Artemisinin derivatives in the treatment of falciparum malaria in pregnancy

TRANSACTIONS

OFTHE ROYAL SOCIETY OFTROPICAL MEDICINE AND HYGIENE (1998) 92,430-433

Artemisinin

derivatives

in the treatment

of falciparum

malaria

in pregnancy

Rose McGready1y2y3, Dubowitz4, Sornchai

Thein Chol, Ju Ju Cho’, Julie A. Simpson”r’, Christine Luxemburger1~2~3, Lilly Looareesuwan2, Nicholas J. White2y3 and FranGois Nosten1y2y3 ‘Shoklo Malaria Research Unit, PO. Box 46, Mae Sot, 63110, Thailand; 2Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; 3Centre for Tropical Medicine, N&field Department of Medicine, John RadclaIe Hospital, Headington, Hospital, London, UK 4Department of Paediatrics, Royal Postgraduate Medical School, Hammersmith

Oxford,

UK;

Abstract derivative (artesunate or artemether) was used for the treatment of multidrug-resistant Plasmodium falciparum malaria in 83 Karen pregnant women in Thailand; 5 5 women were treated for recrudescent infection following quinine or mefloquine, 12 for uncomplicated hyperparasitaemic episodes, and 16 had not declared their pregnancy when treated. The women were followed weekly until delivery. Artesunate and artemether were well tolerated and there was no drug-related adverse effect. Recrudescence within 42 d occurred in 16% of the treated episodes. Overall 73 pregnancies (88%) resulted in live births, 3 (4%) in abortions and 2 (3%) in still births, and 5 women were lost to follow-up before delivery. There was no congenital abnormality in any of the newborn children, and the 46 children followed for more than one year all developed normally. An artemisinin

Keywords: malaria, Plasnzodiumfulciparum, chemotherapy, artesunate, artemether, pregnancy,Thailand Introduction The eastern and western borders of Thailand harbour the most drug-resistant Plasmodium falciparum, in vivo and in vitro, in the world. This situation poses particular problems for pregnant women, a group with an increased risk of developing severe malaria and a higher risk of recrudescent infection following conventional treatment. The standard first-line treatment for uncomplicated falciparum malaria in non-pregnant patients on the north-western border is now a combination of high dose mefloquine and artesunate (NOSTEN et al., 1994). P. falciFor pregnant women with multidrug-resistant parum malaria, the only drug currently recommended is quinine. Alternative treatments are limited either by lack of information on the safety of the drugs in human pregnancy, or by their poor efficacy. In this area of low and seasonal transmission, falciparum malaria in pregnancy is associated with significant maternal and fetal mortality and morbidity due to low maternal premunition (NOSTEN et al., 199 1). Because of multidrug resistance, there is also no effective chemoprophylaxis available for pregnant women. As the use of insecticideimpregnated bed nets had only a marginal preventive effect (DOLAN et al., 1993), early detection and treatment of P. falciparum remains the only available strategy to counter the deleterious effects of malaria in this vulnerable population. Since 1984, in the communities of displaced Karen people living in camps along the Thai-Myanmar borinfections in the first trimester of der, P falciparum pregnancy have been treated routinely with 7 d courses of quinine (30 mglkgid). Declining quinine efficacy in the early 1990s led to the use of high doses of mefloquine (25 mgikg) either as first-line therapy or for the treatment of recrudescences after quinine. Mefloquine has been given only in the second and third trimesters. Resistance to mefloquine has increased steadily in this area and the failure rate in pregnancy now exceeds 20% (unpublished data). Potentially fatal high-grade resistance is now not uncommon. For pregnant women who experience multiple recrudescences following mefloquine or quinine treatment, and for those with uncomplicated but potentially dangerous hyperparasitaemia, the only therapeutic option remaining is one of the oral artemisinin derivatives. These compounds are the most potent antimalarial drugs available for human use, and they retain excellent efficacy against multidrug-resistant strains of P. falciparum (see HIEN & WHITE, 1993). More than 2 million people have been treated with these Address for correspondence: Dr F. Nosten, P.0. Box 46, Mae Sot, 63110,Thailand;

fax +66 55 532 637.

