Intermittent Preventive Therapy for Malaria During Pregnancy Using 2 vs 3 or More Doses of Sulfadoxine-Pyrimethamine and Risk of Low Birth Weight in Africa, systematic review and metanalysis

February 2013

In areas of stable malaria transmission in sub-Saharan Africa, Plasmodium falciparum infection in pregnant women is associated with maternal anemia and low birth weight (LBW) (<2500 g),especially among primigravida and secundigravida and human immunodeficiency virus (HIV)–infected women. The World Health Organization (WHO) recommended intermittent preventive therapy during pregnancy, consisting of at least 2 full treatment doses of sulfadoxine-pyrimethamine for HIV-negative women and at least 3 doses for HIV-positive women not receiving cotrimoxazole, administered presumptively in the second and third trimesters at least 1 month apart. Each dose suppresses or clears any existing asymptomatic infections from the placenta and provides up to 6 weeks of posttreatment prophylaxis. Although the standard 2-dose regimen provides at most 12 weeks of prophylaxis, it has been shown to be effective in reducing LBW and was adopted by 31 of 37 endemic countries in Africa with a policy for intermittent preventive therapy during pregnancy; the remaining countries use a 3-dose or monthly regimen.

The Malaria in Pregnancy Library: a biblometric review

October 2012

Maternal anemia at first antenatal visit: prevalence and risk factors in a malaria-endemic area in Benin

September 2012

The risk factors for maternal anemia (hemoglobin level less than 110 g/L) were studied in human immunodeficiency virus–negative pregnant women in Benin at the time of first antenatal visit and prior to any prevention. Data for the first 1,005 pregnant women included in a multicentre randomized controlled trial were analyzed. Anemia was common (68.3%), and malaria and helminth infestations were prevalent in 15.2% and 11.1% of the women. A total of 33.3%, 31.3% and 3.6% of the women were iron, folic acid and vitamin B12 deficient, respectively. These parasitic infections and nutrient deficiencies were associated with a high risk of anemia. Twenty-one percent, 15%, 12%, 11% and 7% of anemia were attributable to malnutrition, malaria, iron, folic acid deficiencies, and helminth infestations, respectively.
Most anemia was caused by factors that could be prevented by available tools, stressing the need to reinforce their implementation and to evaluate their effectiveness throughout the course of the pregnancy.

Population pharmacokinetics of Artemether and dihydroartemisinin in pregnant women with uncomplicated Plasmodium falciparum malaria in Uganda

August 2012

Malaria in pregnancy increases the risk of maternal anaemia, abortion and low birth weight. Approximately 85.3 million pregnancies occur annually in areas with Plasmodium Falciparum transmission. Pregnancy has been reported to alter the pharmacokinetic properties of many anti-malarial drugs. Reduced drug exposure increases the risk of treatment failure. The objective of this study was to evaluate the population pharmacokinetic properties of artemether and its active metabolite dihydroartemisinin in pregnant women with uncomplicated P. falciparum malaria in Uganda. Twenty-one women with uncomplicated P. falciparum malaria in the second and third trimesters of pregnancy received the fixed oral combination of 80 mg artemether and 480 mg lumefantrine twice daily for three days. Artemether and dihydroartemisinin plasma concentrations after the last dose administration were quantified using liquid chromatography coupled to tandem mass-spectroscopy. A simultaneous drug-metabolite population pharmacokinetic model for artemether and dihydroartemisinin was developed taking into account different disposition, absorption, error and covariate models. A separate modeling approach and a non-compartmental analysis (NCA) were also performed to enable a comparison with literature values and different modeling strategies.

