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Cited by 80Malaria Research and ControlHemoglobinopathies and Related DisordersPregnancy and preeclampsia studies

Diagnosing malaria in pregnancy: An update

Open access
Fried, Michal, Muehlenbachs, Atis, Duffy, Patrick E·2012·Expert Review of Anti-infective Therapy
DOI 10.1586/eri.12.98PMC PMC3552641
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Abstract

Pregnancy malaria (PM) due to Plasmodium falciparum is a major cause of morbidity and mortality for women and their offspring, but is difficult to recognize and diagnose. During PM, parasites typically sequester in the placenta, whereas peripheral blood smears often appear negative. In addition, many infected women remain asymptomatic, especially in areas of high transmission where systemic immunity is high, although sequelae including maternal anemia and intrauterine growth retardation develop insidiously and increase mortality. New rapid diagnostic tests (RDTs) have shown promise for malaria diagnosis in nonpregnant individuals, including a product recently approved by the US FDA for use in the USA. However, the sensitivity and specificity of RDTs for diagnosis of PM may be suboptimal. Here, we review the methods that are used to detect or diagnose PM, including blood smear microscopy, RDTs, PCR-based methods, and finally placental histology, which is often cited as the gold standard for use in research studies and clinical trials.

AI snapshot

Written from the paper’s full text.

TL;DR

Pregnancy malaria is hard to diagnose because *Plasmodium falciparum* parasites sequester in the placenta while peripheral blood smears are often negative, and many infected women are asymptomatic. This review compares blood smear microscopy, rapid diagnostic tests, PCR-based methods, hemozoin detection, and placental histology, concluding that no current tool is fully adequate and that placental histology remains a research gold standard with important limitations.

Key findings

  • Peripheral blood smears frequently miss pregnancy malaria: in Mozambique, over 70% of pregnant women with clinical malaria symptoms had negative blood smears. RDT-HRP2 sensitivity was >90% versus peripheral blood smear and 80–95% versus placental blood smear, with specificity 61–94%, but sensitivity was lower when compared with PCR.
  • OptiMAL (pLDH) sensitivity ranged from 15 to 96.6% and specificity from 90.8 to 98%; one study missed all samples with parasite density <100/μl, while another found 100% sensitivity and 93.3% specificity at >50/μl but only 57.1% sensitivity at lower densities.
  • PCR methods yielded positivity rates 20% or more above blood smear microscopy. In the authors’ Muheza, Tanzania studies, microscopic placental malaria was more frequent in primigravid women, whereas submicroscopic infection was more frequent in multigravid women.
  • Submicroscopic and microscopic placental infection were associated with increased low birthweight among primigravid women (submicroscopic odds ratio 3.025, p = 0.03; microscopic odds ratio 3.98, p = 0.007), while among multigravid women only microscopically detected pregnancy malaria was associated with increased low birthweight risk.

Methods

  • Narrative review of methods used to detect or diagnose pregnancy malaria, including blood smear microscopy, rapid diagnostic tests, PCR-based methods, hemozoin detection, and placental histology.
  • Synthesizes published studies, a recent meta-analysis of RDT performance, a WHO-coordinated RDT evaluation, and the authors’ cohort studies in Muheza, Tanzania.
  • Main analysis is qualitative comparison of diagnostic sensitivity/specificity and associations between diagnostic results and pregnancy outcomes such as maternal anemia, reduced birthweight, low birthweight, and preterm delivery.

Limitations

  • The paper states that placental histology lacks published or standardized criteria defining a positive tissue section, has limited standardization between laboratories in processing and scoring, and is vulnerable to artifacts such as formalin pigment that can mimic hemozoin; most studies use single reads and intraobserver variability has not been analyzed.
  • The paper notes that HRP2-based RDTs cannot distinguish current from recent infection because HRP2 persists for weeks after parasite clearance, and that LAMP performance for pregnancy malaria diagnosis has not yet been reported.
  • Evident from the text: this is a narrative review rather than a systematic review or meta-analysis, and the cited studies use heterogeneous reference standards and sampling methods, which limits direct comparability of sensitivity and specificity estimates.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1586/eri.12.98

Cites

85 of 85 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 142 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    In the authors' studies in Muheza, Tanzania, pregnancy malaria defined by microscopy of placental blood smear is significantly more frequent among primigravid compared with multigravid women.

    “In our studies in Muheza, Tanzania, PM (defined by microscopy of placental BS) is significantly more frequent among primigravid compared with multigravid women, similar to earlier reports.”
    Quote in the paperNot a substantial claim
  • Findingown data

    In the authors' studies, submicroscopic infections were more frequent in multigravid than primigravid women.

