standard care during routine antenatal clinic visits, including 2 doses of tetanus toxoid, ferrous sulphate (300 mg/d) and abdominal/ foetal examination. Women who had haematocrits less than 30% at enrohnent were given ferrous sulphate (600 mg/d) and folic acid (5 mg/d) for the duration of their pregnancy. 17 weeks after the study began agranulocytosis associatedwith AQ prophylaxis was reported among European tourists (NEFTEL et al., 1986) and the undelivered study women in the AQ prophylaxis group were immediately switched to CQS. Perinatal

hospital during the same period of time as the study women. Control women had attended antenatal clinic and had access to CQS chemoprophylaxis, tlough administration had not been supervised. Placental specimens were embedded iri paraffin, stained with haematoxylin and eosin or Thomas’s stain, or both, mounted and examined under oil immersion for intraerythrocytic P. falciparum parasites, thrombi containing pigment, and pigment in leucocytes. An active placental infection was defined as the presencein the placenta of intraerythrocytic P. falciparum asexual parasites. A past placental infection was delined as the presencein the placenta of malaria pigment in Leucocytes. Data analysis

Breakthrough parasitaemia was defined as the presence of parasites on any thick smear among women who had been parasite-free on enrolment or parasite-free for 2 weeks after the first dose of prophylaxis or treatment, or both. Once a woman had breakthrough parasitaemia, she was not included in further analysis. Differences in proportions were tested using the x2 and Fisher’s exact tests. Significant differences were designated at PSO*OS. Initial analysis demonstrated no significant difference in the proportion of women with breakthrough parasitaemia in the CQ prophylaxis group when compared to the AQ prophylaxis group, and a decision was made not to analyse the study results by prophylactic drug as initially planned.

stuay

At delivery a 2 cm segment of the placenta was collected and lixed in 10% formalin. Placental specimens were obtained from control women who were matched for parity and who delivered at the same Table I-Phmodium fafci~ perasiteemie by parity among pregnant women at enmbnent in chemoprophyhsis, Lilongwe, Malawi, October-November 1985

parity

NUdXr cnroued

Parasitaemia at enmhnent’

Geometric mean parasite density C.parasitcs/mm3)

0 1 P2 Total

19 13 43 75

8(42%) 7(54%) 4 (9%) 19(25%)

2155 362 91 574

Results Znitiul parasite infection

*Difference in parasitaetnia prevalence at enrolment for parity 0 and 1 vs parity 22; P = 04002, Fisher’s exact test

75 pregnant women were enrolled in the study and 19 (25%) had P. falciparum parasitaemia at enrolmerit, with a geometric mean parasite density (GMPD) of 574 parasites/nun3 of blood. The percentage of nulliparous and primiparous women with parasitaemia at enrolment (47%) was greater than the percentage of higher parity women (9%) (P = 0302) (Table 1). The GMPD was also greater among infected nulliparous women (2155/mm3) and primiparous women (362/mm3) than among infected women of greater parity (91/mm3).

Table 2-Breakthough of Plasmodium falcippacasitaemia by perity emoog pregoaot women enrolled in chemopmphyhxis, Lilongwe, Malawi, October 1985-April 1986

Parity

Number on prophylaxis

Breakthrough parasitaemias’

Geometric mean parasite density @rasites!mm’)

0 1 r2 Total

19 12 42 73

3(16%) 4(33%) 11(23%) 18(25%)

173 69 155 139

Wifference parity bl:

Effect of prophylaxis sitaemia

and treatment on initial para-

All 19 women who were parasitaemic at enrolment were treated the following week with CQ25. 15 of the

in frequency of breakthrough parasitaemia for parity 0 vs P = 0.236, Fisher’s exact test.

