Macrophage migration inhibitory factor and placental malaria infection in an area characterized by unstable malaria transmission in central Sudan

Reem Eltayeb; Naser Bilal; Awad-Elkareem Abass; Elhassan M. Elhassan; Ahmed Mohammed; Ishag Adam

doi:10.12688/f1000research.7061.1

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Macrophage migration inhibitory factor and placental malaria infection in an area characterized by unstable malaria transmission in central Sudan

[version 1; peer review: 2 approved]

Reem Eltayeb¹, Naser Bilal¹, Awad-Elkareem Abass¹, Elhassan M. Elhassan², Ahmed Mohammed³, Ishag Adam ⁴

Reem Eltayeb¹, Naser Bilal¹, [...] Awad-Elkareem Abass¹, Elhassan M. Elhassan², Ahmed Mohammed³, Ishag Adam ⁴

PUBLISHED 16 Sep 2015

Author details Author details

¹ Faculty of Medical Laboratory Sciences, University of Khartoum, Khartoum, 11115, Sudan
² Faculty of Medicine, University of Geziera, Medani, 11111, Sudan
³ Faculty of Medicine, Ribat University, Khartoum, 11111, Sudan
⁴ Faculty of Medicine, University of Khartoum, Khartoum, 11115, Sudan

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Abstract

Background: The pathogenesis of malaria during pregnancy is not fully understood. A proinflammatory cytokine, macrophage migration inhibitory factor (MIF) is suggested as a factor involved in the pathogenesis of malaria during pregnancy.
Methods: A cross-sectional study was conducted in Medani Hospital, Sudan to investigate MIF levels in placental malaria. Obstetrical and medical characteristics were gathered from each parturient woman using questionnaires. All women (151) were investigated for malaria using blood film and placental histology. MIF levels were measured using ELISA in paired maternal and cord blood samples.
Results: There were no P. falciparum-positive blood films obtained from maternal peripheral blood, placenta or cord samples. Out of 151 placentae, four (2.6%), one (0.7%), 32 (21.2%) showed acute, chronic and past infection on histopathology examinations respectively, while the rest (114; 75.5%) of them showed no signs of infection.There was no significant difference in the median (interquartile) of maternal [5.0 (3.7─8.8) vs 6.2(3.5─12.0) ng/ml, P=0.643] and cord [8.1(3.3─16.9) vs 8.3(4.2─16.9), ng/ml, P= 0.601] MIF levels between women with a positive result for placental malaria infection (n=37) and women with a negative result for placental malaria infection (n=114). In regression models placental malaria was not associated with maternal MIF, hemoglobin or birth weight. MIF was not associated with hemoglobin or birth weight.
Conclusion: There was no association between maternal and cord MIF levels, placental malaria, maternal hemoglobin and birth weight.

Keywords

Macrophage migration inhibitory factor (MIF), malaria, birth weight, hemoglobin, Sudan

Corresponding author: Ishag Adam

Competing interests: The authors declare that they have no competing interests.

Grant information: The author(s) declared that no grants were involved in supporting this work.

Copyright: © 2015 Eltayeb R et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Data associated with the article are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication).

How to cite: Eltayeb R, Bilal N, Abass AE et al. Macrophage migration inhibitory factor and placental malaria infection in an area characterized by unstable malaria transmission in central Sudan [version 1; peer review: 2 approved]. F1000Research 2015, 4:824 (https://doi.org/10.12688/f1000research.7061.1) First published: 16 Sep 2015, 4:824 (https://doi.org/10.12688/f1000research.7061.1) Latest published: 16 Sep 2015, 4:824 (https://doi.org/10.12688/f1000research.7061.1)

Background

Malaria is a large public health problem in endemic tropical countries where there are over 30 million pregnancies at risk of malaria occur in Africa each year¹. Malaria during pregnancy can lead to adverse outcomes (both maternal and perinatal) e.g. anemia and low birth weight (LBW)^2–4. Pregnant women in different regions of Sudan are susceptible to malaria, regardless of their age and parity⁵. Malaria is associated with adverse pregnancy outcomes such as anemia⁶ and LBW⁷, and it is the main cause of maternal mortality⁸.

The sequestration of Plasmodium falciparum–infected erythrocytes and accumulation of infected erythrocytes in placental intervillous spaces is responsible for the malaria-related pathologic changes in the placenta^9,10. The exact mechanism by which malaria infection and placental inflammation result in fetal growth restriction and LBW is poorly understood. However, many chemokines and inflammatory cytokines are associated with malaria infection and malaria-related LBW¹¹.

Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine released from a variety of cells (T cells, monocytes, macrophages, blood dendritic cells, B cells, neutrophils, eosinophils, mast cells) and is implicated in the pathogenesis of sepsis, and inflammatory and autoimmune diseases¹². MIF has been observed in the human endometrium, placental villi, cytotrophoblasts, and it has been implicated in implantation and other reproductive functions^13,14. Several studies have demonstrated the role of MIF in modulating malaria severity and pathogenesis^15,16. It has recently been reported that women with a positive result for placental malaria had significantly higher intervillous plasma MIF levels than women with a negative result for placental malaria¹⁷. There are few published data on MIF and placental malaria and none of them from Sudan. The current study was conducted in Medani Maternity Hospital, Central Sudan, to investigate MIF levels in women with placental malaria, and the effect – if any- on maternal hemoglobin and birth weight. This work is an addition to our previous research on malaria and its pathogenesis during pregnancy e.g. placental malaria infiltration^18,19, hormones and cytokines^20,21 complement, cytokines and malaria infections^22,23.

Material and methods

A cross-sectional study was conducted during the rainy and post-rainy season (September–November) 2013 in Medani Maternity Hospital, Central Sudan which is a referral tertiary hospital. Central Sudan is characterized by unstable malaria transmission and P. falciparum is the sole malaria parasite²⁴.

The sample size of 151 women was calculated to have 80% power and to detect a difference of 5% at α=0.05 and 10% of women might not respond or have incomplete data.

After signing an informed consent form, information on history of obstetrics, medical history, antennal attendance characteristics, and bed net use was gathered from participants using questionnaires applied by a trained medical officer. Maternal weight and height were measured and body mass index was calculated and expressed as weight (kg)/height (m)². Newborns were weighed immediately following birth using a Salter scale and the sex of each newborn was recorded.

Giemsa-stained blood smears for light microscopy

5ml of blood (maternal and cord) were taken and allowed to clot and centrifuged for 10 minutes at 3000 rpm and the serum was separated and stored at -20°C till the analyses.

Maternal, placental, and cord blood films were prepared and stained using 10% Giemsa. If the slides were positive; the number of asexual parasites was counted per 200 leukocytes, assuming a leukocyte count of 8000 leukocytes/μl (for thick films) or per 1000 red blood cells (for thin films). Blood films were considered negative if no parasites were detected in 100 oil immersion fields of a thick blood film, which was double-checked in a blind manner by an expert microscopist. Maternal hemoglobin levels were measured by the HemoCue hemoglobinometer (HemoCue AB, Angelhom, Sweden) and recorded.

Placental histology. The method used for placental histology was mentioned previously^7,18–20. In summary, a 3cm³ placental sample was obtained from the maternal surface at a location approximately halfway between the umbilical cord and the edge of the placenta. Each biopsy sample was immediately placed in 10% neutral buffered formalin. The buffer was used to prevent formation of formalin pigment, which has similar optical characteristics and polarized light activity as malaria pigment²⁵. Placental biopsy samples were processed and were embedded in paraffin wax and 4mm thick slides were stained with hematoxylin-eosin and Giemsa. In these slides, placental malaria infection was characterized as follows²⁶: uninfected (no parasites or pigment), acute (parasites in intervillous spaces), chronic (parasites in maternal erythrocytes and pigment in fibrin, or cells within fibrin and/or chorionic villous syncytiotrophoblast or strom), and previous (no parasites, and pigment confined to fibrin or cells within fibrin).

ELISA for measuring MIF levels

Maternal and cord serum levels were measured using a human MIF ELISA kit (BIOLEGEND catalogue number 438408, Pacific Heights Blvd, San Diego, USA) by following the manufacturer’s protocol.

Statistical analysis

Data were entered into a computer using SPSS for windows (version 16.0). MIF data were not normally distributed and were compared between groups using Mann-Whitney U test. Multivariate analyses were performed using binary models for placental malaria infection as the dependent variable and linear models with hemoglobin, birth weight, and MIF (maternal and cord) levels as continuous dependent variables. Socio-demographic characteristics, education, antenatal care, residence, and placental malaria infections were the independent predictor of interest. Odds ratios (OR) and 95% confidence intervals (CI) were calculated and a P value of <0.05 was considered significant.