Population pharmacokinetic and pharmacodynamic modeling of amodiaquine and desethylamodiaquine in women with Plasmodium vivax malaria during and after pregnancy

August 2012

Amodiaquine is effective for the treatment of P. vivax malaria but there is little information on the pharmacokinetic and pharmacodynamic properties of amodiaquine in pregnant women with malaria. This study evaluated the population pharmacokinetic and pharmacodynamic properties of amodiaquine and its biologically active metabolite, desethylamodiaquine, in pregnant women with P. vivax infection and again after delivery. Twenty-seven pregnant women infected with P. vivax malaria on the Thai-Myanmar border were treated with amodiaquine mono-therapy (10 mg/kg/day) once daily for three days. Nineteen women, with and without P. vivax infections, returned to receive the same amodiaquine dose post-partum. Nonlinear mixed-effect modeling was used to evaluate the population pharmacokinetic and pharmacodynamic properties of amodiaquine and desethylamodiaquine. Amodiaquine plasma concentrations were described accurately by lagged first-order absorption with a two-compartment disposition model followed by a three-compartment disposition of desethylamodiaquine under the assumption of complete in vivo conversion. Body weight was implemented as an allometric function on all clearance and volume parameters. Amodiaquine clearance decreased linearly with age and absorption lag-time was reduced in pregnant patients. Recurrent malaria infections in pregnant women were modeled with a time-to-event model consisting of a constant hazard function with an inhibitory effect of desethylamodiaquine. Amodiaquine treatment reduced the risk of recurrent infections from 22.2% to 7.4% at day 35. In conclusion, pregnancy did not have a clinically relevant impact on the pharmacokinetic properties of amodiaquine or desethylamodiaquine. No dose adjustments are required in pregnancy.

Effect of malaria in pregnancy on foetal cortical brain development: a longitudinal observational study

July 2012

Malaria in pregnancy has a negative impact on foetal growth, but it is not known whether this
also affects the foetal nervous system. The aim of this study was to examine the effects of
malaria on foetal cortex development by three-dimensional ultrasound. Brain images were acquired using a portable ultrasound machine and a 3D ultrasound transducer. All recordings were analysed, blinded to clinical data, using the 4D view software package. The foetal supra-tentorial brain volume was determined and cortical development was qualitatively followed by scoring the appearance and development of six sulci. Multilevel analysis was used to study brain volume and cortical development in individual foetuses. Cortical grading was possible in 161 out of 223 (72%) serial foetal brain images in pregnant women living in a malaria endemic area. There was no difference between foetal cortical development or brain volumes at any time in pregnancy between women with immediately treated malaria infections and non-infected pregnancies. The percentage of images that could be graded was similar to other neuro-sonographic studies. Maternal malaria does not have a gross effect on foetal brain development, at least in this population, which had access to early detection and effective treatment of malaria.

Pharmacokinetics of Piperaquine in Pregnant Women in Sudan with Uncomplicated Plasmodium falciparum Malaria

July 2012

The pharmacokinetic properties of piperaquine were investigated in 12 pregnant and 12 well-matched, non-pregnant women receiving a three-day oral fixed dose combination regimen of dihydroartemisinin and piperaquine for treatment of uncomplicated Plasmodium falciparum at New Halfa Hospital in eastern Sudan. Frequent venous plasma samples were drawn from the patients over a 63-day period and a complete concentration–time profile was collected for 7 pregnant and 11 non-pregnant patients. Piperaquine was quantified using a liquid chromatography–mass spectrometry/mass spectrometry method. Pregnant women had a significantly higher total drug exposure (median area under the curve [range] = 1,770 [1,200–5,600] hr × ng/mL versus 858 [325–2,370] hr × ng/mL; P = 0.018) and longer time to maximal concentration (4.00 [1.50–4.03] hr versus 1.50 [0.500–8.00] hr; P = 0.02) after the first dose compared with non-pregnant women. There was no other significant difference observed in piperaquine pharmacokinetics between pregnant and non-pregnant women, including no difference in total drug exposure or maximum concentration. The overall pharmacokinetic properties of piperaquine in this study were consistent with previously published reports in non-pregnant patients.