Table 3-Active or active and past placental Plasmodium fdciparum infection among 36 pregnant women enrolled in chemoprophylaxis programme and 36 parity matched controls, Lilongwe, Malawi, December 1985-April 1986

Women with active Women with active or past infection P . falciparum infection Number Study women Controls Study women Parity Controls 1(9%) 0 11 7(64%) WWj ;;;g; 1 0 1(25%) 1(5%) 11(57%) 2: 12 (864) yfj %la 36 2(6%) 20(56%) 33 (92%) “Difference between study and control women for active infection, P = O-076; for active and/or past infection, P = 0.0005, Fisher’s exact test. P. fakiparum

00

522 19 women had a thick smearat time of treatment, and 9 (60%) had cleared the oarasitaemia following the initial dose of prophyltii; the 6 women who remained parasitaemic after one dose of prophylaxis were all of paritv 0 or 1. The GMPD of initial parasitaemias-amongthose women who cleared their infections with one doseof oroDhYho& was 353/mm3, compared to 2388/mm3in women who failed to clear: In 5 of the 6 women who did not clear their parasitaemias,there was a decreaseof parasite density by a factor of more than one-fifth following the first prophylactic dose. Seven days after CQ25 treatment, thick smears were obtained from all 19 women with initial parasite infections and 3 (16%) still had parasitaemia. 2 of these women cleared their parasita&ia in 7 or fewer days after taking AQ25; the third woman delivered prematurely before treatment with AQ. Effect of prophykzxis un breakthrough parasitaemia

73 of the 75 women were followed for the duration of their pregnancy. 18 (25%) had a breakthrough parasitaemia, either after enrolment or more than 2 weeks after having been successfully treated for parasitaemia at enrohnent. Breakthrough parasite rates were similar in groups with parity 0, 1 and ~-2, (Table 2). The densities of breakthrough parasitaemias ranged from 23 to 3000 parasites/mm’ of blood and the GMPDs were similar among parity groups. Thick smears just before treatment were available from 13 of the ‘women with breakthrough parasitaemias. 9 women (69%) had cleared their parasitaemia followina the nrevious doseof chemonronhvlaxis, while in 21of the remaining 4 women ‘parasiie density had decreasedat least four-fold. All women cleared their parasitaemias with CQ25.

Assocdion

of malaria infection and haematocrit

10 (13%) of the 75 women initially enrolled in the study had haematocrits <30% at enrolment. Low haematocrits at enrolment were more common among 19 nulliparous and 13 primiparous women (22%) than among 43 women of higher parity (7%) (F’ = O-06). At enrolment. 8 180%) of the 10 women who had haematocrits 230% whre oarasitaemic, while 11 (17%) of the 65 who had haematocrits 530% were parasitaemic (P = O+OOl). An additional 11 women developed haematocrits ~30% during the study; 4 of them (36%) had at least one breakthrough parasitaemia, 2 before onset of the low haematocrit and 2 after onset.

Signs and symptoms of malaria and peripheral parasitmia

None of the 19 women with parasitaemia at enrolment had a history of recent -fever or other symptoms which they perceived asmalaria. 2 (11%) of the 18 women with breakthrough parasitaemiashad a history of recent fever and other signs and symptoms which they perceived as malaria. During the followUD of the 73 studv women. 8 (11%) stated that thev had had malaria during the preceding week and 2 (25%) had peripheral parasitaemiaswith densities of 35 and 23 parasites per mm3. 4 (5%) of the study women gave a history of pruritis after taking their antimalarial drug, but none refused to take the medication at any time during the study.

Effect of prophylaxis a placenta specimens

Stained preparations were made from placental slivers from 36 of the study women and 36 paritymatched controls. 2 (6%) of the placental specimens from study women and 7 (19%) of those from control women had asexual parasites (P = O-076) (Table 3). One of the 2 study women with active placental infection had parasites present at the time of enrolment; neither of these women had a parasite breakthrough during the study. 20 (56%) of the placental specimensfrom study women, and 33 (92%) of those from control women, showed evidence of oresent or past malaria infection (P = O*OOOS)(Tible 3). 9 (45%) of the 20 study women with evidence of placental infection had parasites present on a thick smear at enrohnent, or had a parasite breakthrough during the studv: 7 (44%) of the 16 studv women who had no evident; of placental infection had either an initial parasitaemia at enrolment or a parasite breakthrough (P = 0.60). Discussion