Ethics

The study received ethical clearance from the Research Board at the Faculty of Medicine, University of Khartoum, Sudan.

Results

The basic characteristics of the investigated women were shown in Table 1. There were no P. falciparum-positive blood films obtained from maternal peripheral blood, placenta or cord samples. Out of 151 placentae, four (2.6%), one (0.7%), 32 (21.2%) showed acute, chronic and past infection on histopathology examinations respectively, while the rest (114; 75.5%) of them showed no signs of infection.

Table 1. Basic characteristics of the pregnant women (n = 151) included in the study at Medani Hospital, Sudan.

	Mean (SD)
Age (years)	26.9 (5.5)
Parity	2.0 (1.2)
Body mass index (weight (kg)/height (m)²)	24.2 (2.3)
Hemoglobin, gm/dl	10.5 (1.1)
	Number (%) of
Primiparae	69 (45.6)
Lack of antenatal care	42 (27.8)
Education < secondary level	96 (63.5)
Rural residence	77 (50.9)
Uses bed nets	140 (92.7)
Has anemia	94 (62.2)

None of the investigated factors were associated with placental malaria infection, Table 2. There was no significant difference in the median (interquartile) of maternal [5.0 (3.7–8.8) vs 6.2(3.5–12.0) ng/ml, P=0.643] and cord [8.1(3.3–16.9) vs 8.3(4.2–16.9), ng/ml, P=0.601] MIF levels between women with a positive result for placental malaria infection (n=37) and women with a negative result for placental malaria infection (n=114; Figure 1).

Table 2. Factors associated with placental malaria among pregnant women at Medani Hospital, Sudan using univariate and multivariate analyses.

Variable	Univariate analyses			Multivariate analyses
	OR	95% CI	P	OR	95% CI	P
Age, year	0.9	0.9–1.0	0.438	0.9	0.8–1.0	0.236
Parity	1.2	0.9–1.7	0.091	1.5	0.9–2.3	0.073
Gestational age, weeks	1.0	0.8–1.1	0.849	1.0	0.8–1.1	0.930
Lack of antenatal care	0.7	0.3–1.5	0.441	0.5	0.1–2.1	0.391
Rural residency	1.0	0.4–2.4	0.873	1.0	0.4–2.9	0.851
Education < secondary level	1.4	0.5–3.4	0.438	1.3	0.3–4.6	0.633
Using bed nets	4.2	0.8–20.1	0.151	6.6	1.1–37.7	0.032
Body mass index, weight (kg)/height (m)²	1.0	0.8–1.1	0.927	0.9	0.8–1.2	0.909
Anemia	0.5	0.2–1.1	0.109	0.4	0.1–1.2	0.134
Macrophage inhibitory factor	0.3	0.1–1.1	0.094	0.9	0.9–1.0	0.904

OR = Odds ratio, CI = confidence interval

Figure 1. Maternal and umbilical cord macrophage migration inhibitory factor levels and placental malaria infection.

There was no significant difference in the median (interquartile) MIF levels [5.6(3.6–11.5) vs [7.3(3.0–9.7) ng/ml, P=0.516] between the maternal and cord samples.

In linear regression placental malaria was not associated with maternal MIF, hemoglobin or birth weight. Likewise MIF levels were not associated with maternal hemoglobin or newborn birth weight (Table 3 and Table 4).

Table 3. Factors associated with maternal and cord MIF in pregnant women at Medani Hospital, Sudan using linear regression analyses.

Variable	Maternal MIF			Cord MIF
	Coefficient	SE	P-value	Coefficient	SE	P-value
Age, year	0.209	0.112	0.065	–0.256	0.120	0.036
Parity	–0.596	0.480	0.217	0.394	0.511	0.442
Gestational age, weeks	–0.257	0.146	0.080	–0.105	0.156	0.503
Body mass index, (kg)/(m)²	–0.526	0.233	0.025	0.373	0.251	0.140
Hemoglobin	0.579	0.468	0.218	0.142	0.498	0.776
Placental malaria infection	–0.236	1.261	0.852	–0.023	1.336	0.986
Macrophage inhibitory factor	–	–	–	0.473	0.093	< 0.001

MIF = macrophage inhibitory factor, SE = standard error

Table 4. Factors associated with maternal hemoglobin and birth weight levels at Medani Hospital, Sudan using linear regression analyses.

