Malaria during Pregnancy

May combine two claims.

The biology and clinical presentations of Plasmodium falciparum in semi-immune women interfere with diagnosis during pregnancy, rendering targeted interventions ineffective for control.

“the biology and clinical presentations of Plasmodium falciparum in semi-immune women interfere with diagnosis during pregnancy, rendering targeted interventions ineffective for control (Fig. 1).”

Probably not a substantial claim: may not pass S3 (load-bearing).

One hundred and twenty-five million women in malaria-endemic areas become pregnant each year.

“One hundred and twenty-five million women in malaria-endemic areas become pregnant each year (see Dellicour et al. PLoS Med 7: e1000221 [2010])”

• cites Dellicour et al. PLoS Med 7: e1000221 [2010]Not checked yet

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Probably not a substantial claim: may not pass S4 (based).

Pregnant women are an important reservoir of parasites in the community.

“Pregnant women are an important reservoir of parasites in the community”

May combine two claims.

In low and unstable transmission areas, women are infected infrequently but have low immunity and often rapidly progress to severe disease syndromes when infected.

“Where malaria transmission is low and unstable, women are infected infrequently but therefore have low immunity and often rapidly progress to severe disease syndromes when infected.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Primaquine is the leading drug being assessed as a gametocytocidal agent to block parasite transmission to mosquitoes.

“primaquine is the leading drug being assessed as a gametocytocidal agent to block parasite transmission to mosquitoes”

May combine two claims.

Over successive pregnancies, women can acquire antibodies against CSA-binding infected erythrocytes and resistance to placental malaria.

“Over successive pregnancies, women can acquire antibodies against CSA-binding lE and resistance to placental malaria, suggesting that a vaccine is feasible.”

• cites Fried et al. 1998aNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Malaria during pregnancy takes its greatest toll on the offspring, causing substantial perinatal mortality and significant infant mortality in part due to low birth weight.

“Malaria during pregnancy takes its greatest toll on the offspring, causing substantial perinatal mortality and, in part due to low birth weight, significant infant mortality.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

In areas of stable Plasmodium falciparum malaria transmission, approximately 50 million pregnancies occur each year.

“In areas of stable P. falciparum malaria transmission, where approximately 50 million pregnancies occur each year”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

Although congenital malaria can occur, convincing evidence for transplacental infection is lacking.

“Although congenital malaria can occur, convincing evidence for transplacental infection is lacking.”

May combine two claims.

Effective prophylaxis reduces the risk of low birth weight newborns, and low birth weight is a strong predictor for infant mortality.

“Effective prophylaxis reduces the risk of LBW newborns, and LBW is a strong predictor for infant mortality”

May combine two claims.

First-time mothers lack immunity to CSA-binding parasites and are highly susceptible to parasitemia and chronic infections, making this group an important reservoir of infection in the community.

“First-time mothers lack immunity to CSA-binding parasites and are highly susceptible to parasitemia and to chronic infections, making this group an important reservoir of infection in the community.”

May combine two claims.

In the placenta, infected erythrocytes express the PfEMP1 variant VAR2CSA to bind chondroitin sulfate A but not other common endothelial receptors such as CD36 or ICAM-1.

“In the placenta, infected erythrocytes (lEs) express the PfEMP1 variant VAR2CSA to bind chondroitin sulfate A (CSA) but not other common endothelial receptors such as CD36 or ICAM-1.”

• cites Fried and Duffy 1996Not checked yet

  Not checked in the free run.

May combine two claims.

In areas of stable transmission, women are semiimmune and often carry their infections with few or no symptoms.

“women are semiimmune and often carry their infections with few or no symptoms.”

May combine two claims.

The direct measurement of postneonatal mortality exceeds the estimates of mortality that would result from low birth weight, suggesting that other placental-malaria-related mechanisms might contribute to infant deaths.

“The direct measurement of postneonatal mortality exceeds the estimates of mortality that would result from LBW, suggesting that other PM-related mechanisms might contribute to infant deaths.”

May combine two claims.

