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Am. J. Trop. Med. Hyg., 75(5), 2006, pp. 798-803
Copyright © 2006 by The American Society of Tropical Medicine and Hygiene

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MICROSCOPIC AND SUB-MICROSCOPIC PLASMODIUM FALCIPARUM INFECTION, BUT NOT INFLAMMATION CAUSED BY INFECTION, IS ASSOCIATED WITH LOW BIRTH WEIGHT

AYÔLA A. ADEGNIKA*, JACO J. VERWEIJ, SELIDJI T. AGNANDJI, SANDERS K. CHAI, LUTZ PH. BREITLING, MICHAEL RAMHARTER, MARIJKE FROLICH, SAADOU ISSIFOU, PETER G. KREMSNER, AND MARIA YAZDANBAKHSH
Medical Research Unit, Albert Schweitzer Hospital, Lambaréné, Gabon; Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands; Department of Parasitology, Institute of Tropical Medicine, University of Tübingen, Tübingen Germany; Department of Clinical Chemistry, Leiden University Medical Center, Leiden, The Netherlands


ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Pregnancy-associated malaria is one of the leading causes of low birth weight in malaria endemic areas. In this study, 145 parturient women residing in areas endemic for Plasmodium falciparum in Lambaréné, Gabon, were recruited into the study after delivery, and the association of maternal P. falciparum infection, inflammatory response, and birth weight was studied. At delivery, 10% (15) of the mothers (12 were positive in both peripheral and placental blood smears, 1 was positive in peripheral blood only, and 2 were positive in placenta blood only) were positive for P. falciparum by microscopy and 23% (30) by real-time polymerase chain reaction (PCR). The level of C-reactive protein (CRP) was significantly elevated in microscopically P. falciparum–positive pregnant women (34 mg/L; 95% CI: 3–458) but not in those with sub-microscopic infections (6 mg/L; 95% CI: 1–40) compared with those free of P. falciparum infection (7 mg/L; 95% CI: 1–43). In a multivariate analysis, the presence of microscopic (adjusted OR = 28.6, 95% CI = 4.8–169.0) or sub-microscopic (adjusted OR = 13.2, 95% CI = 2.4–73.0) P. falciparum infection in pregnant women and age of mothers < 21 years (adjusted OR = 9.7 CI = 1.0–89.7), but not CRP levels, were independent predictors for low birth weight. This finding may have important operational implications and emphasizes the need for appropriate diagnostic methods in studies evaluating the outcome of pregnancy-associated malaria.


INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Pregnancy-associated Plasmodium falciparum malaria remains a major public health problem in endemic regions. In Africa > 24 million pregnancies are threatened every year by malaria.1 Pregnant women are at significantly greater risk of being infected with P. falciparum than non-pregnant women,2 and among pregnant women, P. falciparum infection is more often seen in pauciparous3,4 and in the youngest.4–6 Pregnancy-associated P. falciparum infection is one of the major causes of morbidity, leading to severe malaria, abortion, miscarriage, stillbirth in areas of low malaria endemicity, and mainly low birth weight in areas of intense malaria transmission.7–9 Low birth weight (< 2,500 g) constitutes the most important risk factor for infant mortality.10–12

The pathogenesis of low birth weight during malaria and pregnancy has been attributed to malaria-associated anemia in the mother13 and placental malaria, leading to prematurity and intrauterine growth retardation, accentuated in primi-gravid women.14,15 The parasite antigens expressed on the surface of infected erythrocytes bind to specific adhesion receptors in the placenta, especially chondroitin sulphate A, and result in parasite sequestration in the placenta,16,17 which is responsible for many of the harmful effects of malaria during pregnancy. P. falciparum infection has been shown to lead to inflammatory responses such as elevated T-helper 1 cytokines18,19 and increased levels of C-reactive protein (CRP),20,21 and both of these are associated with poor pregnancy outcome.22 However, many P. falciparum infections during pregnancy stay undetected when only microscopy of Giemsa-stained blood smears of peripheral blood but not placental malaria is used for diagnosis. These sub-microscopic infections can only be diagnosed by detection of circulating parasitic antigens or detection of parasite-specific DNA using conventional polymerase chain reaction (PCR), nested PCR,23–30 or the more recently developed real-time PCR.31–33 In previous studies, maternal sub-microscopic P. falciparum infection, as evaluated by nested PCR, was not significantly associated with adverse birth outcomes such as low birth weight.32,34 One recent paper has reported that quantitative PCR is superior to nested PCR in determining the burden of P. falciparum parasites.32 However, in this study, no comparison was made between microscopic and sub-microscopic P. falciparum infections. Here we used real-time PCR to evaluate the effect of sub-microscopic malaria on birth weight and also assessed the role that inflammation, as measured by elevated CRP plays in poor pregnancy outcome.


MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study area. The study took place in Lambaréné, Gabon, which is located amid the tropical rain forest of central Africa. Malaria is hyperendemic in this community with perennial transmission of P. falciparum malaria, and the entomologic inoculation rate (EIR) in this area has been estimated to average 50 infective bites per person per year.35,36 Screening for HIV is not routinely used in this setting. The prevalence of HIV in child-bearing women in Lambaréné has been estimated to be < 4%: data obtained from the mother-to-child HIV transmission clinic in Albert Schweitzer Hospital, a study conducted in 2003 during the study period (unpublished data).

Two mother–child health care centers that are part of the governmental hospital (General Hospital) and the private hospital (Albert Schweitzer Hospital) serve the local population.

Study population. Eligible women were recruited when reporting for delivery at the maternity clinic. Inclusion criteria were defined as 1) singleton fetal pregnancy, 2) residency in Lambaréné or the surrounding regions, and 3) written informed consent.

Exclusion criteria were defined as 1) refusal or withdrawal of consent and 2) serious illness.

After informed consent was obtained, data on demographic background and obstetrical history were recorded, and any missing data were completed by visiting the women after birth. Women were examined for vital signs.

The birth weight of the newborn was determined within 30 minutes after delivery using the mechanical baby scale SECA 725 Balance Beam (32 lb x 0.25 oz) (Gummersbach, Germany). Maternal peripheral blood was drawn within 30 minutes after delivery in an EDTA tube to determine the hemoglobin concentration, using the flow cytometry–based hematology analyzer (CellDyn 3000, Abbott Laboratories, Santa Clara, CA),37 and for CRP measurement (see below). The asexual P. falciparum parasites in maternal peripheral, cord, and placental blood obtained by aspiration between mother and cord interface was assessed by microscopy using the previously published method.38 Placental tissue and the pellet from mother’s peripheral blood obtained after centrifugation from the EDTA tube were collected and stored at –80°C for detection of P. falciparum DNA.

DNA extraction. DNA was extracted from 200 µL of EDTA blood pellet from the maternal peripheral blood and 50 mg of placental tissue, using the QIAamp DNA blood mini Kit (Qiagen, Hilden, Germany) according to the manufacturer’s instruction. In both cases, DNA was recovered in 200 µL of elution buffer from the isolation kit for use in PCR test to detect P. falciparum.

Real-time PCR. P. falciparum–specific PCR primers and a minor groove binding (MGB) Taqman probe were chosen using Primer Express software (Applied Biosystems, Foster City, CA) on the basis of the known SSU RNA gene sequence for P. falciparum (GenBank accession no. M19172), such that a 157-bp fragment within the SSU RNA gene should be amplified and detected specifically for P. falciparum. The P. falciparum–specific primers and probe set consisted of forward primer P-1047F 5'-GTTAAGGGAGTGAAGACGA-TCAGA-3', reverse primer P-1178R 5'-AACCCAAAGAC-TTTGATTTCTCATAA-3', and the P. falciparum–specific MGB Taqman probe Pf -1141 VIC-5'-CTTTCGAGGTGA0-CTTTTAGAT-3'-MGB non-fluorescent quencher (Applied Biosystems).

Amplification reactions were performed in a volume of 25 µL with PCR buffer (HotstarTaq mastermix; Qiagen), 5 mmol/L MgCl2, 12.5 pmol of each Plasmodium-specific primer, 2.5 pmol of P. falciparum–specific MGB Taqman probe, and 5 µL of the DNA sample. Amplification consisted of 15 minutes at 95°C followed by 50 cycles of 15 seconds at 95°C and 60 seconds at 60°C. Amplification, detection, and data analysis were performed with the AB7500 real-time detection system (Applied Biosystems).

CRP measurement. Plasma was separated from maternal blood and umbilical venous blood (obtained from a clamped segment of the cord after birth and delivery of the placenta), collected into heparinized tubes and then centrifuged, and stored at –80°C. The concentration of CRP was detected with an immunoturbidimetric assay in a fully automated P-800 system (Hitachi, Tokyo, Japan). The interassay coefficients of variation (CVs) ranged from 1.8% to 2.5% at different levels, and the sensitivity was 0.5 mg/L.

Definitions. Primigravidae were those who were at their first pregnancy; multigravidae had multiple pregnancies.

Malarial infection status was defined as microscopic P. falciparum infection at delivery in peripheral blood or in placental blood smear. Sub-microscopic infection was defined as negative thick blood smear but positive for P. falciparum species with real-time PCR in peripheral blood and or in placenta tissue. The negative group was defined by the absence of P. falciparum as assessed by thick blood smear and by real-time PCR in peripheral blood and placenta tissue.