drugs. Oral artesunate has been the most widely used of the compounds (BARRADELL & FITTON, 1995). Both safety and efficacy have been documented extensively in non-pregnant patients (NOSTEN & PRICE, 1995), whereas there are only 2 reports on the use of artemisinin (qinghaosu) and its derivatives during pregnancy. LI et al. -( 1390) &died 6 pregnant women (between 17 and 27 weeks of gestation): 2 received iniectable artemether (600 mg total dose) and 4 received artemisinin in oil suspension (500-900 mg total dose). WANG (1989) reported the outcome of 17 pregnancies exposed to artesunate or artemether (dosage not known). Neither study found any evidence of fetal or maternal toxicity of the drugs. Although there is no evidence of teratogenicity or mutagenicity with these drugs, in rats fetal resorption at relatively low doses (28-223 mglkgi d), given orally on days 9-14 of gestation, has been reCO-OPERATIVE RESEARCH GROUP, ported (CHINA 1982).

We report our experience in the treatment with an artemisinin derivative of 83 Karen pregnant women who were monitored carefully and followed until delivery. Methods Study site

The study was conducted in 1992-1996 in the antenatal clinics of the Shoklo Malaria Research Unit (SMRU) among women of the Karen ethnic minority living in camps on the north-western border of Thailand. In this hill-forested region, transmission of P. falciparum is low and seasonal and all patent parasitaemia is symptomatic and requires treatment. The effects of malaria in pregnancy and the epidemiology in the area have been described in detail previously (NOSTEN et al., 1991; LUXEMBURGER et al., 1997). For the period of this study 24% of all pregnant women attending the antenatal clinics in these camps experienced at least one I? falciparum episode during pregnancy. Patients

Artemisinin

derivatives were used for the treatment of or mixed malarial infections if(i) the infection recrudesced following treatment with mefloquine or quinine, (ii) the patient had uncomplicated hyperparasitaemia (>4% of parasitized red cells), (iii) the patient could not tolerate oral therapy, or (iv) the woman had not declared her pregnancy despite specific questioning. The first 3 groups are referred to as the risk group and the fourth as the inadvertent group.

P. falciparum

Study procedures

The risk group had a complete record of symptoms and their duration, and a history of antimalarial use re-

ARTEMISININ

DERIVATIVES

FOR MALARIA

IN PREGNANCY

431

corded at em-olment. A clinical and obstetric history was also recorded and a full clinical examination, including weight, axillary temperature, pulse and blood pressure, fetal heart rate and fundal height, was completed. An estimate of gestational age at enrolment was made from the woman’s history (last menstruation) and assessment of fundal height. A full blood count was done and thick and thin blood films were prepared on admission. Parasitaemia was assessed on Giemsastained thick blood films as the number of parasites per 500 white blood cells, or on thin blood films as the number of narasites ner 1000 red blood cells. All uatients were hollowed daily until their blood films were negative and they were asymptomatic, and then seen weekly in the antenatal clinics for a minimum of 42 d. At each visit a detailed questionnaire on side effects was completed, and a blood film was taken for detection of malaria parasites. After this period of 6 weeks, the routine antenatal clinic follow-up was continued weekly until delivery. Weekly clinical assessment included a blood film, examination and measurement of temperature and weight, and every 2 weeks the haematocrit was determined. If a woman attending an antenatal clinic was found to have had an inadvertent exposure on history taking, the details of the exposure were confirmed by referring to available medical and laboratory records. The gestational age at the time of exposure was calculated retrospectively after birth from the estimated gestational age of the newborn baby by use of the Dubowitz score. Animal studies have indicated that high doses of parenteral artemether or arteether cause an unusual pattern of selective damage to certain brain stem nuclei (BREWER et al., 1994). so a brief neurological examination was performed weekly on each woman up to day 42. This included a Romberg’s test, assessment of heel-toe ataxia, fine finger dexterity (ability to pick up a tablet or rapid sequential finger touching), auditory acuity (using a 256 Hz tuning fork), and an assessment for nystagmus. A neurological assessment was also performed on all newborn infants, which focused on tone, head control and tremor. This testing was designed and taught to local Karen health workers by one of us (Dr L. Dubowitz), and has been practiced since 1992.

ment. Failures were retreated with artesunate for 7 d as described above, unless the failure occurred during the first trimester (in the inadvertent group), in which case quinine was used. The only sources of antimalarials in the camp are the SMRU and Medecins Sans Front&es.