    “However, sub microscopic infections showed the opposite pattern, and were more frequent in multigravid than primigravid women (Figure 1).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Submicroscopic infections identified by PCR, qPCR or RDT when microscopy fails to detect parasites represent true current infections rather than persisting nucleic acid or antigen after parasite clearance.
  • Findingcitation

    The authors and others did not find an association between submicroscopic parasitemia and reduced birthweight.

    “We and others ([42] and Figure 2) did not find an association between sub microscopic parasitemia and reduced birthweight, unlike parasitemia detected by either peripheral or placental BS, which is associated with a significant reduction in birthweight.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] Rantala, 2010, Malar. J. source

      Not checked in the free run.

    • Rests on an assumption: Submicroscopic infections identified by PCR, qPCR or RDT when microscopy fails to detect parasites represent true current infections rather than persisting nucleic acid or antigen after parasite clearance.
  • Premisecitation

    Peripheral blood smears often appear negative in P. falciparum pregnancy malaria, especially in high transmission areas.

    “During P. falciparum infections, parasites sequester in the placenta but are often undetectable in peripheral blood smears (BS), especially in high transmission areas [4].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4] Brabin, 1983, Bull. World Health Organ.

      Not checked in the free run.

  • Premisecitation

    During Plasmodium falciparum pregnancy malaria, parasites typically sequester in the placenta.

    “During P. falciparum infections, parasites sequester in the placenta but are often undetectable in peripheral blood smears (BS), especially in high transmission areas [4].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4] Brabin, 1983, Bull. World Health Organ.

      Not checked in the free run.

  • May combine two claims. 50
  • Classified as probably not a substantial claim. 14

  • May combine two claims.

    Findingown data

    In analyses from the authors' cohort, both submicroscopic and microscopic placental infection were associated with increased low birthweight deliveries among primigravid women, whereas among multigravid women only microscopically detected pregnancy malaria was associated with increased risk of low birthweight.

    “In analyses from our cohort, both submicroscopic and microscopic placental infection were associated with increased LBW deliveries among primigravid women (submicroscopic: odds ratio: 3.025, p = 0.03 and microscopic: odds ratio: 3.98, p = 0.007), whereas among multigravid women only microscopically detected PM was associated with increased risk of LBW.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Submicroscopic infections identified by PCR, qPCR or RDT when microscopy fails to detect parasites represent true current infections rather than persisting nucleic acid or antigen after parasite clearance.

  • May combine two claims.

    Findingcitation

    In anticipation of future interventional trials, the authors developed a grading scheme that used either frozen or formalin-fixed paraffin-embedded tissues and incorporated semiquantitative scoring of inflammation and hemozoin deposition, and found both measures are independently associated with clinical outcomes.

    “In anticipation of future interventional trials, we developed a grading scheme that used either frozen or FFPE tissues and incorporated semiquantitative scoring of inflammation and hemozoin deposition, and found both measures are independently associated with clinical outcomes [54].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] Muehlenbachs, 2010, J. Infect. Dis. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    In the Mother-Offspring Malaria Studies Project experience, only one among 207 parturient women without detectable parasites in placental blood smear had parasites detected by histology, and in that unusual case parasites appeared as a single nidus in one intervillous space.

    “In the Mother–Offspring Malaria Studies Project experience, only one among 207 parturient women without detectable parasites in placental BS had parasites detected by histology, and in that unusual case parasites appeared as a single nidus in one intervillous space [72].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [72] Muehlenbachs, 2007, Hum. Pathol. source

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  • May combine two claims.

    Findingreasoning

    In three of four studies, using peripheral BS as a reference increases the sensitivity and specificity of many RDTs, but the sensitivity and specificity of RDT were lower when placental blood microscopy was used as a reference.

    “In three of four studies (Table 1), using peripheral BS as a reference increases the sensitivity and specificity of many RDTs, but the sensitivity and specificity of RDT were lower when placental blood microscopy was used as a reference”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In low transmission areas, women of all parities have increased susceptibility to malaria, although infection rates may still be highest in primigravidae.

    “In low transmission areas, women of all parities have increased susceptibility to malaria, although infection rates may still be highest in primigravidae [5].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Nosten, 1991, Trans. R. Soc. Trop. Med. Hyg. source

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  • May combine two claims.

    Premisecitation

    Women in low transmission areas lack strong systemic immunity and are more likely to develop severe syndromes like respiratory distress and cerebral malaria.