The ages were grouped into three categories: < 21, between 21 and 27, and > 27 years of age.

The serum concentration of CRP is considered as evidence of inflammation, based on the current internationally accepted reference value39 of CRP is > 6 mg/L.

Low birth weight was defined as a newborn weight ≤ 2,500 g. Anemia was defined if the hemoglobin value was < 11 g/dL and was considered normal if the hemoglobin rate was > 11 g/dL.

According to national guidelines at the time of the study (May 2003 until July 2004), all pregnant women were given chloroquine prophylaxis by the national malaria control program, despite a documented high-grade resistance of P. falciparum against this drug in this area.40,41 Iron and folic acid were given as well. The assessment of compliance with the prescribed regimen of chloroquine sulphate prophylaxis, iron, and folic acid was omitted because of the absence of active follow-up visits during pregnancy in this study.

Ethical issue. The ethics committee of the International Foundation of the Albert Schweitzer Hospital approved the study, and written informed consent was obtained from all participants or their parents in the case of minors.

Statistics analysis. Data were entered in File Maker Pro 5 (FileMaker, Santa Clara, CA) and transferred into SPSS for Windows 11.0 (SPSS, Chicago, IL) for statistical analysis. The age was grouped based on the 33rd and 66th percentile to provide equal numbers in the three groups.

For univariate analysis of categorical variables, Pearson’s {chi}2 test was used. For continuous data, ANOVA t test was used for comparison between group means, except if the variances in the samples were not homogeneous. In this case, the non-parametric Kruskal-Wallis test was used. To estimate adjusted odds ratios (ORs) for low birth weight and inflammation, all factors associated with low birth weight in unadjusted analysis (P ≤ 0.05) were entered into the logistic regression model.


RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
P. falciparum infection in maternal peripheral blood and in placental biopsies. As shown in Table 1Go, of the 145 pregnant women, P. falciparum infection was detected microscopically in 10% (15) of maternal peripheral blood and placental blood. Of these 15 samples positive by microscopy, 12 were positive both in placental and peripheral blood, 1 in peripheral blood only, and 2 in placental blood only.


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TABLE 1
Characteristics of maternal and neonatal study population
 
From the remaining 130 pregnant women who were negative microscopically, 30 (23%) were positive for P. falciparum by real-time PCR and therefore carried sub-microscopic infection.

Three cord blood samples were positive microscopically for P. falciparum; these belonged to pregnant women who were infected both peripherally and placentally. As expected, all microscopic malaria-positive samples were strongly positive in the PCR assay (data not shown).

Levels of hemoglobin. Hemoglobin (mean ± SD) levels were slightly lower in cases with a microscopically detectable P. falciparum infection (9.6 ± 1.7 g/dL) compared with hemoglobin levels in cases with a sub-microscopic infection (10.4 ± 1.3 g/dL), which were lower compared to controls (uninfected mothers; 10.7 ± 1.4 g/dL; P = 0.014).

Levels of CRP in maternal and cord blood. In women with a microscopically detectable P. falciparum infection, the levels of CRP (34 mg/L; 95% CI: 3–458) were significantly higher compared with CRP levels in women with a sub-microscopic P. falciparum infection (6 mg/L; 95% CI: 1–40; P < 0.0001) or CRP levels in non-infected women (7 mg/L; 95% CI: 1–43; P < 0.0001). When considering the levels of CRP > 6 mg/L, which indicates systemic inflammatory reaction, 47% of the pregnant women fell into this category, whereas in cord blood, three samples had levels of CRP > 6 mg/L (Table 1Go).

Association between P. falciparum infection and birth weight. Only 4% of the children born to non-infected women were of low birth weight. This is in contrast to the children delivered by women with a sub-microscopic P. falciparum infection, of which 23% (P = 0.001) had a low birth weight. Of children born to mothers with a microscopically detectable P. falciparum infection, 47% (P < 0.0001) were of low birth weight (Table 2Go). The mean weight of the children born to women with no P. falciparum infection was highest (3,103 ± 397 g), followed by lower birth weight (2,962 ± 473 g) in children born to mothers with sub-microscopic P. falciparum infection, whereas the lowest birth weight (2,806 ± 563 g) was in children born to mothers with microscopically detectable P. falciparum infection (P = 0.026).


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TABLE 2
Risk factors for low birth weight (newborn birth weight ≤ 2,500 g)
 
Association between CRP levels and birth weight. The birth weight (mean ± SD) of newborns from mothers with CRP levels ≥ 6 mg/L was significantly lower (2,913 ± 230 g) compared with those from mothers with CRP levels < 6 mg/L (3,174 ± 394 g, P = 0.0001). Similarly, the proportion of children with a low birth weight born to women with CRP levels that marked systemic inflammation (> 6 mg/L) was significantly higher (17%) than in women who had no evidence of inflammation (6%, P = 0.031; Table 2Go).

