This is an interim intervention report. We have spent limited time to form an initial view of this program and, at this point, our views are preliminary. We may undertake additional work on this program in the future.
- What is the problem? Pregnant women living in malaria-endemic areas are particularly susceptible to malaria infection, creating health risks for both the mother and child.
- What is the program? Intermittent preventive treatment of malaria during pregnancy (IPTp) is a preventive regimen of the antimalarial drug sulfadoxine-pyrimethamine (SP) to be given monthly to all at-risk pregnant women in their second and third trimesters. Each dose treats existing malaria infection in the mother and may protect against new infections for several weeks after receipt.
- What is its evidence of effectiveness? Based on a Cochrane Collaboration meta-analysis of seventeen randomized controlled trials (RCTs), IPTp has mixed evidence of effectiveness for the outcomes we consider most relevant: reducing malaria infections in pregnant women and reducing low birthweight in infants. Specifically, its benefits may be limited to a relatively small proportion of treated women. IPTp appears to be effective at reducing malaria infections and anemia in pregnant women, and reducing low birthweight in infants, though these results come from studies assessing mothers in their first pregnancies. The program may not be effective at generating these outcomes for women with previous pregnancies. The program’s impacts on maternal and infant mortality are uncertain, but it is plausible that reducing malaria infections would reduce mortality. Our current best guess is that IPTp reduces mortality from malaria in women and infants, but we would need to do further work to investigate this preliminary conclusion and determine the magnitude of the effect. Because of the limited nature of this report, we have yet to investigate why program results might only hold for women in their first pregnancy. We also have outstanding questions about the risk of several potential negative consequences of the intervention.
- How cost-effective is it? Our preliminary estimates indicate that IPTp is not as cost-effective as our other priority programs, including other interventions that also treat malaria.
- Does it have room for more funding? According to World Health Organization (WHO) estimates, IPTp coverage in regions affected by malaria remains low, so we would guess that there is substantial room for more funding.
- Bottom line: We do not currently consider IPTp a priority program, but we have not yet conducted a thorough review.
Published: October 2018
What is the problem?
Pregnant women living in malaria-endemic areas are particularly susceptible to malaria infections and are also more likely to develop severe malaria infections, which may pose health risks to pregnant women and their fetuses.1 Malaria infection during pregnancy may lead to low birthweight and pre-term deliveries, and it may also increase mortality rates for mother and child.2
What is the program?
Intermittent preventive treatment in pregnancy (IPTp) is a prophylactic regimen of antimalarial medicine for pregnant women. The World Health Organization (WHO) recommends administering between three and six doses of IPTp using the antimalarial drug sulfadoxine-pyrimethamine (IPTp-SP) to all pregnant women living in areas with moderate to high malaria transmission, including women not currently infected with malaria.3 HIV-positive women taking antiretroviral drugs should not receive the treatment.4 WHO further advises that these treatments should be avoided in the first trimester of pregnancy, begin in the second trimester for maximum impact, and continue to be received at one month intervals until birth.5 Each dose of IPTp-SP treats any existing malaria infection and continues to protect against new infections for a few weeks after receipt.6
Does the program have strong evidence of effectiveness?
To evaluate the effectiveness of IPTp interventions, we relied on Radeva-Petrova et al. 2014, a Cochrane Collaboration meta-analysis of seventeen randomized controlled trials (RCTs) and quasi-RCTs that compared treatment with various IPTp regimens during pregnancy to no preventive treatment.
Note: this evidence base is complicated because trials sometimes used a woman’s number of previous pregnancies as an enrollment criterion, and the results from the trials appear to differ based on this criterion. Trials that enrolled women with fewer previous pregnancies (mostly first pregnancies) had stronger results than trials that enrolled women with two or more previous pregnancies or trials that didn't use the number of previous pregnancies as an enrollment criterion. Because of the limited nature of this report, we have not yet tried to understand why the number of previous pregnancies would affect the results or why studies differed on this enrollment criterion; this remains an unanswered question.
Overall, the evidence does not show strong evidence to support the effectiveness of IPTp programs across the entire population of pregnant women.