    “Women in low transmission areas lack strong systemic immunity and are more likely to develop severe syndromes like respiratory distress and cerebral malaria [5].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Nosten, 1991, Trans. R. Soc. Trop. Med. Hyg. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Susceptibility to malaria diminishes with successive pregnancies, and this pattern is most prominent in high transmission areas where primigravidae are more susceptible to P. falciparum infection and disease than multigravidae.

    “Susceptibility diminishes with successive pregnancies, and this pattern is most prominent in high transmission areas where primigravidae are significantly more susceptible to Plasmodium falciparum infection and disease than multigravidae [3,4].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [3] McGregor, 1984, Am. J. Trop. Med. Hyg. source

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    • cites [4] Brabin, 1983, Bull. World Health Organ.

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  • May combine two claims.

    Interpretationreasoning

    Because antimalarials are often prescribed on clinical rather than laboratory criteria, many pregnant women receive unnecessary treatment with drugs of unclear safety, particularly during the first trimester.

    “Because antimalarials are often prescribed on the basis of clinical and not laboratory criteria, many pregnant women receive unnecessary treatment with drugs that have an unclear safety profile, particularly during the first trimester when teratogenic effects are most likely.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The OptiMAL test, based on pLDH detection, gave varying results between studies when compared with peripheral blood smears, with sensitivity ranging from 15 to 96.6% and specificity from 90.8 to 98%.

    “The OptiMAL test, based on the detection of pLDH, gave varying results between studies when compared with peripheral BS. The sensitivity ranged from 15 to 96.6% and specificity from 90.8 to 98% [10–12].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [10] Mankhambo, 2002, J. Clin. Microbiol. source

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    • cites [11] VanderJagt, 2005, Trop. Med. Int. Health source

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    • cites [12] Tagbor, 2008, Ther. Clin. Risk Manag. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Even under optimal conditions, a large proportion of pregnancy malaria cases are missed by peripheral blood microscopy, which calls into question the use of peripheral blood smear as a reference for pregnancy malaria diagnosis.

    “Even under optimal conditions, a large proportion of PM cases are missed by peripheral blood microscopy ([13] and Table 1), which calls into question the use of peripheral BS as a reference for PM diagnosis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] Leke, 1999, J. Clin. Microbiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a larger study, OptiMal had 100% sensitivity and 93.3% specificity at parasite densities above 50/μl blood, but a sensitivity of only 57.1% at lower parasite densities.

    “In a larger study [12], OptiMal had 100% sensitivity and 93.3% specificity at parasite densities >50/μl blood, but a sensitivity of only 57.1% at lower parasite densities.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12] Tagbor, 2008, Ther. Clin. Risk Manag. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    When performed on peripheral blood for pregnancy malaria diagnosis, RDT-HRP2 sensitivity is more than 90% compared with peripheral blood smear and 80-95% compared with placental blood smear, with specificity between 61 and 94%.

    “When performed on peripheral blood samples for PM diagnoses, RDT-HRP2 sensitivity was more than 90% when compared with peripheral BS, and 80–95% when compared with placental BS, with specificity between 61 and 94% [13–16].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [13] Leke, 1999, J. Clin. Microbiol. source

      Not checked in the free run.

    • cites [14] Mockenhaupt, 2002, J. Clin. Microbiol. source

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    • cites [15] Singer, 2004, Am. J. Trop. Med. Hyg. source

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    • cites [16] Mayor, 2012, Clin. Infect. Dis. source

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  • May combine two claims.

    Premisecitation

    An important weakness of RDT-HRP2 tests is the prolonged half-life of HRP-2 antigen, which can be identified in plasma several weeks after parasite clearance and therefore cannot distinguish current from recent infection.

    “An important weakness of RDT-HRP2 tests is the prolonged half-life of the antigen. HRP-2 can be identified in plasma samples several weeks after parasite clearance, and therefore cannot be used to distinguish current from recent infection [23–25].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [23] Mayxay, 2001, Trans. R. Soc. Trop. Med. Hyg. source

      Not checked in the free run.

    • cites [24] Tjitra, 2001, J. Clin. Microbiol. source

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    • cites [25] Wongsrichanalai, 1999, Acta Trop. source

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  • May combine two claims.

    Premiseown data

    RDT performance using placental blood samples had sensitivity above 87.5% and specificity ranging between 68 and 97% compared to placental blood smear and placental PCR.