Antimalarial

Results From November 1992 to December 1996, 83 pregnant women received a total of 90 courses of artesunate (n=87) or artemether (n=?). The artemisinin derivative was combined with mefloquine (25 mg/kg) in 29 of the cases. Admission variables are summarized in the Table. The mean dose of the artemisinin drug received per woman was 588 mg (~~=68.6, range 456-786). Artemether was given to only 3 women. The first had a recrudescent infection after multiple treatment and was hyperparasitaemic and the second woman had intractable vomiting. The third case was a woman admitted to a chemotherapy study (PRICE et al., 1995) for uncomplicated malaria, who had denied being pregnant. The majority of treatment with artemisinin derivatives among the risk group occurred during the second and third trimesters of pregnancy (74190, 82%). In the inadvertent exposure group, the majority occurred in the first trimester (14/16, 88%).

drug regimens

Patients receiving treatment for recrudescent or hyperinfections received oral parasitaemic l? falciparum artesunate (Guilin no. 1 Factory, Guilin, People’s Republic of China), 4 mg/kg on day 0, 2 mg/kg on days 1 and 2. and 1 mg/kg on davs 3-6, i.e.. a total dose of 12 mgikg over 7 d. Mefloquine (Laham@, Hoffman La Rothe, Basel, Switzerland), 25 mg/kg, usually as a split regimen on days 5 and 6, was added when there had been no previous intake of mefloquine during the pregnancy. Most of the inadvertent exposures received a combination of artesunate 12 mg/kg-over 3 d (4 mgikgld) and mefloauine. usuallv as a snlit dose at 24 h (15 mg/ka) and 48 h (ld mgikgj. Three women in this group-(wy;h an undeclared pregnancy) received artesunate alone, 12 mg/kg total dose over 7 d. When prescribed, artemether (Kunming Pharmaceutical Factory, Kunming, People’s Republic of China) was given at a total dose of 12 mgl kg over 3 or 5 d in combination with mefloquine. The parenteral formulation (3.2 mgikg) was given intramuscularly if the patient could not tolerate oral treatment. Drug administration was observed by the midwives in all cases and, if vomiting occurred within 30 min, drug administration at the full dose was repeated. Ifvomiting occurred between 30 and 60 min, half the dose was repeated. No re-treatment was given to patients vomiting after 60 min. Recrudescent

infections

Treatment failure was defined as the reappearance of parasites in the peripheral blood within 42 d of treat-

Follow-up

and outcome measures

The main outcomes examined were treatment efficacy and safety for the mothers and their offspring. Pregnant women were followed weekly and a blood film was examined at each visit for a minimum of 42 d, and thereafter weekly until delivery in the routine antenatal clinic. Women were encouraged to deliver in the unit with supervision by trained Karen midwives. Obstetric emergencies were transferred to the local Thai hospital by car (l-2 h journey from the camps). Attendance at the antenatal clinic and delivery details were recorded on the patient’s medical record, which was returned to the unit at delivery. The Dubowitz test of gestational age and a neurological examination were performed within 5 d of the delivery. Still birth was defined as delivery of a dead fetus after 28 weeks of gestation and low birth weight as less than 2500 g. Abortion was classified as delivery of a non-viable fetus before 28 weeks of gestation. After birth the children were seen monthly for 12-24 months to assess their physical and neurological development. Statistical

analysis

Data were examined using the statistical program SPSS for Windows@ (SPSS Benelux Inc., Gorinchem, Netherlands). Continuous normally distributed data were described by the mean, standard deviation (SD) and range and non-normally distributed data by the median and range. Percentages were calculated for categorical data, with 95% confidence intervals (95% CI). Failure rates were calculated using Kaplan-Meier survival analysis. Ethics

This investigation was part of a series of studies on the treatment of malaria in pregnancy approved by the ethical committees of Mahidol University (Bangkok) and the Karen Refugee Committee (Mae Sot).