Variable	Hemoglobin			Birth weight
	Coefficient	SE	P-value	Coefficient	SE	P-value
Age, year	0.028	0.022	0.202	0.010	0.010	0.335
Parity	–0.043	0.088	0.077	0.025	0.041	0.544
Gestational age, weeks	–0.044	0.028	0.112	0.011	0.012	0.367
Body mass index, (kg)/(m)²	–0.029	0.045	0.524	0.021	0.020	0.307
Hemoglobin	–	–	–	0.022	0.040	0.583
Placental malaria infection	0.141	0.237	0.552	–0.122	0.106	0.253
Maternal MIF	0.018	0.018	0.316	0.002	0.008	0.847
Cord MIF	0.004	0.016	0.776	0.001	0.007	0.939

MIF = macrophage inhibitory factor, SE = standard error

There was a significant association between maternal blood/placental and cord MIF (0.473 ng/ml, P<0.001), Table 4.

Dataset 1.Raw dataset for Eltayeb et al., 2015 ‘Macrophage migration inhibitory factor and placental malaria infection in an area characterized by unstable malaria transmission in Central Sudan’.

Basic characteristics of the women were gathered using questionnaires. Maternal and cord serum levels were measured using a human MIF ELISA kit. gestweeks=Gestational weeks; antenacare=had antinatal care (1=yes, 0=no); usebednet=used bed nets (1=yes, 0=no); useironfolic=used iron or folic acid (1=yes, 0=no); Wt=weight (Maternal;kg); Ht=height (Maternal;cm), Hb=haemoglobin (Maternal; g/dl); birthwt=birthweight (Child; kg); bloodgroup (Maternal): 0=A, 1=B, 2=AB 3=O; MIFcord= MIF levels in the umbilical cord (ng/ml); MIFmother (ng/ml). Raw data file openable by PSPP, available at https://www.gnu.org/software/pspp/.

Discussion

The main findings of the current study were; there was no significant difference in the MIF levels in women positive for placental malaria infection and women negative placental malaria infection negative. There was no association between MIF, hemoglobin and birth weight.

This goes with previous reports where Singh et al. found no significant difference in the peripheral and cord MIF levels between women with placental malaria infections and women with placental malaria infections negative¹⁷. It is worth mentioning that in Singh’s later study the MIF levels in the intervillous space (which we did not measure) were significantly higher than the peripheral and cord levels and higher in women with placental malaria infection compared with women negative for placental malaria infection¹⁷. Furthermore, the observations of Singh et al. were based on microscopically-diagnosed placental malaria infection and in our cohort none of the women/placentae had microscopically detected malaria infections, except one that was diagnosed via histology. Yet high MIF was reported to be associated with adverse pregnancy outcome regardless of the presence of malaria infection¹⁷. Likewise, Chaisavaneeyakorn et al.²⁷ observed high levels of MIF in the intervillous blood, compared with that in both peripheral and cord plasma and that intervillous (but not peripheral) MIF levels are associated with placental malaria among Kenyan women. Previous results obtained by Chaiyaroj and colleagues reported significantly higher MIF production by intervillous blood monocytes compared to peripheral ones and high MIF levels in placental plasma compared to paired peripheral plasma²⁸. Increased secretion of MIF by syncytiotrophoblasts was observed previously using an in vitro system²⁹. Generally MIF has been shown to play important roles during normal pregnancy³⁰, as well as in preterm delivery³¹ and preeclampsia³² and therefore, intervillous MIF would be expected to be high.

We have previously shown that immunomodulatory hormones (cortisol), cytokines, monocytes and macrophages were implicated in the pathogenesis of malaria during pregnancy which affected pregnant women regardless of their age and parity^{5,7,8,18–21}. Furthermore, histologic studies have shown that malaria-infected placentae have high numbers of macrophages loaded with malarial pigment and these cells could have a critical role in the clearance of the malaria parasites²⁵. Perhaps the high levels of MIF levels observed (by the later studies) in the placenta of women positive for malaria is induced by the malaria parasites that accumulated in the placenta, with MIF helping to retain macrophages in the placenta. Interestingly, it has been shown that MIF is effective in activating macrophages to clear/remove intracellular parasites e.g. Leishmania major³³.