Determinants of Use of Insecticide Treated Nets for the Prevention of Malaria in Pregnancy: Jinja, Uganda

June 2012

One established means of preventing the adverse consequences of malaria during pregnancy is sleeping under an insecticide treated net (ITN) throughout pregnancy. Despite increased access to this intervention over time, consistent ITN use during pregnancy remains relatively uncommon in sub-Saharan Africa. This study sought to identify determinants of ITN use during pregnancy. Utilizing a populationbased random sample, 500 women living in Jinja, Uganda, who had been pregnant in the past year were interviewed. ITN ownership at the start of pregnancy was reported by 359 women (72%) and 28 women (20%) acquired an ITN after the first trimester of pregnancy. Among 387 ITN owners, 73% reported either always sleeping under the ITN during all trimesters of pregnancy, or after acquiring their net. Owning more than 1 net was slightly associated with always sleeping under an ITN during pregnancy (RR: 1.13; 95% CI: 1.00, 1.28). Women who always slept under an ITN during pregnancy were more likely to be influenced by an advertisement on the radio/poster than being given an ITN free of charge (RR: 1.48; 95% CI: 1.24, 1.76). No differences were found between other socio-demographic factors, pregnancy history, ANC use or socio-cultural factors.

Population pharmacokinetics of dihydroartemisinin and piperaquine in pregnant and non-pregnant women with uncomplicated malaria.

April 2012

Pregnant women are particularly vulnerable to malaria. The pharmacokinetic properties of antimalarial drugs are often affected by pregnancy, resulting in lower drug concentrations and a consequently higher risk of treatment failure. The objective of this study was to evaluate the population pharmacokinetic properties of piperaquine and dihydroartemisinin in pregnant and nonpregnant women with uncomplicated malaria. Twenty-four pregnant and 24 matched nonpregnant women on the Thai-Myanmar border were treated with a standard fixed oral 3-day treatment, and venous plasma concentrations of both drugs were measured frequently for pharmacokinetic evaluation. Population pharmacokinetics were evaluated with nonlinear mixed-effects modeling. The main pharmacokinetic finding was an unaltered total exposure to piperaquine but reduced exposure to dihydroartemisinin in pregnant compared to nonpregnant women with uncomplicated malaria. Piperaquine was best described by a three-compartment disposition model with a 45% higher elimination clearance and a 47% increase in relative bioavailability in pregnant women compared with nonpregnant women. The resulting net effect of pregnancy was an unaltered total exposure to piperaquine but a shorter terminal elimination half-life. Dihydroartemisinin was best described by a one-compartment disposition model with a 38% lower relative bioavailability in pregnant women than nonpregnant women. The resulting net effect of pregnancy was a decreased total exposure to dihydroartemisinin. The shorter terminal elimination half-life of piperaquine and lower exposure to dihydroartemisinin will shorten the posttreatment prophylactic effect and might affect cure rates. The clinical impact of these pharmacokinetic findings in pregnant women with uncomplicated malaria needs to be evaluated in larger series.

Artesunate/dihydroartemisinin pharmacokinetics in acute falciparum malaria in pregnancy: absorption, bioavailability, disposition and disease effects

March 2012

The pharmacokinetic properties of many antimalarials are altered during pregnancy. There is often an expanded apparent volume of distribution and increased clearance resulting in lower drug exposure which contributes to higher treatment failure rates. In low transmission settings treatment responses to antimalarial drug regimens are worse in pregnant women than in age-matched women from the same location who are not pregnant.The artemisinin

derivatives are now central to the treatment of falciparum malaria and artemisinin combination treatments are recommended in the second and third trimesters of pregnancy. Previous studies have suggested that plasma concentrations of the artemisinin derivatives and their common active metabolite dihydroartemisinin (DHA) are low in pregnancy. Finding the correct dose of artesunate (ARS) in pregnancy is necessary not only to obtain optimal cure rates for the individual patient but also to limit the emergence and spread of resistance.

Antenatal receipt of sulfadoxine-pyrimethamine does not exacerbate pregnancy-associated malaria despite the expansion of drug-resistant Plasmodium falciparum: clinical outcomes from the QuEERPAM study

March 2012

Antenatal intermittent preventive therapy with 2 doses of sulfadoxine-pyrimethamine (IPTp-SP) is the mainstay of efforts in sub-Saharan Africa to prevent pregnancy-associated malaria (PAM). Recent studies report that drug resistance may cause IPTp-SP to exacerbate PAM morbidity, raising fears that current policies will cause harm as resistance spreads.

