Administering antimalarial drugs to prevent malaria in infants

What is the aim of the review?

This Cochrane Review aimed to find out if administering repeated doses of antimalarial treatment to infants living in sub-Saharan Africa can prevent malaria. We found and analysed results from 12 relevant studies conducted between 1999 and 2013 that addressed this question in infants (defined as young children aged between 1 to 12 months).

Key messages

Intermittent preventive treatment with sulfadoxine-pyrimethamine (SP)

Giving SP as preventive antimalarial treatment to infants probably reduced the risk of clinical malaria, anaemia, and hospital admissions in the African countries it was evaluated. However, this effect was attenuated in more recent studies.

Intermittent preventive treatment with artemisinin-based combination therapy (ACT)

Giving ACT as preventive antimalarial treatment to infants may reduce the risk of clinical malaria. It may also reduce the proportion of infants with malaria parasites in their blood.

What was studied in the review?

In areas where malaria is common, infants often suffer repeated episodes of malarial illness. In areas where malaria transmission occurs all-year, some authorities recommend intermittent preventive treatment, which requires giving drugs at regular intervals (at child vaccination visits) regardless of whether the child has malaria symptoms or not to prevent malarial illness.

We studied the effects of IPTi with SP and other medicines (including ACTs) on malaria-related outcomes. Review outcomes included clinical malaria, severe malaria, death, hospital admission, parasitaemia, anaemia, change in haemoglobin level, and side effects.

What are the main results of the review?

We included 12 studies that enrolled 19,098 infants. All studies were done in sub-Saharan Africa (Gabon, Ghana, Kenya, Mali, Mozambique, Tanzania, and Uganda). These studies compared infants who received IPTi to those who received placebo pills or nothing. The infants in the IPTi group were given different medicines, in different doses, and for different lengths of time.

Ten studies evaluated IPTi with SP from 1999 to 2013. The effect of SP appear to wane over time, with trials conducted after 2009 showing little or no effect of the intervention. The studies show that IPTi with SP probably resulted in fewer episodes of clinical malaria, anaemia, hospital admission, and blood parasites without symptoms (moderate-certainty evidence). IPTi with SP probably made little or no difference to the risk of death (moderate-certainty evidence).

Since 2009, IPTi some small studies have evaluated artemisinin-based combination medicines and indicate impact on clinical malaria and blood parasites. A small study of IPTi with dihydroartemisinin-piperaquine in 2013 showed up to 58% reduction in episodes of clinical malaria (moderate-certainty evidence) and reductions in proportion of infants with blood parasites (moderate-certainty evidence).

How up-to-date is this review?

The review authors searched for studies published up to 3 December 2018.

Authors' conclusions: 

In areas of sub-Saharan Africa, giving antimalarial drugs known to be effective against the malaria parasite at the time to infants as IPT probably reduces the risk of clinical malaria, anaemia, and hospital admission. Evidence from SP studies over a 19-year period shows declining efficacy, which may be due to increasing drug resistance. Combinations with ACTs appear promising as suitable alternatives for IPTi.

Read the full abstract...
Background: 

Intermittent preventive treatment could help prevent malaria in infants (IPTi) living in areas of moderate to high malaria transmission in sub-Saharan Africa. The World Health Organization (WHO) policy recommended IPTi in 2010, but its adoption in countries has been limited.

Objectives: 

To evaluate the effects of intermittent preventive treatment (IPT) with antimalarial drugs to prevent malaria in infants living in malaria-endemic areas.

Search strategy: 

We searched the following sources up to 3 December 2018: the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (the Cochrane Library), MEDLINE (PubMed), Embase (OVID), LILACS (Bireme), and reference lists of articles. We also searched the metaRegister of Controlled Trials (mRCT) and the WHO International Clinical Trials Registry Platform (ICTRP) portal for ongoing trials up to 3 December 2018.

Selection criteria: 

We included randomized controlled trials (RCTs) that compared IPT to placebo or no intervention in infants (defined as young children aged between 1 to 12 months) in malaria-endemic areas.

Data collection and analysis: 

The primary outcome was clinical malaria (fever plus asexual parasitaemia). Two review authors independently assessed trials for inclusion, evaluated the risk of bias, and extracted data. We summarized dichotomous outcomes and count data using risk ratios (RR) and rate ratios respectively, and presented all measures with 95% confidence intervals (CIs). We extracted protective efficacy values and their 95% CIs; when an included trial did not report this data, we calculated these values from the RR or rate ratio with its 95% CI. Where appropriate, we combined data in meta-analyses and assessed the certainty of the evidence using the GRADE approach.

Main results: 

We included 12 trials that enrolled 19,098 infants; all were conducted in sub-Saharan Africa. Three trials were cluster-RCTs. IPTi with sulfadoxine-pyrimethamine (SP) was evaluated in 10 trials from 1999 to 2013 (n = 15,256). Trials evaluating ACTs included dihydroartemisinin-piperaquine (1 trial, 147 participants; year 2013), amodiaquine-artesunate (1 study, 684 participants; year 2008), and SP-artesunate (1 trial, 676 participants; year 2008). The earlier studies evaluated IPTi with SP, and were conducted in Tanzania (in 1999 and 2006), Mozambique (2004), Ghana (2004 to 2005), Gabon (2005), Kenya (2008), and Mali (2009). One trial evaluated IPTi with amodiaquine in Tanzania (2000). Later studies included three conducted in Kenya (2008), Tanzania (2008), and Uganda (2013), evaluating IPTi in multiple trial arms that included artemisinin-based combination therapy (ACT).

Although the effect size varied over time and between drugs, overall IPTi impacts on the incidence of clinical malaria overall, with a 27% reduction (rate ratio 0.73, 0.65 to 0.82; 10 studies, 10,602 participants). The effect of SP appeared to attenuate over time, with trials conducted after 2009 showing little or no effect of the intervention. IPTi with SP probably resulted in fewer episodes of clinical malaria (rate ratio 0.79, 0.74 to 0.85; 8 trials, 8774 participants, moderate-certainty evidence), anaemia (rate ratio 0.82, 0.68 to 0.98; 6 trials, 7438 participants, moderate-certainty evidence), parasitaemia (rate ratio 0.66, 0.56 to 0.79; 1 trial, 1200 participants, moderate-certainty evidence), and fewer hospital admissions (rate ratio 0.85, 0.78 to 0.93; 7 trials, 7486 participants, moderate-certainty evidence). IPTi with SP probably made little or no difference to all-cause mortality (risk ratio 0.93, 0.74 to 1.15; 9 trials, 14,588 participants, moderate-certainty evidence).

Since 2009, IPTi trials have evaluated ACTs and indicate impact on clinical malaria and parasitaemia. A small trial of DHAP in 2013 shows substantive effects on clinical malaria (RR 0.42, 0.33 to 0.54; 1 trial, 147 participants, moderate-certainty evidence) and parasitaemia (moderate-certainty evidence).

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