As mentioned above, the malaria placental infections in the current study were past infections and this could explain the lack of significant difference in MIF levels. The other plausible explanation could be the submicroscopic/subpatent infections that we did not investigate in the current study. We have recently shown that in the same hospital, submicroscopic/subpatent infections that were detected by PCR rather than histology were significantly associated with low birth weight⁷.

Conclusion

The current study failed to show a significant association between maternal blood/placental and cord MIF levels, placental malaria, maternal hemoglobin or birth weight.

Data availability

F1000Research: Dataset 1. Raw dataset for Eltayeb et al., 2015 ‘Macrophage migration inhibitory factor and placental malaria infection in an area characterized by unstable malaria transmission in Central Sudan’, 10.5256/f1000research.7061.d102039³⁴

Author contributions

RE and IA coordinated and carried out the study. NEB and AA participated in the statistical analysis. EME and AAM participated in the clinical work and conducted the laboratory work. All the authors have read and approved the final version of this manuscript.

Competing interests

The authors declare that they have no competing interests.

Grant information

The author(s) declared that no funding was involved in supporting this work.

Acknowledgement

Authors would like to thank the women who were involved in the study and the midwives and the nursing staff of the Medani Hospital.

Supplementary materials

Data collection questionnaire.

Questionnaire was applied by a medical professional to participants in the study. ANC: antenatal care; HB: haemoglobin; WT: weight

Click here to access the data.