Risk factors for low birth weight. Table 2Go shows the risk factors for low birth weight as assessed in this study. In the univariate analysis, low birth weight was associated with microscopic P. falciparum infection (unadjusted OR = 21.0; 95% CI, 5.0–87.0; P = 0.0001), sub-microscopic P. falciparum infection (unadjusted OR = 7.3; 95% CI, 1.9–27.0; P = 0.003), and primigravidae (unadjusted OR = 3.1; 95% CI, 1.3–7.2; P = 0.008). Women < 21 years of age had a significantly increased risk for delivering neonates with low birth weight compared with women between 21 and 27 years of age (unadjusted OR = 15.9; 95% CI, 2.0–128.1; P = 0.019). Evidence of inflammation (CRP > 6 mg/L) increased the risk of low birth weight compared with the group with no sign of inflammation (unadjusted OR = 3.5; 95% CI, 1.0–11.7; P = 0.031). However, after adjusting in a multivariate analysis for P. falciparum infection status, parity, age group, and CRP levels ≥ 6 mg/L, it was found that the independent risk factors for low birth weight were the presence of microscopic P. falciparum parasite infection (adjusted OR = 28.6; 95% CI = 4.8–169.0), sub-microscopic P. falciparum parasite infection (adjusted OR = 13.2; 95% CI = 2.4–73.3), and age < 21 years (adjusted OR = 9.7; 95% CI = 1–89.7) remained independent risk factors for low birth weight.


DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Pregnancy-associated malaria remains a major public health problem in endemic regions because of its detrimental effect on pregnancy outcome. It is important to assess the effects of different burdens of P. falciparum on pregnant women to determine accurately the morbidity caused by malaria in this population at risk. This cross-sectional study focused on microscopic and sub-microscopic P. falciparum infection and the presence of systemic inflammation at delivery and its implication on low birth weight.

Our major finding indicates that women with submicroscopic levels of P. falciparum infection (detected by using the real-time PCR) at delivery had a 13-fold increased risk of delivering a child with low birth weight compared with non-infected pregnant women. Our results show that women with a microscopically detectable P. falciparum infection have a 2-fold increased risk for low birth weight compared with women with a sub-microscopic P. falciparum infection and 29-fold higher risk compared with non-infected women. The results in this study are consistent with the recent report32 on association between women with sub-microscopic P. falciparum infection using real-time PCR and the risk of having underweight offspring. However, their analysis was slightly different, in that although they have shown an association but did not assess sub-microscopic infection as a risk factor using multivariate analysis, as done in this study. Conversely, these findings are in contrast with previous reports,28,34 where no statistically significant effect of sub-microscopic P. falciparum infection on low birth weight was observed.

Most studies investigating sub-microscopic P. falciparum infections have focused on its effect on maternal anemia or on systemic inflammation.26,27,42,43 Our results of assessing the risk factors for low birth weight are in accordance with findings from Cameroon with regard to the influence of age.4 However, in contrast to the above-mentioned study, we found no association between maternal anemia and low birth weight. Women participating in our study had higher hemoglobin levels compared with pregnant women in other malaria endemic regions3,44; this might be because of public health measures including regular iron and folic acid supplementations administered during antenatal visits, all of which may act as potential confounders in this study regarding the lack of association between anemia and birth weight. Indeed, this study shows a lower prevalence of P. falciparum (31%: 10% microscopic and 21% sub-microscopic) in pregnant women than reported in a previous study, in which 44% of pregnant women in the area of Lambaréné were positive for submicroscopic P. falciparum infection.26 Not only the difference in the extent of health care provided but also the difference in the diagnostic methods used might explain the discrepancies in the prevalence of sub-microscopic P. falciparum infections in pregnant women in the same area.

In this study, microscopic P. falciparum infection was associated with high CRP levels compared with those carrying sub-microscopic P. falciparum infection (P < 0.0001) and those free of detectable infection (P < 0.0001). This finding is in contrast to recent reports from Ghana where submicroscopic P. falciparum infections have been shown to lead to elevated CRP levels.43 This discrepancy might again be caused by the use of the different diagnostic methods and cut-off values used to categorize the infected and the uninfected groups. Furthermore, because of the anti-inflammatory effect of chloroquine,45 it could affect the CRP level found. However, the chloroquine level was not determined, and the prophylaxis dose might not sufficient to have an anti-inflammatory effect.