We conducted a serial, cross-sectional analysis of the relationships between IPTp-SP receipt, SP-resistant Plasmodium falciparum, and PAM morbidity in delivering women during a period of 9 years at a single site in Malawi. PAM morbidity was assessed by parasite densities, placental histology, and birth outcomes.

The prevalence of parasites with highly SP-resistant haplotypes increased from 17% to 100% (P < .001), and the proportion of women receiving full IPTp (≥2 doses) increased from 25% to 82% (P < .001). Women who received full IPTp with SP had lower peripheral (P = .018) and placental (P < .001) parasite densities than women who received suboptimal IPTp (<2 doses). This effect was not significantly modified by the presence of highly SP-resistant haplotypes. After adjustment for covariates, the receipt of SP in the presence of SP-resistant P. falciparum did not exacerbate any parasitologic, histologic, or clinical measures of PAM morbidity.

How Hidden Can Malaria Be in Pregnant Women? Diagnosis by Microscopy, Placental Histology, Polymerase Chain Reaction and Detection of Histidine-Rich Protein 2 in Plasma

March 2012

A major and not sufficiently recognized contributor to the burden of infectious diseases in developing countries is the lack of access to high-quality diagnostic techniques for effective clinical management and monitoring of control interventions. In particular, early diagnosis and treatment of Plasmodium falciparum infection are key to reducing malaria-related morbidity and mortality and are a fundamental aspect in the control and eradication of this disease. Microscopy has been the cornerstone of malaria diagnosis and is recommended where its quality can be maintained. However, rapid diagnostic tests (RDTs) detecting Plasmodium-specific antigens have emerged during recent years as an attractive alternative to microscopy that is able to extend diagnosis to remote and poorly resourced areas.

Adaptive evolution and fixation of drug-resistant Plasmodium falciparum
genotypes in pregnancy-associated malaria: 9-year results
from the QuEERPAM study

March 2012

Sulfadoxine-pyrimethamine (SP) has been widely deployed in Africa for malaria control and molecular evidence of parasite drug-resistance is prevalent. However, the temporal effects on the selection of Plasmodium falciparum are not well understood. A retrospective serial cross-sectional study was conducted between 1997 and 2006 to investigate changes in drug-resistant malaria among pregnant women delivering at a single hospital in Blantyre, Malawi. P. falciparum parasites were genotyped for parasite clone multiplicity and drug-resistance mutations, and the strength of selection upon mutant genotypes was quantified. Results underscore the pressing need for new preventive measures for pregnancy-associated malaria and provide a real-world model of the selection landscape malaria parasites.

Combination of probenecid-sulphadoxine-pyrimethamine for intermittent preventive treatment in pregnancy

February 2012

The antifolate sulphadoxine-pyrimethamine (SP) has been used in the intermittent prevention of malaria in pregnancy (IPTp). SP is an ideal choice for IPTp, however, as resistance of Plasmodium falciparum to SP increases, data are accumulating that SP may no longer provide benefit in areas of high-level resistance. Probenecid was initially used as an adjunctive therapy to increase the blood concentration of penicillin; it has since been used to augment concentrations of other drugs, including antifolates. The addition of probenecid has been shown to increase the treatment efficacy of SP against malaria, suggesting that the combination of probenecid plus SP may prolong the useful lifespan of SP as an effective agent for IPTp. Here, the literature on the pharmacokinetics, adverse reactions, interactions and available data on the use of these drugs in pregnancy is reviewed, and the possible utility of an SP-probenecid combination is discussed. This article concludes by calling for further research into this potentially useful combination.

LSTM study by MiP Consortium members leads WHO to update its malaria prevention policy

February 2013

Members of the MiP Consortium, together with other leading scientisits have published a systematic review and meta-analysis on Intermittent Preventive Therapy for Malaria During Pregnancy Using 2 vs 3 or More Doses of Sulfadoxine-Pyrimethamine and Risk of Low Birth Weight in Africa in the February 2013 edition of the Journal of the American Medical Association (JAMA).

The study led by Liverpool School of Tropical Medicine has been a critical element in helping the World Health Organization (WHO) to update its policy recommendation on intermittent preventive treatment for the prevention of malaria in pregnant women (IPTp) who live in malaria-endemic regions of sub-Saharan Africa.