Parasitological

and clinical

responses

All treatments were supervised closely and compliance was good in all cases. Of 83 women treated, 12 delivered before the end of the follow-up period, 5 did not return to the clinic, and 2 aborted before day 42. Therefore 23% (191 83) of the women did not complete the follow-un. The mean duration of follow-uu was 34 d (SD=1

1):

Of the 68 patients who were followed daily until aparasitaemic, 64 (94%) had negative blood films by day 3

ROSEMCGREADY ETAL.

432

Table. Clinical malaria

features

and treatment

No. of treatmentsa Age (years)b No. of patients Febrile Anaemic Parasitaemia (per PL)~ No. of treatment coursesC Total no. of treatment failures/ no. evaluated Artesunate alone Artesunate + mefloquine Artemether + mefloquine

of experimental

groups

of pregnant

Recrudescent infections

Hyperparasitaemia

61 25(17-38)

22 (l?32)

9/58(16%) 41157 (72%) 814(16-130385) 3 (2-8)

3113 (23%) 6/12(50%) 115484(960-312924) 1 (l-5)

4153 117 Oil

115 017 Oil

women

with

falciparum

Inadvertent

exposures

16 29(15-40) 619 (67%) 217 (29%) 20788(50-394881) 1 (l-3) 113 2112 l/l

aData refer to each treatment (except for age); - there were 90 treatments among 83 women. bMean (range in parentheses).. CMedian (range in parentheses). (median; range l-5). Overall, 10 treatments resulted in parasite recrudescence within 42 d and the median time to recrudescence was 29 d (range 20-4 1) (Table). Using survival analysis the cumulative failure rate was 16% (95% CI 6-26). Considering only the 53 patients treated with artesunate alone for a recrudescent infection, the cumulative failure rate was 9.4% (95% CI 0.4-18.4). Of the 72 parasitaemic episodes without gametocytaemia on admission, 2 women (3%) later developed gametocytaemia. On admission, 67% (619) of women in the inadvertent group and 17% (12171) of the patients in the risk group had fever (PO.02). All 13 febrile patients assessed at 48 h had cleared their fever. Adverse effects

There was no serious or clinically significant drugrelated adverse reaction in any of the pregnant women. A total of 189 neurological tests was done on 39 women given at-tesunate (42% of exposures examined). The median number of tests per woman was 5 (range l-8). No adverse neurological effect was found in this subgroup. Pregnancy

outcomes

Among the 83 women followed in this study, 73 pregnancies resulted in live births (72 singletons and 1 set of twins), 2 in still births (2.6%) and 3 in abortions (3.9%); 5 women moved away before delivery. No congenital abnormality was detected in this series and the neurological examinations performed on 52 of the newborn babies were normal. The mean estimated gestation at delivery by Dubowitz testing was 38.5 weeks (SD=2.0, range 31.541.2). There were 16 exposures to artesunate before 13 weeks of gestation. In these first trimester cases, the mean estimated gestational age at treatment was 7.7 weeks (SD=?& range 3-l 2). There were 12 normal deliveries, one patient moved to Burma and could not be traced, and 3 women had spontaneous abortions. The estimated gestational ages at the time of artesunate exposure for the pregnancies with abortions were 3,7 and 12 weeks, with abortions occurring 3, 7.5 and 5.5 weeks, respectively, after the artesunate treatment. A comprehensive neonatal neurological assessment was performed on 8 of the first trimester exposures and no significant abnormality was detected. Of the 74 live births, 46 (62%) were followed prospectively for more than one year. There was no neonatal death among the singletons. One infant died at 2 months of age from an undefined febrile illness. The physical and neurological development of the children was normal. Discussion Artemisinin derivatives should not be given in pregnancy unless there is no safe and effective alternative