In agreement with the understanding that CRP is not produced by the fetal liver, no elevated levels of CRP were observed in cord blood samples, with the exception of three cases. These results indicate that CRP does not cross the placenta.46

In previous studies, elevated CRP levels found in amniotic fluid were associated with higher adverse pregnancy outcome reflected in preterm deliveries, intra-amniotic infection, chorioamnionitis, funisitis, and preeclampsia.22,47–49 In our study, we found that women with elevated CRP levels in plasma had a 3-fold increased risk for low birth weight compared with those who did not show signs of systemic inflammation; however, when adjusted for P. falciparum infection, no independent effect was observed. Taken together, P. falciparum (both microscopic and sub-microscopic) infection was the main cause of low birth weight in our study population.

However, we could not distinguish between premature delivery or in utero growth retardation as the cause of low birth weight.

Consistent with previous studies,8,9,11,50,51 it was found that even asymptomatic P. falciparum infections during pregnancy play an important role in the pathogenesis of low birth weight. It was further observed that only 3 of 15 (data not shown) microscopically positive women in this study were suffering from clinical malaria.

A potential limit of this study is the absence of data on HIV infection status, potentially confounding risk factor analysis for pregnancy adverse outcome including newborn weight, anemia in pregnancy, peripheral malaria, and placental malaria in our population. However, the HIV infection prevalence among pregnant women is estimated to be < 4% in Lambaréné (unpublished data).

Altogether, this study indicates that there is a need for highly sensitive and accurate diagnostic methods to study P. falciparum infections in pregnant women.

Currently intermittent presumptive treatment in pregnancy is recommended by the World Health Organization52 for areas of high malaria transmission. While this strategy seems desirable on an operational basis, further studies should elucidate whether sulfadoxine pyrimethamine (SP), the drug of choice, is efficacious enough to eliminate completely P. falciparum infections and therefore prevent adverse birth outcome caused by sub-microscopic parasitemia.

Received February 22, 2006. Accepted for publication July 26, 2006.

Acknowledgments: We thank all pregnant women who participated in this study and the midwives at the General Hospital and the Albert Schweitzer Hospital in Lambaréné. We also thank Brigitte Migombet and Anselme Ndzengue for excellent technical assistance and Dr. Bertrand Lell and Eric Kendjo for critical comments on the statistics.

Financial support: This study was funded by the Netherlands Foundation for the Advancement of Tropical Research Grant W93-385 20077, and A.A.A. was financially supported by the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR) ID A30863.

* Address correspondence to Ayola Akim Adegnika, Department of Parasitology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA P4-37 Leiden, The Netherlands. E-mail: aadegnika{at}yahoo.fr Back

Authors’ addresses: Ayôla A Adegnika, Selidji T Agnandji, Sanders K. Chai, Lutz Ph. Breitling, Michael Ramharter, Saadou Issifou, Peter G. Kremsner, and Maria Yazdanbakhsh, Medical Research Unit, Albert Schweitzer Hospital, Lambaréné, BP: 13901 Libreville Gabon, Telephone: 00241 581099, Fax: 00241 581196, E-mail: aadegnika{at}yahoo.fr. Ayôla A Adegnika, Jaco J.Verweij, and Maria Yazdanbakhsh, Department of Parasitology, Leiden University Medical Center Albinusdreef 2 2333, ZA P4-37 Leiden, The Netherlands. Ayôla A. Adegnika, Selidji T Agnandji, Michael Ramharter, Saadou Issifou, and Peter G. Kremsner, Institute of Tropical Medicine, University of Tübingen, Wilhelmstrasse 27, 72074 Tübingen, Germany. Marijke Frolich, Department of Clinical Chemistry, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. Lutz Ph. Breitling, Research Institute for Integrative and Comparative Biology, University of Leeds, Leeds LS2 9JT, UK.


REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Ramsay S, 2003. Preventing malaria in pregnancy. Lancet Infect Dis 3: 4.[ISI][Medline]
  2. Bray RS, Anderson MJ, 1979. Falciparum malaria and pregnancy. Trans R Soc Trop Med Hyg 73: 427–431.[ISI][Medline]
  3. Bouyou-Akotet MK, Ionete-Collard DE, Mabika-Manfoumbi M, Kendjo E, Matsiegui PB, Mavoungou E, Kombila M, 2003. Prevalence of Plasmodium falciparum infection in pregnant women in Gabon. Malar J 2: 18.[Medline]
  4. Tako EA, Zhou A, Lohoue J, Leke R, Taylor DW, Leke RF, 2005. Risk factors for placental malaria and its effect on pregnancy outcome in Yaounde, Cameroon. Am J Trop Med Hyg 72: 236–242.[Abstract/Free Full Text]
  5. Shi YP, Sayed U, Qari SH, Roberts JM, Udhayakumar V, Oloo AJ, Hawley WA, Kaslow DC, Nahlen BL, Lal AA, 1996. Natural immune response to the C-terminal 19-kilodalton domain of Plasmodium falciparum merozoite surface protein 1. Infect Immun 64: 2716–2723.[Abstract]
  6. Oeuvray C, Theisen M, Rogier C, Trape JF, Jepsen S, Druilhe P, 2000. Cytophilic immunoglobulin responses to Plasmodium falciparum glutamate-rich protein are correlated with protection against clinical malaria in Dielmo, Senegal. Infect Immun 68: 2617–2620.[Abstract/Free Full Text]
  7. Adam I, Ali DM, Elbashir MI, 2004. Manifestations of falciparum malaria in pregnant women of Eastern Sudan. Saudi Med J 25: 1947–1950.[ISI][Medline]
  8. Steketee RW, Wirima JJ, Slutsker L, Heymann DL, Breman JG, 1996. The problem of malaria and malaria control in pregnancy in sub-Saharan Africa. Am J Trop Med Hyg 55: 2–7.[ISI][Medline]
  9. Okoko BJ, Enwere G, Ota MO, 2003. The epidemiology and consequences of maternal malaria: A review of immunological basis. Acta Trop 87: 193–205.[ISI][Medline]
  10. McCormick MC, 1985. The contribution of low birth weight to infant mortality and childhood morbidity. N Engl J Med 312: 82–90.[Abstract]
  11. Menendez C, 1995. Malaria during pregnancy: a priority area of malaria research and control. Parasitol Today 11: 178–183.[ISI][Medline]
  12. Steketee RW, Nahlen BL, Parise ME, Menendez C, 2001. The burden of malaria in pregnancy in malaria-endemic areas. Am J Trop Med Hyg 64: 28–35.[Abstract]
  13. Brabin BJ, 1983. An analysis of malaria in pregnancy in Africa. Bull World Health Organ 61: 1005–1016.[ISI][Medline]
  14. Guyatt HL, Snow RW, 2004. Impact of malaria during pregnancy on low birth weight in sub-Saharan Africa. Clin Microbiol Rev 17: 760–769.[Abstract/Free Full Text]
  15. Whitty CJ, Edmonds S, Mutabingwa TK, 2005. Malaria in pregnancy. BJOG 112: 1189–1195.[ISI][Medline]
  16. Fried M, Duffy PE, 1996. Adherence of Plasmodium falciparum to chondroitin sulfate A in the human placenta. Science 272: 1502–1504.[Abstract]
  17. Lekana Douki JB, Traore B, Costa FT, Fusai T, Pouvelle B, Sterkers Y, Scherf A, Gysin J, 2002. Sequestration of Plasmodium falciparum-infected erythrocytes to chondroitin sulfate A, a receptor for maternal malaria: monoclonal antibodies against the native parasite ligand reveal pan-reactive epitopes in placental isolates. Blood 100: 1478–1483.[Abstract/Free Full Text]
  18. Torre D, Speranza F, Giola M, Matteelli A, Tambini R, Biondi G, 2002. Role of Th1 and Th2 cytokines in immune response to uncomplicated Plasmodium falciparum malaria. Clin Diagn Lab Immunol 9: 348–351.[Medline]
  19. Bates MD, Quenby S, Takakuwa K, Johnson PM, Vince GS, 2002. Aberrant cytokine production by peripheral blood mononuclear cells in recurrent pregnancy loss? Hum Reprod 17: 2439–2444.[Abstract/Free Full Text]
  20. Kemp K, Kurtzhals JA, Akanmori BD, Adabayeri V, Goka BQ, Behr C, Hviid L, 2002. Increased levels of soluble CD30 in plasma of patients with Plasmodium falciparum malaria. Clin Diagn Lab Immunol 9: 720–722.[Medline]
  21. Graninger W, Thalhammer F, Hollenstein U, Zotter GM, Kremsner PG, 1992. Serum protein concentrations in Plasmodium falciparum malaria. Acta Trop 52: 121–128.[ISI][Medline]