Extrapolating from the reduction in low birth weight, malaria prevention was estimated to reduce the mortality of neonates born to Gambian primigravidae by 42%, and the postneonatal mortality by 18%.

“extrapolating from this reduction in LBW, malaria prevention was estimated to reduce the mortality of neonates born to Gambian primigravidae by 42%, and the postneonatal mortality by 18% (Greenwood et al. 1992).”

• cites Greenwood et al. 1992Not checked yet

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May combine two claims.

Maternal anemia increases risks of low birth weight, preterm delivery, perinatal mortality, and neonatal mortality in low-and middle-income countries.

“maternal anemia increases risks of LBW, preterm delivery (PTD), perinatal mortality, and neonatal mortality in low-and middle-income countries (Rahman et al. 2016).”

• cites Rahman et al. 2016Not checked yet

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May combine two claims.

In communities in which malaria control has improved and the incidence of malaria decreases, the incidence of Plasmodium falciparum pregnancy malaria also decreases, but malaria-specific antibodies wane and the parasite burden and sequelae during any individual infection increase.

“In communities in which malaria control has improved and the incidence of malaria decreases, the incidence of P. falciparum pregnancy malaria also decreases, but malaria-specific antibodies wane and the parasite burden and sequelae during any individual infection increase (Mayor et al. 2015).”

• cites Mayor et al. 2015Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Primaquine is being explored at low doses as a mass administration tool for elimination, but is contraindicated during pregnancy owing to the risk of hemolysis in G6PD-deficient fetuses.

“the gametocytocidal drug primaquine is being explored at low doses as a mass administration tool for elimination, but is contraindicated during pregnancy owing to the risk of hemolysis in G6PD-deficient fetuses.”

• AssumptionRests on an assumption: Primaquine is contraindicated in pregnancy because the glucose-6-phosphate dehydrogenase status and hence hemolysis risk of the fetus would be unknown.

May combine two claims.

Efforts to target treatment to pregnant women based on malaria diagnoses have generally failed as a control strategy, and control has relied on mass drug administration programs.

“Possibly as a result, efforts to target treatment to pregnant women based on malaria diagnoses have generally failed as a control strategy, and control has relied on mass drug administration programs.”

May combine two claims.

In areas of stable transmission, primigravid women are at greatest risk, and over successive pregnancies women naturally acquire resistance to Plasmodium falciparum that reduces parasite density and prevents disease.

“In areas of stable transmission, primigravid women are at greatest risk, and over successive pregnancies women naturally acquire resistance to P. falciparum that reduces parasite density and prevents disease.”

May combine two claims.

Malaria prevention improves child outcomes, both before and after delivery.

“Malaria prevention similarly improves child outcomes, both before and after delivery.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Disease for mother and offspring often develops as an insidious process, making it difficult to relate outcomes such as severe maternal anemia or low birth weight back to the infection that caused these sequelae.

“Disease for mother and offspring often develops as an insidious process, and this can make it difficult to relate outcomes such as severe maternal anemia or low birth weight (LBW) back to the infection that caused these sequelae.”

May combine two claims.

Chemoprophylaxis with pyrimethamine/dapsone in The Gambia provided significant benefits to primigravid and grandmultigravid women: primigravidae on prophylaxis had lower rates of parasitemia and higher hematocrits.

“Chemoprophylaxis with pyrimethamine/dapsone (Maloprim) in The Gambia provided significant benefits to primigravid (Greenwood et al. 1992) and grandmultigravid ( parity .7)women (Greenwood et al. 1989;Menendez et al. 1994): primigravidae on prophylaxis had lower rates of parasitemia and higher hematocrits.”

• cites Greenwood et al. 1992Not checked yet

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• cites Greenwood et al. 1989Not checked yet

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• cites Menendez et al. 1994Not checked yet

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May combine two claims.

In that trial, PM (by BS or histology), birth weight, and LBW rates were similar between MQ and SP groups.

“The rates of maternal parasitemia (by BS) at delivery, mild anemia at delivery, and clinical malaria during pregnancy were significantly lower in the MQ group, while PM (by BS or histology), birth weight, and LBW rates were similar (Gonzalez et al. 2014a).”