(WHO, 1994). This includes situations when the life of the mother is at risk, and when malaria is caused by parasites resistant to the drugs known to be safe in pregnancy. In communities living along the western border of Thailand, P. falciparum has developed resistance to all antimalarial drugs except artemisinin derivatives. The majority of treatments described here involved use of artestunate for pregnant women who presented with multiple treatment failures following mefloquine and quinine. The failure rate with artesunate alone was 9.4% (95% CI 0.4-18.4) after treatment of recrudescent infections, compared to 37% for quinine and 36% for mefloquine when used to treat recrudescent infections (unpublished observations). The excellent efficacy of artemisinin derivatives in this context suggests that these compounds are likely to be used increasingly in pregnancy, and evidence on their safety profile is needed urgently. Additionally, the artemisinin-based regimens reduce gametocyte carriage and thus transmission potential (PRICE et al., 1996). In a separate cohort of pregnant women from the same population, 39 of 327 patients (12%) had patent gametocytaemia 7 dafter being treated with quinine or mefloquine, whereas only 2 of 72 patients (3%) treated with an artemisinin derivative developed gametocytaemia. If reduction in transmission of Z? falciparum following the widespread use of artesunate is confirmed, any impact on the remaining reservoir of gametocytes, such as that in pregnant women, is likely to be substantial. Twelve of 13 women with uncomplicated hyperparasitaemia were treated with oral artesunate in this study. The advantage of oral artesunate over intravenous quinine in non-pregnant patients with uncomplicated hyperparasitaemia has been well documented in this area (LUXEMBURGER et al., 1995). In this series, none of the patients deteriorated clinically and only one had failed treatment by day 28. The benefits of rapid clearance of parasites, low toxicity and efficacy of artesunate make this a much more suitable treatment than intravenous quinine, which is associated with an increased risk of hypoglycaemia in pregnancy (LOOAREESUWAN et al., 1987). Artemisinin derivatives are now deployed in several countries of Asia and an increasing number of women of child-bearing age are treated with these drugs in the first weeks of gestation, either because they did not know they were pregnant or they did not declare it. The 16 women who received artesunate in the first trimester, for some of them as early as the first month of gestation, showed no evidence of fetal or maternal toxicity. The rate of abortion (3115; 20%) of those exposed in the first trimester was within the rate observed in the general population. However, this was a small series and the true denominator of pregnancies exposed to artesunate

ARTEMISININ

DERIVATIVES

FOR MALARIA

IN PREGNANCY

in the first trimester is not known, so this result should be interpreted with caution. No adverse effect was found in women or neonates. Neurological testing of newborn infants, particularly those resulting from the 3 pregnancies exposed to artemether, failed to find any evidence of neurotoxicity, and all children who could be followed showed normal neurological development over the first year of life. These preliminary findings are reassuring and should encourage further and larger treatment studies to define the true safety of the artemisinin compounds in pregnancy. Acknowledgements We thank the Karen staff of the SMRU for their excellent work. This study was part of the Wellcome-Mahidol University-oxford Tropical Medicine Research Programme funded by the Wellcome Trust of Great Britain. References Barradell, L. B. & Fitton, A. (1995). Artesunate, a review of its pharmacology and therapeutic efficacy in the treatment of malaria. Drugs, 50, 714-741. Brewer, T. G., Grate, S. J., Peggins, J. O., Weina, I? J., Petras, J. M., Levins, B. S., Heiffer, M. H. & Schuster, B. G. (1994). Fatal neurotoxicity of arteether and artemether. American Society of Tropical Medicine and Hygiene, 51, 251-259. China Co-operative Research Group [on Qinghaosu and its Derivatives] (1982). Studies on the toxicity of qinghaosu and its derivatives. Journal of Traditional Chinese Medicine, 2, 31-38. Dolan, G., ter Kuile, F. O., Jacoutot, V., White, N. J., Luxemburger, C., Malankirii [sic], L., Chongsuphajaisiddhi, T. & Nosten, F. (1993). Bed nets for the prevention of malaria and anaemia in pregnancy. Transactions of the Royal Society of Tropical Medicine and Hygiene, 87, 620-626. Hien, T. T. & White, N. J. (1993). Qinghaosu. Lancet, 341, 603-608. Li, G. Q., Guo, X. B. & Fu, Y. (1990). Clinical Trials on Qinghaosu and its Derivatives. Guangzhou, China: Guangzhou College of Traditional Chinese Medicine, Sanya Tropical Medicine Institute. Looareesuwan, S., White, N. J., Silamut, K., Phillips, R. E. &

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