The results of IPTp regimens differ markedly for studies limited primarily to mothers in their first pregnancy7 compared to studies across the entire population with no restrictions on birth order:
- For studies that recruited mothers across all birth orders, the meta-analysis does not find strong evidence of any effects of treatment. This includes a lack of significant improvements in most maternal indicators of infection and an estimate of zero improvement in birthweight outcomes for newborns.8
- For mothers in their first pregnancy, the meta-analysis finds statistically significant reductions in maternal infection with malaria parasites and anaemia, as well as increases in mean birthweight, reductions in low birthweight, and fewer cases where malaria parasites were detected in the placenta.9 However, the meta-analysis found evidence suggesting that the impact on birthweight may have decreased over time.10
Both sets of studies had a relatively large number of participants contributing data on birthweight, and the total sample size for the studies that included all births was larger than for the studies of first pregnancies.11
Neither of these groups of studies found statistically significant evidence of mortality effects from the program, but this evidence is not conclusive since the studies generally did not have enough participants to detect differences in relatively rare outcomes like mortality.12 The mortality evidence that the Cochrane authors rate most highly is "moderate quality" evidence that the program did not avert stillbirths and perinatal, neonatal, or infant deaths in the studies that recruited all birth orders.13 However, we believe that if the program reduces malaria infections, this is a plausible mechanism that likely leads to reductions in mortality from malaria.
We have not yet researched observational evidence for IPTp that may provide additional information about the program at a large-scale population level, including evidence cited by WHO in support of its guidelines and observational evidence on mortality. According to the Cochrane authors, RCT-based meta-analysis results are broadly consistent with, and perhaps stronger than, results from observational studies due to better treatment compliance.14
Potential negative impacts of the program
Launching a large-scale IPTp program poses several risks. We would need to conduct additional research on these issues to form an opinion on the likelihood that any of these factors would lead to major negative consequences from IPTp. More information is available here, where we have considered similar issues in the context of seasonal malaria chemoprevention programs.
The risks of IPTp include:
- A risk of increasing rates of SP drug resistance that would make the drug less effective or ineffective at treating malaria for people living in the program region. According to WHO, IPTp-SP may still be effective in areas with SP resistance,15 but we are unsure to what degree scaling up its use may accelerate resistance and eventually render the drug ineffective at attacking malaria parasites.
- A potential risk of harming the embryo or reducing the effectiveness of treatment if IPTp is administered during the first trimester of pregnancy. Based on very limited research, it appears that this risk is related to the interaction between the SP drug and folic acid, but we would need to do further research to understand the extent of this risk in practice.16
- A risk of adverse drug reactions if HIV-positive women receive IPTp and certain antiretroviral drugs concurrently.17
Is the program cost-effective?
We created a rough cost-effectiveness estimate for this program (see our model here) that suggests IPTp may be similar in cost-effectiveness to GiveDirectly’s cash transfers program but below the cost-effectiveness range of our other priority programs, including other malaria-related interventions.
Note that our cost-effectiveness analyses are simplified models that do not take into account a number of factors. There are limitations to this kind of cost-effectiveness analysis, and we believe that cost-effectiveness estimates such as these should not be taken literally, due to the significant uncertainty around them. We provide these estimates (a) for comparative purposes and (b) because working on them helps us ensure that we are thinking through as many of the relevant issues as possible.
Major uncertainties in our model include:
- Treatment costs per person. Our cost-effectiveness estimate uses a preliminary cost estimate of $40 per treated woman from Malaria Consortium for an IPTp pilot program, but these costs are highly uncertain and may fall as a hypothetical program scales up.18
- Increase in adult consumption from increases in birthweight. Our model assumes that increases in early life growth will confer developmental benefits that cause increases in adult consumption/income. The data that underlie this assumption are from studies of birth weight differences between identical twins and are highly uncertain in this context.
- The proportion of pregnancies that benefits from treatment. This program appears to improve birthweight in first pregnancies, but not later ones. We model cost-effectiveness by assuming that the program would attempt to treat all pregnant women, but only a fraction of pregnancies would receive the estimated birthweight benefit while the rest would not benefit. Since the estimated population birthweight benefit (from studies recruiting all birth orders) is zero, we can also see an argument that the overall expected benefit should be zero.19 Researching reasons for this difference in results would be a key focus of further investigation.
- Mortality reductions for pregnant women and children attributable to IPTp. Our preliminary cost-effectiveness model includes rough estimates for mortality benefits of the program. Direct RCT mortality data are based on limited evidence that is not statistically significant, making our assumptions about mortality benefits very uncertain. We instead model mortality reductions for women and children indirectly based on the RCT evidence for reductions in malaria infections.
Does the program have room for more funding?
We would guess that this program has substantial room for more funding as program coverage rates remain low. WHO reports that among countries that have already adopted IPTp-SP, less than 20% of eligible women receive the minimum recommended number of doses.20
Focus of further investigation
Questions we would ask as part of further investigation include:
- Why do IPTp treatment outcomes differ so much by birth order?