• cites Gonzalez et al. 2014aNot checked yet

  Not checked in the free run.

May combine two claims.

In Plasmodium vivax-endemic areas, management is complicated because primaquine is contraindicated due to fetal hemolysis risk and, therefore, liver hypnozoite parasite forms remain and cause relapses in the mother.

“management is complicated because primaquine is contraindicated due to fetal hemolysis risk and, therefore, liver hypnozoite parasite forms remain and cause relapses in the mother.”

• AssumptionRests on an assumption: Primaquine is contraindicated in pregnancy because the glucose-6-phosphate dehydrogenase status and hence hemolysis risk of the fetus would be unknown.

May combine two claims.

For decades, the increased susceptibility to malaria during pregnancy was attributed to immunological changes associated with pregnancy, but this could not explain the reduction in infection rate and placental parasite burden over successive pregnancies.

“For decades, the increased susceptibility to malaria during pregnancy was attributed to immunological changes associated with pregnancy, but this could not explain the reduction in infection rate and placental parasite burden over successive pregnancies.”

May combine two claims.

Several studies have related placental malaria to increased risks of malaria infection and to severe malaria in offspring during infancy, but this relationship has not been observed in other studies.

“Several studies have related PM to increased risks of malaria infection (Schwarz et al. 2008;Goncalves et al. 2014) and to severe malaria (Goncalves et al. 2014) in offspring during infancy, but this relationship has not been observed in other studies (Awine et al. 2016).”

• cites Schwarz et al. 2008Not checked yet

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• cites Goncalves et al. 2014Not checked yet

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• cites Awine et al. 2016Not checked yet

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May combine two claims.

A prominent feature of Plasmodium falciparum malaria during pregnancy is the accumulation of parasites in the placenta, whereas parasite density in the peripheral circulation is low or undetectable.

“A prominent feature of P. falciparum malaria during pregnancy is the accumulation of parasites in the placenta, whereas parasite density in the peripheral circulation is low or undetectable (Brabin 1983;McGregor 1984).”

• cites Brabin 1983Not checked yet

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• cites McGregor 1984Not checked yet

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May combine two claims.

During pregnancy, infected erythrocytes accumulate in the intervillous spaces or bind to the surface of the syncytiotrophoblast in the placenta.

“During pregnancy, IEs accumulate in the intervillous spaces or bind to the surface of the syncytiotrophoblast in the placenta.”

May combine two claims.

In stable transmission zones, malaria during pregnancy has a unique epidemiology characterized by parity-dependent susceptibility: primigravid women are infected more frequently and with higher placental parasite densities than multigravid women.

“In stable transmission zones, malaria during pregnancy has a unique epidemiology characterized by parity-dependent susceptibility: primigravid women are infected more frequently and with higher placental parasite densities than multigravid women.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

Mixed malaria infections such as Plasmodium falciparum and Plasmodium vivax might also alter pregnancy malaria outcomes, but many mixed infections appear to be mono-infections when diagnosed by peripheral blood smear.

“Mixed malaria infections such as P. falciparum and Plasmodium vivax might also alter pregnancy malaria outcomes, but many mixed infections appear to be mono-infections when diagnosed by peripheral blood smear (BS).”

May combine two claims.

Plasma cytokine levels at birth predict levels measured later during infancy, particularly for interleukin 1b and tumor necrosis factor a, and also predict the risks of malaria infection and severe disease.

“Plasma cytokine levels at birth predict levels measured later during infancy, particularly for interleukin 1b (IL-1b) and tumor necrosis factor a (TNF-a), and also predict the risks of malaria infection and severe disease (Kabyemela et al. 2013)”

• cites Kabyemela et al. 2013Not checked yet

  Not checked in the free run.

May combine two claims.

Analyses of the binding profile of placental infected erythrocytes have shown that this parasite subpopulation adheres to placental chondroitin sulfate A, and not to CD36, which commonly supports the binding of infected erythrocytes from nonpregnant individuals.