    “In these studies, RDT tests had a sensitivity of >87.5%, but a relatively large variation in the test specificity ranging between 68 and 97% (Table 2) in comparison to placental BS and placental PCR.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    RDTs that detect pLDH are designed to detect only live parasites, but their sensitivity for diagnosing pregnancy malaria is low.

    “RDTs that detect pLDH are designed to detect only live parasites; however, the sensitivity for diagnosing PM is low.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Real-time quantitative PCR methods have good sensitivity and range that allows monitoring parasitemia levels.

    “Real-time quantitative PCR (qPCR) methods have followed, with good sensitivity and range that allows monitoring parasitemia levels [29,30].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [29] Lee, 2002, J. Clin. Microbiol. source

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    • cites [30] Perandin, 2004, J. Clin. Microbiol. source

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

    Premisecitation

    LAMP is a newer alternative to PCR and qPCR that does not require DNA purification, uses simple instrumentation, and can be completed in less than 1 hour.

    “Loop-mediated isothermal amplification (LAMP) is a newer alternative to PCR and qPCR. This method does not require DNA purification, utilizes simple instrumentation (water bath or a heat block), and can be completed in less than 1 h [33,34].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [33] Poon, 2006, Clin. Chem. source

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    • cites [34] Polley, 2010, J. Clin. Microbiol. source

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  • May combine two claims.

    Interpretationreasoning

    These shortcomings hinder the use of existing RDTs for managing malaria and for monitoring treatment efficacy.

    “These shortcomings hinder the use of existing RDT for managing malaria, and also for monitoring treatment efficacy [23–25].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [23] Mayxay, 2001, Trans. R. Soc. Trop. Med. Hyg. source

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    • cites [24] Tjitra, 2001, J. Clin. Microbiol. source

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    • cites [25] Wongsrichanalai, 1999, Acta Trop. source

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  • May combine two claims.

    Premisecitation

    LDMS does not distinguish malaria species, and macrophages containing hemozoin can yield positive results, complicating differentiation of current versus past infection.

    “However, LDMS does not distinguish malaria species, and macrophages containing hemozoin can yield positive results, which complicates the differentiation of current versus past infection [52].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] Nyunt, 2005, Am. J. Trop. Med. Hyg. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Although PCR and qPCR are more sensitive for parasite detection than microscopy, their test format and time to obtain results are not suitable for use in a primary care setting.

    “Although these tools are more sensitive for parasite detection compared with microscopy, the test format and the time to obtain results are not suitable for use in a primary care setting.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Hemozoin can be detected by polarized light, by fluorescent properties allowing quantification in tissue, and by laser desorption mass spectrometry.

    “Hemozoin can be detected by polarized light [48], by the fluorescent properties of hemozoin which allows quantification in tissue [49], and by laser desorption mass spectrometry (LDMS) that identifies distinct spectral features [50].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [48] Jamjoom, 1991, Trans. R. Soc. Trop. Med. Hyg. source

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    • cites [49] Sullivan, 1996, Parasitol. Today (Regul. Ed.) source

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    • cites [50] Demirev, 2002, Anal. Chem. source

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

    Premisecitation

    An earlier study reported higher rates of submicroscopic infection with increasing parity, whereas other studies reported similar rates among women of different parities.

    “An earlier study also reported higher rates of submicroscopic infection with increasing parity [47], whereas other studies have reported similar rates of sub microscopic infections among women of different parities [16,38,40].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [47] Mockenhaupt, 2000, Trop. Med. Int. Health source

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    • cites [16] Mayor, 2012, Clin. Infect. Dis. source

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    • cites [38] Saute, 2002, Trop. Med. Int. Health source

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    • cites [40] Walker-Abbey, 2005, Am. J. Trop. Med. Hyg. source

      Not checked in the free run.

    • Rests on an assumption: Submicroscopic infections identified by PCR, qPCR or RDT when microscopy fails to detect parasites represent true current infections rather than persisting nucleic acid or antigen after parasite clearance.

  • May combine two claims.

    Interpretationown data

    An increased rate of submicroscopic infection among multigravid women suggests that acquired immunity to pregnancy malaria controls parasite density but does not prevent and does not completely clear infection.

    “An increased rate of submicroscopic infection among multigravid women suggests that acquired immunity to PM controls parasite density but does not prevent and does not completely clear infection.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Submicroscopic infections identified by PCR, qPCR or RDT when microscopy fails to detect parasites represent true current infections rather than persisting nucleic acid or antigen after parasite clearance.

  • May combine two claims.