- How serious are the program risks that we have identified above (inducing drug resistance, drug interactions, or folic acid interactions)?
- How do outcomes from the WHO-recommended SP drug compare to other antimalarial drugs used in the RCTs or that could be used for IPTp? In the Cochrane review, the authors found that results on first pregnancies in an analysis limited to SP studies were similar to the main results on first pregnancies in analyses that included studies using other antimalarial drugs,21 but we have not looked at these results in detail.
- How did the number of IPTp treatments per pregnant woman and their timing differ between the RCTs and what the average woman might receive today outside of clinical trials? How might any differences affect program results?
- Why does program impact seem to be declining over time in trials?
- How much less effective is IPTp today than during trials, due to SP drug resistance?
- Is there large-scale observational evidence available on the relationship between IPTp and mortality that is more informative than the RCT evidence we have considered?
- What are the long-term outcomes for children whose mothers were treated with IPTp?
- This program seems complex to implement at scale in accordance with the WHO guidelines above, and the WHO reports that implementation difficulties may have hampered past program efforts.22 As a result, we have remaining uncertainties about the feasibility of the program, including how difficult it is to identify gestational age correctly, to avoid treating HIV-positive women, and to generate demand for at least three doses of IPTp to each pregnant woman.
- Does simultaneous use of IPTp and insecticide-treated nets reduce the effectiveness of either treatment?
|Radeva-Petrova et al. 2014||Source (archive)|
|WHO, Intermittent preventive treatment in pregnancy (IPTp), 2018||Source (archive)|
|WHO et al. 2018||Source (archive)|
|ScienceDirect Summary, Pyrimethamine||Source (archive)|
“[P]regnancy is known to increase the risk of malaria infection and the severity of the illness compared to non-pregnant women in the same age group.” Radeva-Petrova et al. 2014, p. 6.
- “IPTp reduces maternal malaria episodes, maternal and fetal anaemia, placental parasitaemia, low birth weight, and neonatal mortality.” WHO, Intermittent preventive treatment in pregnancy (IPTp), 2018
- “Studies have also shown a strong association between malaria infection in pregnancy and consequent maternal anaemia, and low birthweight in infants, particularly in women in their first or second pregnancy.” Radeva-Petrova et al. 2014, p. 6.
“Intermittent preventive treatment of malaria in pregnancy is a full therapeutic course of antimalarial medicine given to pregnant women at routine antenatal care visits, regardless of whether the recipient is infected with malaria. . . .
WHO recommends IPTp with sulfadoxine-pyrimethamine (IPTp-SP) in all areas with moderate to high malaria transmission in Africa.” WHO, Intermittent preventive treatment in pregnancy (IPTp), 2018
“Pregnant women living with HIV and taking co-trimoxazole prophylaxis should not receive SP, as concomitant administration of SP and co-trimoxazole could increase adverse drug reactions. When taken daily, co-trimoxazole provides protection against MiP. Despite this, it is especially important that pregnant women living with HIV sleep under an ITN, and seek prompt diagnosis and receive effective treatment if they experience symptoms of malaria.” WHO et al. 2018, p. 5.
- "As of October 2012, WHO recommends that this preventive treatment be given to all pregnant women starting as early as possible in the second trimester (i.e. not during the first trimester). The women should receive at least 3 doses of SP during her pregnancy, with each dose being given at least 1 month apart – SP can safely be administered up until the time of delivery." WHO, Intermittent preventive treatment in pregnancy (IPTp), 2018
- "The period between 13 and 20 weeks is critical for irreversible negative consequences of MiP [Malaria in Pregnancy], when parasite densities are highest, and major benefit can be achieved from malaria prevention. For effective MiP programming, contact with a health provider early in the second trimester (between 13 and 16 weeks) is critical to ensuring timely access to the first dose of IPTp-SP for maximal impact." WHO et al. 2018, p. 2.
“[IPTp] combines elements of a treatment effect through clearance or suppression of existing malaria infections in the placental and peripheral blood of mother, and a post-treatment prophylactic effect by preventing new infections for several weeks after each dose.” Radeva-Petrova et al. 2014, p. 6.
We refer to this set of studies as "results on first pregnancies" in this report for simplicity, but second pregnancies make up a small proportion of the treatment group in these trials (about 12.5%, if we assume that first and second pregnancies are represented equally in studies that included both). In contrast, the Radeva-Petrova et al. 2014 meta-analysis refers to this set of studies as results on first and second pregnancies. However, we are unsure to what extent the results apply to second pregnancies, since they are primarily based on first pregnancies. We have not seen results for second pregnancies alone.