Faculty Opinions recommended

References

1. WHO: World Malaria Report 2012. Geneva, Switzerland: World Health Organization; 2013. Reference Source
2. Menendez C, Ordi J, Ismail MR, et al.: The impact of placental malaria on gestational age and birth weight. J Infect Dis. 2000; 181(5): 1740–1745. PubMed Abstract | Publisher Full Text
3. Rogerson SJ, Pollina E, Getachew A, et al.: Placental monocyte infiltrates in response to Plasmodium falciparum malaria infection and their association with adverse pregnancy outcomes. Am J Trop Med Hyg. 2003; 68(1): 115–119. PubMed Abstract
4. Ahmed R, Singh N, ter Kuile FO, et al.: Placental infections with histologically confirmed Plasmodium falciparum are associated with adverse birth outcomes in India: a cross-sectional study. Malar J. 2014; 13: 232. PubMed Abstract | Publisher Full Text | Free Full Text
5. Ali AA, Elhassan EM, Magzoub MM, et al.: Hypoglycaemia and severe Plasmodium falciparum malaria among pregnant Sudanese women in an area characterized by unstable malaria transmission. Parasit Vectors. 2011; 4: 88. PubMed Abstract | Publisher Full Text | Free Full Text
6. Adam I, Khamis AH, Elbashir MI: Prevalence and risk factors for anaemia in pregnant women of eastern Sudan. Trans R Soc Trop Med Hyg. 2005; 99(10): 739–43. PubMed Abstract | Publisher Full Text
7. Mohammed AH, Salih MM, Elhassan EM, et al.: Submicroscopic Plasmodium falciparum malaria and low birth weight in an area of unstable malaria transmission in Central Sudan. Malar J. 2013; 12: 172. PubMed Abstract | Publisher Full Text | Free Full Text
8. Adam I, Elhassan EM, Haggaz AE, et al.: A perspective of the epidemiology of malaria and anaemia and their impact on maternal and perinatal outcomes in Sudan. J Infect Dev Ctries. 2011; 5(2): 83–7, Review. PubMed Abstract | Publisher Full Text
9. Miller LH, Baruch DI, Marsh K, et al.: The pathogenic basis of malaria. Nature. 2002; 415(6872): 673–9. PubMed Abstract | Publisher Full Text
10. Muthusamy A, Achur RN, Bhavanandan VP, et al.: Plasmodium falciparum-infected erythrocytes adhere both in the intervillous space and on the villous surface of human placenta by binding to the low-sulfated chondroitin sulfate proteoglycan receptor. Am J Pathol. 2004; 164(6): 2013–25. PubMed Abstract | Publisher Full Text | Free Full Text
11. Umbers AJ, Aitken EH, Rogerson SJ: Malaria in pregnancy: small babies, big problem. Trends Parasitol. 2011; 27(4): 168–75. PubMed Abstract | Publisher Full Text
12. Calandra T, Roger T: Macrophage migration inhibitory factor: a regulator of innate immunity. Nat Rev Immunol. 2003; 3(10): 791–800. PubMed Abstract | Publisher Full Text
13. Arcuri F, Ricci C, Ietta F, et al.: Macrophage migration inhibitory factor in the human endometrium: expression and localization during the menstrual cycle and early pregnancy. Biol Reprod. 2001; 64(4): 1200–5. PubMed Abstract | Publisher Full Text
14. Arcuri F, Cintorino M, Vatti R, et al.: Expression of macrophage migration inhibitory factor transcript and protein by first-trimester human trophoblasts. Biol Reprod. 1999; 60(6): 1299–303. PubMed Abstract | Publisher Full Text
15. Awandare GA, Ouma Y, Ouma C, et al.: Role of monocyte-acquired hemozoin in suppression of macrophage migration inhibitory factor in children with severe malarial anemia. Infect Immun. 2007; 75(1): 201–210. PubMed Abstract | Publisher Full Text | Free Full Text
16. Jain V, McClintock S, Nagpal AC, et al.: Macrophage migration inhibitory factor is associated with mortality in cerebral malaria patients in India. BMC Res Notes. 2009; 2: 36. PubMed Abstract | Publisher Full Text | Free Full Text
17. Singh PP, Lucchi NW, Blackstock A, et al.: Intervillous macrophage migration inhibitory factor is associated with adverse birth outcomes in a study population in Central India. PLoS One. 2012; 7(12): e51678. PubMed Abstract | Publisher Full Text | Free Full Text
18. Salih MM, Mohammed AH, Mohmmed AA, et al.: Monocytes and macrophages and placental malaria infections in an area of unstable malaria transmission in eastern Sudan. Diagn Pathol. 2011; 6: 83. PubMed Abstract | Publisher Full Text | Free Full Text
19. Batran SE, Salih MM, Elhassan EM, et al.: CD20, CD3, placental malaria infections and low birth weight in an area of unstable malaria transmission in Central Sudan. Diagn Pathol. 2013; 8: 189. PubMed Abstract | Publisher Full Text | Free Full Text
20. Bayoumi NK, Bakhet KH, Mohmmed AA, et al.: Cytokine profiles in peripheral, placental and cord blood in an area of unstable malaria transmission in eastern Sudan. J Trop Pediatr. 2009; 55(4): 233–7. PubMed Abstract | Publisher Full Text
21. Bayoumi NK, Elhassan EM, Elbashir MI, et al.: Cortisol, prolactin, cytokines and the susceptibility of pregnant Sudanese women to Plasmodium falciparum malaria. Ann Trop Med Parasitol. 2009; 103(2): 111–7. PubMed Abstract | Publisher Full Text
22. Alim A, E Bilal N, Abass AE, et al.: Complement activation, placental malaria infection, and birth weight in areas characterized by unstable malaria transmission in central Sudan. Diagn Pathol. 2015; 10(1): 49. PubMed Abstract | Publisher Full Text | Free Full Text
23. Chandrasiri UP, Randall LM, Saad AA, et al.: Low antibody levels to pregnancy-specific malaria antigens and heightened cytokine responses associated with severe malaria in pregnancy. J Infect Dis. 2014; 209(9): 1408–17. PubMed Abstract | Publisher Full Text
24. Malik EM, Atta HY, Weis M, et al.: Sudan Roll Back Malaria Consultative Mission: Essential Actions to Support the Attainment of the Abuja Targets. Sudan RBM Country Consultative Mission Final Report. Geneva: Roll Back Malaria Partnership; 2004. Reference Source
25. Bulmer JN, Rasheed FN, Francis N, et al.: Placental malaria. I. Pathological classification. Histopathology. 1993; 22(3): 211–218. PubMed Abstract | Publisher Full Text
26. Bulmer JN, Rasheed FN, Morrison L, et al.: Placental malaria. II. A semi-quantitative investigation of the pathological features. Histopathology. 1993; 22(3): 219–225. PubMed Abstract | Publisher Full Text
27. Chaisavaneeyakorn S, Moore JM, Othoro C, et al.: Immunity to placental malaria. IV. Placental malaria is associated with up-regulation of macrophage migration inhibitory factor in intervillous blood. J Infect Dis. 2002; 186(9): 1371–5. PubMed Abstract | Publisher Full Text
28. Chaiyaroj SC, Rutta AS, Muenthaisong K, et al.: Reduced levels of transforming growth factor-beta1, interleukin-12 and increased migration inhibitory factor are associated with severe malaria. Acta Trop. 2004; 89(3): 319–327. PubMed Abstract | Publisher Full Text
29. Lucchi NW, Peterson DS, Moore JM: Immunologic activation of human syncytiotrophoblast by Plasmodium falciparum. Malar J. 2008; 7: 42. PubMed Abstract | Publisher Full Text | Free Full Text
30. Young A, Thomson AJ, Ledingham M, et al.: Immunolocalization of proinflammatory cytokines in myometrium, cervix, and fetal membranes during human parturition at term. Biol Reprod. 2002; 66(2): 445–449. PubMed Abstract | Publisher Full Text
31. Ietta F, Todros T, Ticconi C, et al.: Macrophage migration inhibitory factor in human pregnancy and labor. Am J Reprod Immunol. 2002; 48(6): 404–409. PubMed Abstract | Publisher Full Text
32. Todros T, Bontempo S, Piccoli E, et al.: Increased levels of macrophage migration inhibitory factor (MIF) in preeclampsia. Eur J Obstet Gynecol Reprod Biol. 2005; 123(2): 162–166. PubMed Abstract | Publisher Full Text
33. Jüttner S, Bernhagen J, Metz CN, et al.: Migration inhibitory factor induces killing of Leishmania major by macrophages: dependence on reactive nitrogen intermediates and endogenous TNF-alpha. J Immunol. 1998; 161(5): 2383–90. PubMed Abstract
34. Eltayeb R, Bilal NE, Abass A, et al.: Dataset 1. Raw dataset for Eltayeb et al., 2015 ‘Macrophage migration inhibitory factor and placental malaria infection in an area characterized by unstable malaria transmission in Central Sudan’. F1000Research. 2015. Data Source