    Premisecitation

    In placental samples, polarized microscopy has aided in detecting low placental parasitemia, and in the absence of parasitemia indicates past infection.

    “In placental samples, polarized microscopy has aided in detecting low placental parasitemia, and in the absence of parasitemia indicates past infection [51].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Romagosa, 2004, Acta Trop. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Artifacts such as formalin pigment and dust particles can mimic hemozoin and can result in misdiagnosis.

    “However, artifacts such as formalin pigment and dust particles can mimic hemozoin [51] and can result in misdiagnosis (see below).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Romagosa, 2004, Acta Trop. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HRP2 or pLDH detected in placental blood has been associated with increased rates of low birthweight in some studies but not in Mozambique.

    “HRP2 or pLDH detected in placental blood has been associated with increased rates of LBW in some studies [10,15,53] but not in Mozambique [16].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [10] Mankhambo, 2002, J. Clin. Microbiol. source

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    • cites [15] Singer, 2004, Am. J. Trop. Med. Hyg. source

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    • cites [53] Mockenhaupt, 2006, Malar. J. source

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    • cites [16] Mayor, 2012, Clin. Infect. Dis. source

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  • May combine two claims.

    Premisecitation

    Positive placental blood PCR was associated with an increased rate of low birthweight in one study but not in several others.

    “Positive placental blood PCR was associated with an increased rate of LBW in one study [15] but not several others [10,16,53].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [15] Singer, 2004, Am. J. Trop. Med. Hyg. source

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    • cites [10] Mankhambo, 2002, J. Clin. Microbiol. source

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    • cites [16] Mayor, 2012, Clin. Infect. Dis. source

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    • cites [53] Mockenhaupt, 2006, Malar. J. source

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  • May combine two claims.

    Premisecitation

    In another study, birthweight was associated with positive RDT-pLDH assays but not with positive PCR assays performed on placental blood or peripheral blood.

    “In another study, birthweight was associated with positive RDT-pLDH assays but not positive PCR assays performed on placental blood or peripheral blood [10].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Mankhambo, 2002, J. Clin. Microbiol. source

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

    Premisereasoning

    Fresh frozen samples require the least processing: red blood cells lyse while parasites remain intact, and host cell morphology can change with loss of fine cellular and nuclear detail.

    “Fresh frozen samples require the least amount of processing: red blood cells (RBCs) lyse (parasites remain intact) and host cell morphology can change with loss of fine cellular and nuclear detail.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    Challenges with placental histology studies of pregnancy malaria include limited standardization between laboratories in processing and scoring tissue, and limited infrastructure to properly collect, process and analyze placental samples in some tropical areas.

    “Challenges with placental histology studies of PM include limited standardization between laboratories in processing and scoring tissue, and limited infrastructure to properly collect, process and analyze placental samples in some tropical areas.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Placental histology has been referred to as the gold standard for its ability to detect sequestered parasites when none are detected in the peripheral circulation.

    “Placental histology has been referred to as the ‘gold standard’ for its ability to detect sequestered parasites when none are detected in the peripheral circulation [55].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] Bulmer, 1993, Histopathology source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Inflammatory infiltrates occur in a subset of women with active malaria infection, particularly first-time mothers, and are strongly linked to low birthweight.

    “Inflammatory infiltrates occur in a subset of women with active malaria infection, particularly first-time mothers, and is strongly linked to LBW.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Histology does not have a role in clinical diagnosis of pregnancy malaria, but serves as a valuable tool in epidemiological studies and clinical trials in which pregnancy malaria is an end point.

    “Histology does not have a role in clinical diagnosis of PM, but serves as a valuable tool in epidemiological studies and clinical trials in which PM is an end point.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Hemozoin can persist for months following treatment of a documented infection, and the extent of hemozoin deposition is thought to correlate with cumulative exposure, with levels associated with gravidity, degree of parasitemia at treatment and reinfection before delivery.

    “Hemozoin can persist for months in women following treatment of a documented infection [58], and the extent of hemozoin deposition is thought to correlate with cumulative exposure [54] such that levels have been associated with gravidity, the degree of parasitemia at the time of treatment and reinfection before delivery [57].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [58] McGready, 2002, Trans. R. Soc. Trop. Med. Hyg. source

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    • cites [54] Muehlenbachs, 2010, J. Infect. Dis. source

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    • cites [57] Muehlenbachs, 2012, Malar. J. source

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  • May combine two claims.

    Premisenone given

    Erythrocytes can be altered by histology processing methods in different ways, which can hinder recognition of true parasites or introduce artifacts that falsely appear as parasites.