  22. Ghezzi F, Franchi M, Raio L, Di Naro E, Bossi G, D’Eril GV, Bolis P, 2002. Elevated amniotic fluid C-reactive protein at the time of genetic amniocentesis is a marker for preterm delivery. Am J Obstet Gynecol 186: 268–273.[ISI][Medline]
  23. Malek A, Bersinger NA, Di Santo S, Mueller MD, Sager R, Schneider H, Ghezzi F, Karousou E, Passi A, De Luca G, Raio L, 2005. C-reactive protein production in term human placental tissue. Placenta 27: 619–625.[Medline]
  24. Ramharter M, Grobusch MP, Kiessling G, Adegnika AA, Moller U, Agnandji ST, Kramer M, Schwarz N, Kun JF, Oyakhirome S, Issifou S, Borrmann S, Lell B, Mordmuller B, Kremsner PG, 2005. Clinical and parasitological characteristics of puerperal malaria. J Infect Dis 191: 1005–1009.[ISI][Medline]
  25. Kassberger F, Birkenmaier A, Khattab A, Kremsner PG, Klinkert MQ, 2002. PCR typing of Plasmodium falciparum in matched peripheral, placental and umbilical cord blood. Parasitol Res 88: 1073–1079.[ISI][Medline]
  26. Mayengue PI, Rieth H, Khattab A, Issifou S, Kremsner PG, Klinkert MQ, Ntoumi F, 2004. Sub-microscopic Plasmodium falciparum infections and multiplicity of infection in matched peripheral, placental and umbilical cord blood samples from Gabonese women. Trop Med Int Health 9: 949–958.[ISI][Medline]
  27. Walker-Abbey A, Djokam RR, Eno A, Leke RF, Titanji VP, Fogako J, Sama G, Thuita LH, Beardslee E, Snounou G, Zhou A, Taylor DW, 2005. Malaria in pregnant Cameroonian women: The effect of age and gravidity on sub-microscopic and mixed-species infections and multiple parasite genotypes. Am J Trop Med Hyg 72: 229–235.[Abstract/Free Full Text]
  28. Singer LM, Newman RD, Diarra A, Moran AC, Huber CS, Stennies G, Sirima SB, Konate A, Yameogo M, Sawadogo R, Barnwell JW, Parise ME, 2004. Evaluation of a malaria rapid diagnostic test for assessing the burden of malaria during pregnancy. Am J Trop Med Hyg 70: 481–485.[Abstract/Free Full Text]
  29. Ntoumi F, Contamin H, Rogier C, Bonnefoy S, Trape JF, Mercereau-Puijalon O, 1995. Age-dependent carriage of multiple Plasmodium falciparum merozoite surface antigen-2 alleles in asymptomatic malaria infections. Am J Trop Med Hyg 52: 81–88.[Abstract/Free Full Text]
  30. Snounou G, Bourne T, Jarra W, Viriyakosol S, Brown KN, 1992. Identification and quantification of rodent malaria strains and species using gene probes. Parasitology 105: 21–27.
  31. Andrews L, Andersen RF, Webster D, Dunachie S, Walther RM, Bejon P, Hunt-Cooke A, Bergson G, Sanderson F, Hill AV, Gilbert SC, 2005. Quantitative real-time polymerase chain reaction for malaria diagnosis and its use in malaria vaccine clinical trials. Am J Trop Med Hyg 73: 191–198.[Abstract/Free Full Text]
  32. Malhotra I, Dent A, Mungai P, Muchiri E, King CL, 2005. Real-time quantitative PCR for determining the burden of Plasmodium falciparum parasites during pregnancy and infancy. J Clin Microbiol 43: 3630–3635.[Abstract/Free Full Text]
  33. Swan H, Sloan L, Muyombwe A, Chavalitshewinkoon-Petmitr P, Krudsood S, Leowattana W, Wilairatana P, Looareesuwan S, Rosenblatt J, 2005. Evaluation of a real-time polymerase chain reaction assay for the diagnosis of malaria in patients from Thailand. Am J Trop Med Hyg 73: 850–854.[Abstract/Free Full Text]
  34. Mankhambo L, Kanjala M, Rudman S, Lema VM, Rogerson SJ, 2002. Evaluation of the OptiMAL rapid antigen test and species-specific PCR to detect placental Plasmodium falciparum infection at delivery. J Clin Microbiol 40: 155–158.[Abstract/Free Full Text]
  35. Wildling E, Winkler S, Kremsner PG, Brandts C, Jenne L, Wernsdorfer WH, 1995. Malaria epidemiology in the province of Moyen Ogoov, Gabon. Trop Med Parasitol 46: 77–82.[ISI][Medline]
  36. Sylla EH, Kun JF, Kremsner PG, 2000. Mosquito distribution and entomological inoculation rates in three malaria-endemic areas in Gabon. Trans R Soc Trop Med Hyg 94: 652–656.[ISI][Medline]
  37. Borrmann S, Oyakhirome S, Esser G, Trinkle C, Issifou S, Grobusch MP, Krishna S, Kremsner PG, 2004. Short report: Evaluation of a simple and inexpensive photometric device for the measurement of hemoglobin. Am J Trop Med Hyg 71: 691–692.[Abstract/Free Full Text]
