The Expert Committee recommended the listing of sulfadoxine + pyrimethamine
500 mg + 25 mg fixed-dose combination tablet on the core list of the EML for
the new indication of intermittent preventive treatment of malaria in pregnancy
(IPTp) on the basis of demonstrated efficacy in terms of improved outcomes
for mothers and newborns, and acceptable safety, and in alignment with WHO
malaria treatment guidelines.
The Expert Committee noted the lack of evidence of the impact of the
use of SP-IPTp on antimicrobial resistance, and encouraged further assessment
and monitoring in this regard within programme delivery.
The application requested listing of sulfadoxine + pyrimethamine (SP) fixeddose
combination tablet on the core list of the EML for the new indication of
intermittent preventive treatment (of malaria) in pregnancy (IPTp).
Sulfadoxine + pyrimethamine 500 mg + 25 mg tablets are currently included
on the EML and EMLc for use in combination with artesunate 50 mg for the
curative treatment of malaria.
Public health relevance
Malaria is one of the leading causes of illness, death, and lost economic
productivity globally. While there has been successful scale up and use of critical
commodities, malaria still resulted in over 219 million cases and more than
435 000 deaths in 2017; most of the deaths occurred in children under 5 years of
age and pregnant women (1).
In sub-Saharan Africa (SSA), over 30 million pregnant women are
annually exposed to infection from malaria (2). Of these, an estimated 10 000
pregnant women and up to 200 000 newborns die from malaria in pregnancy
(MiP), primarily due to infection with Plasmodium falciparum (3). Furthermore,
recent data indicate that up to 20% of stillbirths in SSA are attributable to
WHO recommends that IPTp-SP be given to all pregnant women at
each antenatal care visit, starting as early as possible in the second trimester (i.e.
not during the first trimester) (5). Each IPTp-SP dose should be given at least
one month apart, with at least three doses during each pregnancy. The expected
benefits of IPTp-SP include:
–– Prevention of the adverse consequences of malaria on maternal
and fetal outcomes, such as placental infection, clinical
malaria, maternal anaemia, fetal anaemia, low-birth-weight
and neonatal mortality (6).
–– A cost-effective intervention for both prevention of maternal
malaria and reduction of neonatal mortality in areas with
moderate or high malaria transmission (7).
–– Protection against both neonatal mortality (protective efficacy
18%) and low-birth-weight (21% reduction) under routine
programme conditions (8).
To date, 39 African countries have adopted this policy. However, there
is an unacceptably low proportion of eligible pregnant women receiving IPTp
with quality-assured SP: only an estimated 22% of pregnant women received
three doses of IPTp-SP in 2017 (1). It has been estimated that if all women with
at least three antenatal care visits in Africa received IPTp-SP, that an additional
215 000 (95% credible interval (crI) 128 000 to 318 000) low-birth-weight
deliveries could be prevented (9).
The application presented the findings of a systematic review of seven trials (6281
pregnancies) in which a direct comparison of two doses of IPTp-SP with three or
more doses at least one month apart was evaluated (10). The trials were conducted
in Burkina Faso, Kenya, Malawi, Mali and Zambia between 1996 and 2008. In
comparison with two doses of SP, three or more doses was associated with:
■ increased mean birth weight by an average of 56 g (95%CI 29 to 83;
seven trials, 2190 participants, high quality evidence);
■ fewer low-birth-weight infants by about 20% (relative risk (RR) 0.80;
95%CI 0.69 to 0.94; absolute risk reduction, 33 per 1000 (95%CI 10 to
52); NNT = 31; seven trials, 2190 participants, high quality evidence);
■ reduced placental parasitaemia by about 50% (RR, 0.51; 95%CI 0.38
to 0.68; absolute risk reduction, 31 per 1000 (95%CI 20 to 39); six
trials, 1436 participants, high quality evidence); and
■ reduced maternal parasitaemia by about 33% (RR, 0.68; 95%CI 0.52
to 0.89; seven trials, 2096 participants, moderate quality evidence).
The reduction in risk for low-birth-weight was consistent for a wide
range of levels of resistance to SP.
There were no differences in rates of serious adverse events between treatment
groups in the systematic review mentioned above (10).
IPTp-SP is generally very well tolerated. Mild and transient side-effects
including nausea, vomiting, weakness and dizziness have been reported by some
women, particularly with the first dose. Studies have demonstrated that sideeffects
tend to decrease with the administration of further doses (11, 12).
The adverse effects reported are mainly those associated with
sulfonamides, including gastrointestinal disturbances, headache, dizziness and
skin reactions such as photosensitivity, rash, pruritus, urticaria and slight hair loss
(13–16). Potentially fatal skin reactions, namely erythema multiforme, Stevens–
Johnson syndrome and toxic epidermal necrolysis, have also been reported.
Demonstrated drug–drug interactions have been observed between
SP and high doses (>5 mg) folic acid resulting in reduced efficacy of SP
(17). Concurrent use with trimethoprim, alone or in combination with
sulfamethoxazole should be avoided due to increased risk of severe cutaneous
There is limited evidence of potential teratogenicity when SP is used
during the first trimester of pregnancy (13, 19). Use of SP during the first
trimester is not recommended.
Cost / cost effectiveness
SP is an inexpensive medicine, and most countries already have a delivery
system for IPTp-SP in place, which is often integrated into a comprehensive
focused antenatal care (FANC) package.
In comparison to placebo, in Mozambique, delivery of two doses
of IPTp-SP has been estimated to cost US$ 41.46 (95%CI 20.50 to 96.70) per
maternal outpatient visit averted. This same study estimated an incremental
cost effectiveness ratio (ICER) of US$ 1.08 (95%CI 0.43 to 3.48) per disabilityadjusted
life-year (DALY) averted (7). Additionally, using data from seven
countries, the incremental cost-effectiveness of three or more doses of IPTp-SP
(compared to two doses) has been estimated at US$ 7.28 (20).
The WHO recommendations on intermittent screening and treatment in
pregnancy and the safety of ACTs in the first trimester (21) state that IPTp-SP
remains highly cost-effective in preventing the adverse consequences of malaria
on maternal and fetal outcomes, and should therefore be actively scaled up in
line with the current WHO recommendations. The threshold level of malaria
transmission below which IPTp-SP is no longer cost-effective has not been
identified. Therefore, in areas where IPTp-SP is implemented and transmission
has been reduced to low levels as a result of successful control strategies, WHO
recommends continued IPTp-SP implementation until the area approaches
interruption of transmission.
The 2015 WHO Guidelines for the treatment of malaria (5) make the following
recommendation regarding IPTp-SP:
In malaria-endemic areas in Africa, provide IPTp-SP to all women in
their first or second pregnancy as part of antenatal care. Dosing should start
in the second trimester and doses should be given at least one month apart,
with the objective of ensuring that at least three doses are received (strong
recommendation, high quality evidence).
Quality assured sulfadoxine + pyrimethamine 500 mg + 25 mg tablets are
available from Guilin Pharmaceuticals (China) with WHO prequalification
status. Quality-assured sulfadoxine + pyrimethamine 500 mg/25 mg tablets are
also available from Remedica Pharmaceuticals (Cyprus).
Starting as early as possible in the second trimester, IPTp-SP is recommended
for all pregnant women at each scheduled antenatal care visit until the time of
delivery, provided that the doses are given at least one month apart. IPTp-SP
should ideally be administered as directly observed therapy (DOT) of three
tablets sulfadoxine + pyrimethamine 500 mg + 25 mg giving the total required
dosage of 1500 mg + 75 mg SP.
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