    “Erythrocytes can be altered by histology processing methods in different ways, which can hinder recognition of true parasites or introduce artifacts that falsely appear as parasites (Figure 3).”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    With formalin-fixed paraffin-embedded tissues, some erythrocytes often diffuse out during storage and processing, and are thus not sampled for histology.

    “With FFPE tissues, some erythrocytes often diffuse out during storage and processing, and are thus not sampled for histology.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Because a single infection during pregnancy contributes to poor pregnancy outcomes, submicroscopic infections among primigravid women may indicate an earlier patent infection causing low birthweight, which would also be reflected by increased pigment deposition.

    “Because a single infection during pregnancy contributes to poor pregnancy outcomes [2], submicroscopic infections among primigravid women may indicate an earlier patent infection causing LBW, which would also be reflected by increased pigment deposition (calculated as the percentage of fields containing pigment in intervillous fibrin) [54].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [2] Desai, 2007, Lancet Infect. Dis. source

      Not checked in the free run.

    • cites [54] Muehlenbachs, 2010, J. Infect. Dis. source

      Not checked in the free run.

    • Rests on an assumption: Submicroscopic infections identified by PCR, qPCR or RDT when microscopy fails to detect parasites represent true current infections rather than persisting nucleic acid or antigen after parasite clearance.

  • May combine two claims.

    Premisecitation

    During dehydration, tissue contracts and causes an artifactual separation between trophoblast surface and red blood cells, which can make adhesion of infected red blood cells to trophoblasts difficult to appreciate.

    “During dehydration, tissue contracts and causes an artifactual separation between trophoblast surface and RBCs, which can make adhesion of infected RBCs to trophoblasts difficult to appreciate, although this interaction has been well demonstrated by electron microscopy [59].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [59] Walter, 1982, Am. J. Pathol.

      Not checked in the free run.

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

    Interpretationnone given

    In the current era of decreasing transmission and increasing interventions, rates of placental parasitemia are expected to decrease.

    “In the current era of decreasing transmission and increasing interventions, rates of placental parasitemia are expected to decrease.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Formalin pigment can mimic hemozoin, and most studies do not comment on specimen quality, nor whether samples were excluded due to background artifact or read in the presence of formalin pigment.

    “However, as noted above, formalin pigment can mimic hemozoin, and unfortunately most studies do not comment on the specimen quality, nor whether samples were excluded due to background artifact or read in the presence of formalin pigment.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Formalin pigment is optically indistinguishable from malarial hemozoin.

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

    Premisecitation

    The most widely used classification scheme was developed by Bulmer in 1993 with acute, chronic and past infection categories, based on the presence of parasitized erythrocytes and/or hemozoin in fibrin.

    “The most widely used classification scheme was developed by Bulmer in 1993 [55] with acute, chronic and past infection categories, based on the presence of parasitized erythrocytes and/or hemozoin in fibrin.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] Bulmer, 1993, Histopathology source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Rare infected erythrocytes are difficult to detect by histology and there are concerns regarding both sensitivity and specificity.

    “Rare infected erythrocytes are difficult to detect by histology and there are concerns regarding both sensitivity and specificity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Histological classification of pregnancy malaria is useful for epidemiological studies and has been utilized in interventional trials.

    “Histological classification of PM is useful for epidemiological studies, and has been utilized in interventional trials.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Premisenone given

    Histopathological processing and interpretation takes considerable training.

    “Histopathological processing and interpretation takes considerable training.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Several studies have incorporated multiple reads, including reads by microscopists at different institutions.

    “Several studies have incorporated multiple reads [16,55,62,63,65,66] including reads by microscopists at different institutions [55,66].”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [16] Mayor, 2012, Clin. Infect. Dis. source

      Not checked in the free run.

    • cites [55] Bulmer, 1993, Histopathology source

      Not checked in the free run.

    • cites [62] Ismail, 2000, Hum. Pathol. source

      Not checked in the free run.

    • cites [63] Rogerson, 2003, Am. J. Trop. Med. Hyg. source

      Not checked in the free run.

    • cites [65] Okoko, 2002, J. Health. Popul. Nutr.

      Not checked in the free run.

    • cites [66] Anchang-Kimbi, 2009, Malar. J. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationreasoning

    Because pregnancy malaria histology is retrospective, there has been little scrutiny of it as a gold standard, unlike other histologic diagnoses where a false positive can lead to a disastrous intervention.