For more information on the article, please view the latest MiPc press release, available online at the MiPc and LSTM websites.

MiP Consortium members and stakeholders present at Challenges in Malaria Research Conference in Basel, Switzerland

October 2012

Members and stakeholders from the MiP Consortium will coordinate and act as keynote speakers during the forthcoming 2 day conference to be held between 10-12 October 2012 in Basel, Switzerland. The "Challenges in Malaria Research: Progress Towards Elimination" conference is hosted by the BioMed Central, in conjunction with its journals Malaria Journal and Parasites & Vectors.

Following the success of the inaugural malaria conference in 2010, entitled “Parasite to Prevention: Advances in the understanding of malaria”, this second conference will bring together leading malaria researchers to review current progress and to chart future challenges. Internationally renowned speakers will present their insights into malaria elimination, including social science and policies; Artemisinin resistance; new drugs; vaccines; diagnostic challenges and vector controls.

For more information on the Challenges conference including the latest agenda visit here.

MiP Consortium members attend Maternal Health Task Force Technical Meeting in Istanbul, Turkey

June 2012

New clinician joins crucial MiP Consortium IPTp study in Papua New Guinea

May 2012

Dr. Holger Unger originally from Scotland recently joined the Papua New Guinea Institute of Medical Research (IMR), Port Moresby, PNG as project clinician working with the IPTp team on “Intermittent preventive treatment with azithromycin-containing regimens for the prevention of malarial infections and anaemia and the control of sexually transmitted infections in pregnant women in Papua New Guinea”.

The IPTp study began recruiting women late in 2009, with the aim of enrolling almost 3000 women across seven sites around Madang, PNG in their second trimester of pregnancy. These women are followed until delivery and their babies until their first birthday.

The committed team also work closely on a number of collaborative malaria in pregnancy sub-studies with the University of Melbourne, Australia including: understanding the use of combined treatment of malaria and sexually transmitted infections (STIs), betelnut chewing and pregnancy, and maternal malaria prevention and early childhood illnesses.

A recent media article about the studies has been published by the IMR in their quarterly newsletter. For details see here.

MiP Consortium PREGACT initiative undertakes pioneering research into the safety and efficacy of new combination ACT’s

May 2012

Coordinated by Prof. Umberto D’Alessandro at the Institute of Tropical Medicine, Antwerp, the PREGACT study “Safe and efficacious artemisinin-based combination treatments for African pregnant women with malaria” aims to study the effects of newly-available artemisinin-based combination treatments on P.faciparum infected pregnant women and to collect explanatory variables for treatment failure and recurrent parasitaemia.

The PREGACT study began recruiting women in the second and third trimester of pregnancy across 4 treatment centres in Burkina Faso, Ghana, Malawi and Zambia in 2010, with the aim of enrolling 3840 women by the end of 2012.

A dissemination document highlighting the study has been published in the online journal International Innovation. For details see here.

MiP Consortium Multicentre Mefloquine treatment study concludes recruitment
March 2012

The MiP Consortium is pleased to announce the completion of recruitment for the multi-centre study “Evaluation of alternative antimalarial drugs to sulfadoxine-pyrimethamine for intermittent preventive treatment in pregnancy (IPTp) in the context of insecticide treated nets” coordinated by Prof. Clara Menendez, of the Barcelona Centre for International Health Research (CRESIB, Hospital Clínic-Universitat de Barcelona), Barcelona, Spain and Dr. Meghna Desai, from Kenya Medical Research Institute/ Centers for Disease Control and Prevention, (Kemri CDC), Kisumu, Kenya.

The study, conducted in 5 African countries: Mozambique, Benin, Gabon, Tanzania and Kenya, aims to evaluate the safety, tolerability and efficacy of an alternative drug for preventive treatment of malaria in pregnancy. Up to the end of January 2012, the study has recruited 4,734 pregnant women.

A press release from study co-funders EDCTP can be downloaded here. For further details about the study visit the MiP Consortium project page or read the EDCTP project profile here.