“Analyses of the binding profile of placental IE have shown that this parasite subpopulation adheres to placental CSA, and not to CD36, which commonly supports the binding of IE from nonpregnant individuals (Fried and Duffy 1996).”

• cites Fried and Duffy 1996Not checked yet

  Not checked in the free run.

May combine two claims.

Plasmodium vivax, like Plasmodium falciparum, is associated with poor pregnancy outcomes, but, unlike Plasmodium falciparum, sequelae may be more common in multigravid pregnancies.

“P. vivax, like P. falciparum, is associated with poor pregnancy outcomes, but, unlike P. falciparum, sequelae may be more common in multigravid pregnancies (reviewed in Duffy 2001).”

• cites Duffy 2001Not checked yet

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The quote only partly states this claim.

The amount of pigment deposition was significantly higher in the IPTp-SP groups than in the DP groups.

“Although, among primigravid women, the rate of PM was similar between the three groups, the amount of pigment deposition was significantly higher in the IPTp-SP groups, which might indicate higher parasite densities in past infections.”

• cites Kakuru et al. 2016Not checked yet

  Not checked in the free run.

May combine two claims.

In a trial comparing two doses of IPTp with SP or MQ in women who also received long-lasting insecticide-treated nets, rates of maternal parasitemia (by BS) at delivery, mild anemia at delivery, and clinical malaria during pregnancy were significantly lower in the MQ group.

“The rates of maternal parasitemia (by BS) at delivery, mild anemia at delivery, and clinical malaria during pregnancy were significantly lower in the MQ group, while PM (by BS or histology), birth weight, and LBW rates were similar (Gonzalez et al. 2014a).”

• cites Gonzalez et al. 2014aNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

A relationship between placental malaria and cord cytokine profiles has not been defined.

“however, a relationship between PM and cord cytokine profiles has not been defined.”

May combine two claims.

Non-falciparum infections were infrequent and did not appear to impact pregnancy outcomes in West Africa, where Plasmodium vivax was absent outside Mali.

“Non-falciparum infections were infrequent and did not appear to impact pregnancy outcomes in West Africa, where P. vivax was absent outside Mali (Williams et al. 2016).”

• cites Williams et al. 2016Not checked yet

  Not checked in the free run.

May combine two claims.

In this model, the placenta presents a new receptor for infected erythrocyte adhesion, thereby selecting a parasite subpopulation to which women are naive before their first pregnancy, making first-time mothers most susceptible.

“In this model, the placenta presents a new receptor for IE adhesion, thereby selecting a parasite subpopulation to which women are naı ¨ve before their first pregnancy, making first-time mothers most susceptible.”

May combine two claims.

In that comparison, birth weight, LBW, and maternal anemia were similar between IPTp-SP and IPTp-MQ groups.

“PM was significantly less frequent in the MQ group, but other endpoints including birth weight, LBW, and maternal anemia were similar (Briand et al. 2009).”

• cites Briand et al. 2009Not checked yet

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May combine two claims.

In that West African comparison, maternal anemia, infection rate during pregnancy detected by PCR, and birth weight did not differ between groups.

“Maternal anemia, infection rate during pregnancy detected by PCR, and birth weight did not differ between groups.”

• cites Denoeud-Ndam et al. 2014Not checked yet

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May combine two claims.

Dihydroartemisinin-piperaquine has shown promise as monthly presumptive treatment to prevent poor pregnancy outcomes, although it may not reduce PM prevalence.

“dihydroartemisinin -piperaquine has shown promise as the monthly presumptive treatment to prevent poor pregnancy outcomes, although it may not reduce PM prevalence.”

• cites Kakuru et al. 2016Not checked yet

  Not checked in the free run.

May combine two claims.

In a multicenter study in East and Southeast Africa, peripheral and placental parasitemia (defined by BS, PCR, or histology) and nonobstetric admission were less frequent among women who received three doses of IPTp-MQ than among controls.