    “Because PM histology is retrospective, there has been little scrutiny of it as a ‘gold standard’, unlike other histologic diagnoses where a false positive can lead to a disastrous intervention.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Staining can introduce debris in both formalin-fixed paraffin-embedded and frozen sections that may mimic hemozoin within erythrocytes or in fibrin.

    “Finally, staining can introduce debris in both FFPE and frozen sections that may mimic hemozoin within erythrocytes or in fibrin.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Past infection can be determined much more reliably in histology studies, and is based on the presence of hemozoin deposition in fibrin.

    “Past infection can be determined much more reliably in histology studies, and is based on the presence of hemozoin deposition in fibrin.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Extensive processing of red blood cells in histological sections affects their morphology and can introduce pigment artifact.

    “Extensive processing of RBCs in histological sections (described above) affects their morphology and can introduce pigment artifact (Figure 3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    False negatives are expected in the presence of more sensitive tests including PCR, RDT or placental blood smear, whereas a high false-positive rate would result in incorrect assessment of the accuracy of other diagnostic tests, such as RDT, that could have widespread clinical utility to screen pregnant women.

    “False negatives are expected in the presence of more sensitive tests including PCR, RDT or placental BS, whereas a high false-positive rate would result in incorrect assessment of the accuracy of other diagnostic tests, such as RDT, that could have widespread clinical utility to screen pregnant women.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Soluble endoglin increases during PM and, like sFlt1, is a marker of preeclampsia.

    “and soluble endoglin, which increases during PM and, like sFlt1, is a marker of preeclampsia [83].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [83] Silver, 2011, PLoS ONE source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Sequestered parasite biomass in pregnant women is often limited to placental intervillous spaces, which represents a small proportion of the total body vasculature.

    “That indicates that the sequestered parasite biomass in pregnant women is often limited to placental intervillous spaces, which represents a small proportion of the total body vasculature.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: During PM, parasites sequester in the placenta.
    • Rests on an assumption: Most of the parasites collected from the peripheral blood of pregnant women during the antenatal period or at delivery bind to the placenta receptor chondroitin sulfate A.

  • May combine two claims.

    Interpretationreasoning

    Biomass concentration in the placenta and hemodilution could be the main reasons for the lower performance of RDTs to detect PM.

    “These two factors, biomass concentration in the placenta and hemodilution, could be the main reasons for the lower performance of RDTs to detect PM.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    PM provides an opportunity to relate parasite biomass (placental parasitemia at delivery) with RDT sensitivity.

    “On the other hand, PM provides an opportunity to relate parasite biomass (placental parasitemia at delivery) with RDT sensitivity.”
    Quote in the paperSubstantial claim

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

    Interpretationnone given

    The reported higher sensitivity of placental histology compared with placental BS could have various explanations, including differences in placenta sampling methods, and false positives by histology.

    “The reported higher sensitivity of placental histology compared with placental BS could have various explanations, including differences in placenta sampling methods, and false positives by histology.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    PM is associated with inflammatory immune responses, with increased levels of soluble mediators like TNF-α, TNF receptor I, TNF receptor II and IL-10 in peripheral blood.

    “PM is associated with inflammatory immune responses [75–79], with increased levels of soluble mediators like TNF-α, TNF receptor I, TNF receptor II and IL-10 in peripheral blood [80,81].”
    Quote in the paperSubstantial claim0 of 7 sources checked
    • cites [75] Fried, 1998, J. Immunol. source

      Not checked in the free run.

    • cites [76] Suguitan, 2003, J. Infect. Dis. source

      Not checked in the free run.

    • cites [77] Rogerson, 2003, Infect. Immun. source

      Not checked in the free run.

    • cites [78] Chaisavaneeyakorn, 2003, Clin. Diagn. Lab. Immunol. source

      Not checked in the free run.

    • cites [79] Kabyemela, 2008, Infect. Immun. source

      Not checked in the free run.

    • cites [80] Kabyemela, 2008, Malar. J. source

      Not checked in the free run.

    • cites [81] Thévenon, 2010, J. Immunol. source

      Not checked in the free run.

56 of 56

  • The paper relies on this without support.

    Submicroscopic infections identified by PCR, qPCR or RDT when microscopy fails to detect parasites represent true current infections rather than persisting nucleic acid or antigen after parasite clearance.

    “Infections identified by PCR, qPCR or RDT when microscopy fails to detect parasites on BS are defined as submicroscopic or subpatent infections (although distinguishing subpatent infection from persisting nucleic acid or antigen after parasites are cleared is not always possible).”

  • The paper relies on this without support.