- “In trials giving chemoprevention to all pregnant women irrespective of parity, the average effects of chemoprevention measured in all women indicated it may prevent severe anaemia (defined by authors, but at least < 8 g/L: RR 0.19, 95% CI 0.05 to 0.75; two trials, 1327 participants, low quality evidence), but consistent benefits have not been shown for other outcomes.” P. 2.
- According to the "infant outcomes" table on pp. 27-28, the evidence suggests that IPTp had no effect on mean birthweight (treatment mean 0.54 grams lower, 95% CI 24.6 g lower to 23.6 g higher, moderate quality evidence). The estimated incidence of low birthweight was in fact slightly higher for infants whose mothers were treated, but this result was not statistically significant (RR 1.06, 95% CI 0.89 to 1.27, low quality evidence).
- For maternal outcomes, “Chemoprevention was associated with fewer episodes of presumed clinical malaria (history of fever), but this outcome was only reported in two small trials (RR 0.37, 95% CI 0.18 to 0.74; two trials, 307 participants, Analysis 1.5, low quality evidence). Instead most trials reported antenatal parasitaemia, defined as either parasitaemia at delivery or parasitaemia at 34 to 36 weeks, with most trials showing benefits but wide variation in the size of the reduction (RR 0.39, 95% CI 0.26 to 0.58; eight trials, 3663 participants, I2 = 82; Analysis 1.6, high quality evidence). This heterogeneity is probably not unexpected given the differences in chemoprevention regimens and malaria endemicity.” Pp. 14-15.
- ”Overall, chemoprevention was associated with a 40% reduction in the risk of moderate to severe anaemia in the third trimester (RR 0.60, 95% CI 0.47 to 0.75; three trials, 2503 participants, Analysis 1.2, high quality evidence)... Chemoprevention was also associated with a reduction in the risk of any anaemia (defined as Hb < 10/11/12 g/dL or PCV < 33%/30%), although this reduction was generally of smaller magnitude (RR 0.83, 95% CI 0.74 to 0.93; five trials, 3662 participants, Analysis 1.3, high quality evidence).” P. 14.
- For infant outcomes, “Chemoprevention was associated with fewer low birthweight infants (RR 0.73, 95% CI 0.61 to 0.87; eight trials, 3619 participants, Analysis 1.14, moderate quality evidence). and mean birthweight was higher with chemoprevention (MD 92.72 g, 95% CI 62.05 to 123.39; nine trials, 3936 participants, Analysis 1.15, moderate quality evidence).” P. 15.
- ”Chemoprevention resulted in fewer cases of placental parasitaemia (RR 0.54, 95% CI 0.43 to 0.69; seven trials, 2830 participants, Analysis 1.17, high quality evidence).” P. 15.
“Overall, chemoprevention with SP reduced the incidence of low birthweight but this effect seems to be reducing over time, with large effects in the older trials and no effect seen in the more recent trials using two doses of SP (four trials, 3043 participants, Analysis 2.12, moderate quality evidence). However, mean birthweight was higher with SP, and this effect was still present in the most recent trials (MD 105.5 g, 95% CI 68.02 to 142.9, four trials, 2693 participants, Analysis 2.13, moderate quality evidence)." Radeva-Petrova et al. 2014, p. 16.
The total number of participants summed across treatment and control groups in the mean birthweight analysis was 3,936 for the first pregnancies subset of results and 6,007 for the all births subset. The all births analysis does not include the data from the studies of first pregnancies. Radeva-Petrova et al. 2014, Analysis 1.15, p. 91.
“The evidence for effects on maternal, foetal and neonatal mortality is generally considered of low or very low quality because the trials and the meta-analysis remain significantly underpowered to confidently prove or exclude clinically important effects.” Radeva-Petrova et al. 2014, p. 33.
“In trials recruiting women of all parities, no differences were demonstrated for spontaneous abortions (three trials, 5767 participants, Analysis 1.9, low quality evidence), stillbirths (five trials, 7130 participants, Analysis 1.10, moderate quality evidence), perinatal deaths (four trials, 5216 participants, Analysis 1.11, moderate quality evidence), or neonatal and infant deaths (five trials, 6313 participants, Analysis 1.12, moderate quality evidence). We also pooled across all trials for these outcomes (including those which only recruited women in their first or second pregnancies), and no differences were demonstrated.” Radeva-Petrova et al. 2014, p. 16. (See also infant outcomes table, pp. 27-28.)