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¹ Faculty of Medical Laboratory Sciences, University of Khartoum, Khartoum, 11115, Sudan
² Faculty of Medicine, University of Geziera, Medani, 11111, Sudan
³ Faculty of Medicine, Ribat University, Khartoum, 11111, Sudan
⁴ Faculty of Medicine, University of Khartoum, Khartoum, 11115, Sudan

Competing interests

The authors declare that they have no competing interests.

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The author(s) declared that no grants were involved in supporting this work.

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© 2015 Eltayeb R et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Data associated with the article are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication).

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Eltayeb R, Bilal N, Abass AE et al. Macrophage migration inhibitory factor and placental malaria infection in an area characterized by unstable malaria transmission in central Sudan [version 1; peer review: 2 approved]. F1000Research 2015, 4:824 (https://doi.org/10.12688/f1000research.7061.1)

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Reviewer Report 04 May 2016

Diana Boraschi, Institute of Protein Biochemistry, National Research Council, Naples, Italy

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https://doi.org/10.5256/f1000research.7601.r13184

I am in total favour of publishing reports of negative results, if the study is well conducted, as this one is. Malaria during pregnancy is an outstanding health issue that needs significant investigation. Biomarkers able to predict adverse outcomes are ... Continue reading

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Reviewer Report 22 Sep 2015

Bernhard Zelger, Department of Dermatology, Medical University Innsbruck, Innsbruck, Austria

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https://doi.org/10.5256/f1000research.7601.r10368

Proper study, well outlined and performed.

Some minor critique regarding thickness of paraffin slides which should read 4 micromillimeter or with Greek letter μm, not "4mm". "strom" should read correctly "stroma". Finally, acronyms of authors in section "Authors contributions" are not clear ... Continue reading

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Bernhard Zelger, Medical University Innsbruck, Innsbruck, Austria
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Reviewer Report

14 Views

04 May 2016 | for Version 1

Diana Boraschi, Institute of Protein Biochemistry, National Research Council, Naples, Italy

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Approved

I am in total favour of publishing reports of negative results, if the study is well conducted, as this one is. Malaria during pregnancy is an outstanding health issue that needs significant investigation. Biomarkers able to predict adverse outcomes are needed, and inflammation-related factors are a logical choice.

This study on the correlation between MIF (either in the maternal or in the cord blood), placental infection and pregnancy outcomes (maternal hemoglobin and birth weight) goes in this direction, and quite clearly shows that there is no correlation. The number of cases is possibly low, and no cases with blood malaria were found in the cohort. Although possibly preliminary, the study is nevertheless very clear and straight forward in its design, conduction and logical conclusions.