    Formalin pigment is optically indistinguishable from malarial hemozoin.

    “Formalin pigment (acid hematin) is the most damaging artifact because it is optically indistinguishable from malarial hemozoin.”

  • The paper relies on this without support.

    There are no published or standardized criteria that define a positive placental tissue section for malaria.

    “While BS have well-established criteria for defining positives (WHO), there are no published or standardized criteria that define a positive tissue section.”

  • The paper relies on this without support.

    RDT-HRP2 has higher sensitivity compared with BS or RDT-pLDH on peripheral blood samples.

    “Although RDT-HRP2 has higher sensitivity compared with BS or RDT-pLDH on peripheral blood samples, it fails to detect many PM cases detected by placental BS.”
    “Although RDT-HRP2 has higher sensitivity compared with BS or RDT-pLDH on peripheral blood samples, it fails to detect many PM cases detected by placental BS.”

  • The paper relies on this without support.

    In areas with high malaria transmission levels, women with substantial systemic immunity often have negative peripheral BS and/or remain asymptomatic during infection.

    “This is especially common in areas with high malaria transmission levels where women with substantial systemic immunity often have negative peripheral BS and/or remain asymptomatic during infection.”
    “This is especially true in areas with high malaria transmission levels where women with substantial systemic immunity often have negative BS and/or remain asymptomatic during infection.”

  • The paper relies on this without support.

    During PM, parasites sequester in the placenta.

    “During PM, parasites sequester in the placenta”

  • The paper relies on this without support.

    Most of the parasites collected from the peripheral blood of pregnant women during the antenatal period or at delivery bind to the placenta receptor chondroitin sulfate A.

    “most of the parasites collected from the peripheral blood of pregnant women during the antenatal period or at delivery bind to the placenta receptor chondroitin sulfate A.”

  • The paper relies on this without support.

    One weakness of HRP2-based tests is the persistence of antigen for several weeks after effective treatment, which reduces the test specificity.

    “One weakness of HRP2-based tests is the persistence of antigen for several weeks after effective treatment, which reduces the test specificity.”
8 of 8

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Cites

Flagged first, then by citations

Research works printed but not linked: 4

  1. Brabin, 1983, Bull. World Health Organ., 61, 1005
  2. Duffy PE. Immunity to malaria: different host, different parasite. In:Malaria in Pregnancy: Deadly Parasite, Susceptible Host. Duffy PE, Fried M (Eds). Taylor & Francis, NY, USA, 71–127 (2001).
  3. Walter, 1982, Am. J. Pathol., 109, 330
  4. Okoko, 2002, J. Health. Popul. Nutr., 20, 4

Cited by

Sorted by citations

Related

Authors
Fried, M., Muehlenbachs, A., & Duffy, P. E.
Affiliations
  • Center for Infectious Disease Research (US)
  • University of Washington (US)
Corresponding author
Fried, Michal
ORCID
Venue
Expert Review of Anti-infective Therapy
Publisher
Informa UK Limited
Published
2012-10
Volume
10
Issue
10
Pages
1177-1187
ISSN
  • 1478-7210 (ISSN-L)
  • 1744-8336
DOI
10.1586/eri.12.98
PMC
PMC3552641
OpenAlex
W1974973604
Semantic Scholar
d07721797909b5b1f6127a2a1722ccde2788487a
Cited by
80
References
85
Citations by year
2026: 5 · 2025: 6 · 2024: 5 · 2023: 7 · 2022: 4 · 2021: 5 · 2020: 9 · 2019: 4 · 2018: 8 · 2017: 7 · 2016: 5 · 2015: 8 · 2014: 4 · 2013: 3
FWCI
0.75
Type
journal article
Language
en
Open access
Locations
  • Expert Review of Anti-infective Therapy (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Bill and Melinda Gates Foundation
  • National Institutes of Health
  • National Institute of Allergy and Infectious Diseases (AI52059, U19AI065664, R01AI052059, ZIAAI001153)
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Malaria Research and Control
  • Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
  • Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
Keywords
Plasmodium falciparum, malaria diagnosis, rapid diagnostic tests, blood smear microscopy, PCR diagnosis, placental histology, anemia in pregnancy, fetal growth restriction
MeSH terms
Disease Susceptibility, Female, Hemeproteins, Humans, Infant, Low Birth Weight, Infant, Newborn, Placenta, Pregnancy, Pregnancy Complications, Hematologic, Pregnancy Outcome, Pregnancy Complications, Parasitic, Malaria, Falciparum

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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