  38. Planche T, Krishna S, Kombila M, Engel K, Faucher JF, Ngou-Milama E, Kremsner PG, 2001. Comparison of methods for the rapid laboratory assessment of children with malaria. Am J Trop Med Hyg 65: 599–602.[Abstract]
  39. Dati F, Schumann G, Thomas L, Aguzzi F, Baudner S, Bienvenu J, Blaabjerg O, Blirup-Jensen S, Carlstrom A, Petersen PH, Johnson AM, Milford-Ward A, Ritchie RF, Svendsen PJ, Whicher J, 1996. Consensus of a group of professional societies and diagnostic companies on guidelines for interim reference ranges for 14 proteins in serum based on the standardization against the IFCC/BCR/CAP Reference Material (CRM 470). International Federation of Clinical Chemistry. Community Bureau of Reference of the Commission of the European Communities. College of American Pathologists. Eur J Clin Chem Clin Biochem 34: 517–520.[ISI][Medline]
  40. Borrmann S, Binder RK, Adegnika AA, Missinou MA, Issifou S, Ramharter M, Wernsdorfer WH, Kremsner PG, 2002. Reassessment of the resistance of Plasmodium falciparum to chloroquine in Gabon: Implications for the validity of tests in vitro vs. in vivo. Trans R Soc Trop Med Hyg 96: 660–663.[ISI][Medline]
  41. Ramharter M, Wernsdorfer WH, Kremsner PG, 2004. In vitro activity of quinolines against Plasmodium falciparum in Gabon. Acta Trop 90: 55–60.[ISI][Medline]
  42. Saute F, Menendez C, Mayor A, Aponte J, Gomez-Olive X, Dgedge M, Alonso P, 2002. Malaria in pregnancy in rural Mozambique: The role of parity, sub-microscopic and multiple Plasmodium falciparum infections. Trop Med Int Health 7: 19–28.[ISI][Medline]
  43. Mockenhaupt FP, Rong B, Till H, Eggelte TA, Beck S, Gyasi-Sarpong C, Thompson WN, Bienzle U, 2000. Sub-microscopic Plasmodium falciparum infections in pregnancy in Ghana. Trop Med Int Health 5: 167–173.[ISI][Medline]
  44. Achidi EA, Kuoh AJ, Minang JT, Ngum B, Achimbom BM, Motaze SC, Ahmadou MJ, Troye-Blomberg M, 2005. Malaria infection in pregnancy and its effects on haemoglobin levels in women from a malaria endemic area of Fako Division, South West Province, Cameroon. J Obstet Gynaecol 25: 235–240.[Medline]
  45. van den Borne BE, Landewe RB, Rietveld JH, Goei The HS, Griep EN, Breedveld FC, Dijkmans BA, 1999. Chloroquine therapy in patients with recent-onset rheumatoid arthritis: The clinical response can be predicted by the low level of acute-phase reaction at baseline. Clin Rheumatol 18: 369–372.[ISI][Medline]
  46. Di Naro E, Ghezzi F, Raio L, Romano F, Mueller MD, McDougall J, Cicinelli E, 2003. C-reactive protein in vaginal fluid of patients with preterm premature rupture of membranes. Acta Obstet Gynecol Scand 82: 1072–1079.[ISI][Medline]
  47. Chen SU, Ko TM, Hwa HL, Lu PJ, Ho HN, Yang YS, 2001. Maternal serum C-reactive protein level does not change significantly after fetal reduction: It could be used as an indicator of chorioamnionitis. J Assist Reprod Genet 18: 336–340.[ISI][Medline]
  48. Yoon BH, Romero R, Shim JY, Shim SS, Kim CJ, Jun JK, 2003. C-reactive protein in umbilical cord blood: A simple and widely available clinical method to assess the risk of amniotic fluid infection and funisitis. J Matern Fetal Neonatal Med 14: 85–90.[Medline]
  49. Mwanyumba F, Inion I, Gaillard P, Mandaliya K, Praet M, Temmerman M, 2003. Placental inflammation and perinatal outcome. Eur J Obstet Gynecol Reprod Biol 108: 164–170.[ISI][Medline]
  50. Luxemburger C, McGready R, Kham A, Morison L, Cho T, Chongsuphajaisiddhi T, White NJ, Nosten F, 2001. Effects of malaria during pregnancy on infant mortality in an area of low malaria transmission. Am J Epidemiol 154: 459–465.[Abstract/Free Full Text]
  51. Singh N, Mehra RK, Srivastava N, 2001. Malaria during pregnancy and infancy, in an area of intense malaria transmission in central India. Ann Trop Med Parasitol 95: 19–29.[ISI][Medline]
  52. WHO Expert Committee on Malaria. 2000. World Health Organ Tech Rep Ser 892: i74.



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