“The findings of this Cochrane Review are consistent with previous editions (Garner 2006; ter Kuile 2007). The findings are also consistent with the findings of a review comparing observational and randomized evidence (McClure 2013). McClure 2013 points out that the fairly modest effects seen in RCTs, where delivery of care is often strengthened and adherence assured, were attenuated in the observational studies where, the authors surmise, delivery of the intervention and adherence to it may be attenuated. However, this contrasts with a study estimating the effects of IPT with SP on low birthweight and neonatal mortality from survey data: the trial estimates are remarkably similar to the results observed with IPT with SP from the trial data reported in this and previous analysis.” Radeva-Petrova et al. 2014, p. 33.
"SP is the only drug currently recommended for administration in the context of IPTp, and it is important to note that SP continues to show benefit for both the mother and her baby, even in areas of SP resistance." WHO et al. 2018, p. 2.
- "High doses of 5 mg of folic acid and greater counteract the antimalarial efficacy of SP and should not be given along with SP. In areas where only high-dose folic acid is available, there is presently no scientific consensus on how long high doses of folic acid should be withheld following the dose of SP." WHO et al. 2018, p. 5.
- "Pyrimethamine is an inhibitor of folic acid synthesis that is also used in the treatment of toxoplasmosis and Pneumocystis pneumonia. In malaria treatment it is only applied in combination with another folic acid antagonist such as sulfadoxine (Section 2.6.7). This particular combination is used for intermittent preventive treatment (IPT) during pregnancy. However, increasing resistance has started to limit the effectiveness of this popular combination (Newman 2003).
As animal experiments indicated embryotoxic effects, concerns had been raised about the use of these folic acid antagonists in early pregnancy. Numerous investigations, however, have not demonstrated an increased malformation risk in humans (e.g. Manyando 2010, Phillips-Howard 1996)." ScienceDirect Summary, Pyrimethamine
"Pregnant women living with HIV and taking co-trimoxazole prophylaxis should not receive SP, as concomitant administration of SP and co-trimoxazole could increase adverse drug reactions. When taken daily, co-trimoxazole provides protection against MiP. Despite this, it is especially important that pregnant women living with HIV sleep under an ITN, and seek prompt diagnosis and receive effective treatment if they experience symptoms of malaria." WHO et al. 2018, p. 5.
- 18. This per-person program cost figure is a highly uncertain estimate. It is based on a rough draft of costs for an IPTp pilot program and research study provided to us by Malaria Consortium.
These costs are projections for a potential future program rather than conclusive costs based on experience with an established program. Unit costs seem high, but they incorporate estimated fixed costs for items such as program development, staff training costs, and monitoring & evaluation that are spread over relatively few initial participants. Malaria Consortium has identified the following costs to us as specific to start-up: situational analysis, development of training and BCC tools and messaging that do not exist in the public domain for c-IPTp, and pre-testing of tools for community health workers to determine gestational age to ensure that the SP drug is administered safely after 13 weeks of pregnancy. Malaria Consortium believes that program costs are likely to fall over time as the program scales up and these fixed start-up costs are already covered.
Our cost input excludes additional research study-specific costs from the total. We are not aware of other sources with conclusive cost data for a fully-scaled IPTp distribution program at this time.
- 19. For newborns, the evidence suggests that IPTp had no effect on mean birthweight (treatment mean 0.54 grams lower, 95% CI 24.6 g lower to 23.6 g higher, moderate quality evidence). The estimated incidence of low birthweight was in fact slightly higher for infants whose mothers were treated, but this result was not statistically significant (RR 1.06, 95% CI 0.89 to 1.27, low quality evidence). Radeva-Petrova et al. 2014, "Infant outcomes" table, pp. 27-28
“As of 2016, 36 African countries have adopted a policy of providing 3 or more doses of IPTp-SP to pregnant women. Recent progress in adherence to this policy has increased only marginally: among the 23 countries that reported in 2016, an estimated 19% of eligible pregnant women received 3 or more doses of IPTp, compared with 18% in 2015 and 13% in 2014.” WHO, Intermittent preventive treatment in pregnancy (IPTp), 2018
“In an analysis confined only to intermittent preventive therapy with SP, the estimates of effect and the quality of the evidence were similar.” Radeva-Petrova et al. 2014, p. 2. (See also the "outcomes" tables on pp. 29-32.)
“In high-burden countries, IPTp noticeably lags behind other malaria control measures. This does not appear to be due to low levels of antenatal clinic attendance. Uncertainty among health workers about SP administration for IPTp may have also played a role. Simplified IPTp messages and health worker training have been shown to improve IPTp coverage.” WHO, Intermittent preventive treatment in pregnancy (IPTp), 2018