In this study pregnant women were observed to have CQ-resistant, P. fulciparum at enrohnent, low haematocrits associatedwith P. falciparum infection before beginning prophylaxis, breakthrough parasitaemiaswhile on prophylaxis, and evidence of active or past infection of the placenta. However, CQ prophylaxis appeared to reduce parasitaemia and placental infection rates in the study group and to reduce parasite density in infected women. This study was begun during the lowest malaria transmission seasonin Malawi, yet about one-quarter of enrolled pregnant women had asymptomatic P. falcipanfm infections. Consistent with findings of other investigators (MACGREGOR,1984; REINHARTet al.. 1978: BRABIN. 1983: BRAY & ANDERSON. 1979).

infection’rates were highest among women in their first and secondpregnancies. The proportion of initial malaria infections which failed to clear after CQ25 (16%) was similar to that in Kenya, where 27% of pregnant women failed to clear P. falciparum parasites within 7 d of receiving CQ25 (STEKETEEet al., 1988), and similar to the CQ-resistance rate of 24% found among children 5-10 years of age in Lilongwe (Wirima, unpublished data). As in the Kenya study (STEKETEEet al., 1988), we observed that failure to clear parasitaemia with CQ treatment was most common in women in their first or second pregnancy. Despite our detection of CQ-resistant parasites, clearance or marked reduction of parasitaemiawas seenin most infected women following one dose of prophylaxis. This low dose of drug did not, however, assure continued clearance of peripheral or placental infection. Placental malaria infection was common in this study, regardless of whether peripheral parasitaemias were noted during the pregnancy or at the time of delivery. Results of examination of placentas from control women suggested some protective effect of prophylaxis among study women. A possible explanation of the higher placental infection rates among non-study women was irregular compliance with the voluntary chemoprophylaxis programme. Studies in Malawi have shown that, among pregnant women enrolled in the voluntary prophylaxis programme, only 34% had urine CQ or CQ metabolites present,

523 compatible with their having taken a prophylactic dose during the preceding 7 d (Heymann, unpublished data). Our study. in which less than one-half of women who had pla&taI infections had parasites present in a peripheral blood smear at enrohnent or while taking prophylaxis, confmed the observation of other investigators that placental infection is not always accurately reflected by maternal parasitaemia (KORTMANN, 1972; GALBRAITH et al., 1980; MORLEY et al., 1964). Some African countries have relied on a policy of treating febrile illness in pregnant women, as opposed to regular chemoprophylaxis. In our investigation, recent fever or signs and symptoms suggestive of malaria were reported infieqbently bj;- infected women, and onlv 25% of such women had detectable parasitaemia, suggesting that perceived malaria among pregnant women is not a reliable predictor of current malaria infection, which is similar to the findings of other investigitors (WALTON, 1949). The results of this studv lose a Droblem for health policy makers in Malawi &d other countries with similar prevalence of malaria and CQ-resistant parasites. If the objective of chemooro~hvlaxis during pregnancy is to prevent the adverb e&&s associated with P. falcifmtum infection bv maintaininn the peripheral- b&d and placenta f&e of para.&, the programme is not highly effective, even with regular, supervised administration. An /additional option, treating women with fever or signs and symptoms of malaria to prevent placental infection, would add little to the overall efficacy of the programme. The question remains whether a programme of CQ chemoprophylain some xis, which clears or reduces ~arasitaemia women, can lead to an increase& infant birth weight and alleviate some of the adverse effects of P. fakipawn infections during pregnancy. Acknowledgments Mr Rodney Tembenu, Mr Ali Gowelo and the nursemidwives of Old Win8 Maternity, Kamuzu Central Hospital assistedin the conduct of the field study, and Dr Marquerite Pappaioanou assisted with statistical analysis. Tbis work was supported by US AID PASA-BAS-0421PHC-2233. References Archibald, H. M. (1956). The influence of malaria infection of the placenta on the incidence of prematurity. Bulletin of the Worki Health Omanization. 15. 842-845. Bra& B. J. (1983). An a&ysis of &la& in pregnancy in Africa. Bulletin of the World Health Organization, 61, 1005-1016. Bray, R. S. & Anderson, M. J. (1979). Falciparum malaria and pregnancy. Transactiom of the Royal Society of

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Received 14 May 1987; revised 8 Janwry accepted for publication 16 February 1988

1988;