“and Southeast Africa, peripheral and placental parasitemia (defined by BS, PCR, or histology) and nonobstetric admission were less frequent among women that received three doses of IPTp-MQ, while maternal anemia, birth weight, and gestational age at delivery were similar between groups (Gonzalez et al. 2014b).”

• cites Gonzalez et al. 2014bNot checked yet

  Not checked in the free run.

May combine two claims.

The failure of ISTp-DP to improve on IPTp with the failing drug SP echoes the early evaluation of IPTp-SP in 1992-1994, in which case management was inferior to IPTp-SP.

“The failure of ISTp-DP to improve on IPTp with the failing drug SP echoes the early evaluation of IPTp-SP in 1992-1994(Parise et al. 1998) in which case management was inferior to IPTp-SP.”

• cites Parise et al. 1998Not checked yet

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May combine two claims.

A multicenter trial reported high cure rate with four different ACTs (artemether-lumefantrine, amodiaquine-artesunate, dihydroartemisinin-piperaquine, and mefloquine-artesunate), with artemether-lumefantrine showing the lowest cure rate of 94.8%.

“A multicenter trial reported high cure rate with four different ACTs (artemether-lumefantrine, amodiaquine -artesunate, dihydroartemisinin-piperaquine, and mefloquine -artesunate), with artemether-lumefantrine showing the lowest cure rate of 94.8% (The PREGACT Study Group 2016).”

• cites The PREGACT Study Group 2016Not checked yet

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May combine two claims.

In that study, maternal anemia, birth weight, and gestational age at delivery were similar between groups.

“and Southeast Africa, peripheral and placental parasitemia (defined by BS, PCR, or histology) and nonobstetric admission were less frequent among women that received three doses of IPTp-MQ, while maternal anemia, birth weight, and gestational age at delivery were similar between groups (Gonzalez et al. 2014b).”

• cites Gonzalez et al. 2014bNot checked yet

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May combine two claims.

In an area of high malaria transmission and high SP resistance in Kenya, risks of malaria infection, mild anemia (HGB <11 g/dL), stillbirth, and early infant mortality were significantly reduced in women receiving IPTp-DP rather than IPTp-SP or ISTp-DP.

“Risks of malaria infection, mild anemia (HGB , 11 g/dL), stillbirth, and early infant mortality were significantly reduced in women receiving IPTp-DP rather than IPTp-SP or ISTp-DP, while ISTp-DP and IPTp-SP groups did not differ (Desai et al. 2015).”

• cites Desai et al. 2015Not checked yet

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May combine two claims.

Pregnant women are at increased risk of malaria, making this demographic group an important parasite reservoir in the community and a key target for interventions during elimination efforts.

“Pregnant women are at increased risk of malaria, making this demographic group an important parasite reservoir in the community and a key target for interventions during elimination efforts (Fig. 1).”

• cites Fig. 1Not checked yet

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May combine two claims.

A replacement drug has yet to be identified that is sufficiently safe, tolerable, and effective as prevention, although studies of dihydroartemisinin-piperaquine are encouraging.

“a replacement drug has yet to be identified that is sufficiently safe, tolerable, and effective as prevention, although studies of dihydroartemisinin -piperaquine are encouraging.”

• AssumptionRests on an assumption: Drugs currently used for malaria prevention during pregnancy have lost or are losing their efficacy.
• AssumptionRests on an assumption: The drugs CQ and SP used as preventive interventions have lost or are losing their benefits.

Probably not a substantial claim: may not pass S4 (based). May combine two claims.

This dearth of safe and effective tools to control malaria in pregnant women will hinder future malaria elimination campaigns, because any woman of childbearing age will likely be excluded from participation if pregnancy status is unknown.

“This dearth of safe and effective tools to control malaria in pregnant women will hinder future malaria elimination campaigns, because any woman of childbearing age will likely be excluded from participation if pregnancy status is unknown.”

• AssumptionRests on an assumption: Existing diagnostic tools are inadequate to detect malaria infection in semi-immune women.
• AssumptionRests on an assumption: The drugs CQ and SP used as preventive interventions have lost or are losing their benefits.