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No competing interests were disclosed.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

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Reviewer Report

17 Views

22 Sep 2015 | for Version 1

Bernhard Zelger, Department of Dermatology, Medical University Innsbruck, Innsbruck, Austria

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Approved

Proper study, well outlined and performed.

Some minor critique regarding thickness of paraffin slides which should read 4 micromillimeter or with Greek letter μm, not "4mm". "strom" should read correctly "stroma". Finally, acronyms of authors in section "Authors contributions" are not clear to me with regard to the list of authors on title page. Please, amend, respectively.

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No competing interests were disclosed.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

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[1] 1. WHO: World Malaria Report 2012. Geneva, Switzerland: World Health Organization; 2013. Reference Source

[2] 2. Menendez C, Ordi J, Ismail MR, et al.: The impact of placental malaria on gestational age and birth weight. J Infect Dis. 2000; 181(5): 1740–1745. PubMed Abstract | Publisher Full Text

[3] 3. Rogerson SJ, Pollina E, Getachew A, et al.: Placental monocyte infiltrates in response to Plasmodium falciparum malaria infection and their association with adverse pregnancy outcomes. Am J Trop Med Hyg. 2003; 68(1): 115–119. PubMed Abstract

[4] 4. Ahmed R, Singh N, ter Kuile FO, et al.: Placental infections with histologically confirmed Plasmodium falciparum are associated with adverse birth outcomes in India: a cross-sectional study. Malar J. 2014; 13: 232. PubMed Abstract | Publisher Full Text | Free Full Text

[5] 5. Ali AA, Elhassan EM, Magzoub MM, et al.: Hypoglycaemia and severe Plasmodium falciparum malaria among pregnant Sudanese women in an area characterized by unstable malaria transmission. Parasit Vectors. 2011; 4: 88. PubMed Abstract | Publisher Full Text | Free Full Text

[6] 6. Adam I, Khamis AH, Elbashir MI: Prevalence and risk factors for anaemia in pregnant women of eastern Sudan. Trans R Soc Trop Med Hyg. 2005; 99(10): 739–43. PubMed Abstract | Publisher Full Text

[7] 7. Mohammed AH, Salih MM, Elhassan EM, et al.: Submicroscopic Plasmodium falciparum malaria and low birth weight in an area of unstable malaria transmission in Central Sudan. Malar J. 2013; 12: 172. PubMed Abstract | Publisher Full Text | Free Full Text

[8] 8. Adam I, Elhassan EM, Haggaz AE, et al.: A perspective of the epidemiology of malaria and anaemia and their impact on maternal and perinatal outcomes in Sudan. J Infect Dev Ctries. 2011; 5(2): 83–7, Review. PubMed Abstract | Publisher Full Text

[9] 9. Miller LH, Baruch DI, Marsh K, et al.: The pathogenic basis of malaria. Nature. 2002; 415(6872): 673–9. PubMed Abstract | Publisher Full Text

[10] 10. Muthusamy A, Achur RN, Bhavanandan VP, et al.: Plasmodium falciparum-infected erythrocytes adhere both in the intervillous space and on the villous surface of human placenta by binding to the low-sulfated chondroitin sulfate proteoglycan receptor. Am J Pathol. 2004; 164(6): 2013–25. PubMed Abstract | Publisher Full Text | Free Full Text

[11] 11. Umbers AJ, Aitken EH, Rogerson SJ: Malaria in pregnancy: small babies, big problem. Trends Parasitol. 2011; 27(4): 168–75. PubMed Abstract | Publisher Full Text

[12] 12. Calandra T, Roger T: Macrophage migration inhibitory factor: a regulator of innate immunity. Nat Rev Immunol. 2003; 3(10): 791–800. PubMed Abstract | Publisher Full Text

[13] 13. Arcuri F, Ricci C, Ietta F, et al.: Macrophage migration inhibitory factor in the human endometrium: expression and localization during the menstrual cycle and early pregnancy. Biol Reprod. 2001; 64(4): 1200–5. PubMed Abstract | Publisher Full Text

[14] 14. Arcuri F, Cintorino M, Vatti R, et al.: Expression of macrophage migration inhibitory factor transcript and protein by first-trimester human trophoblasts. Biol Reprod. 1999; 60(6): 1299–303. PubMed Abstract | Publisher Full Text

[15] 15. Awandare GA, Ouma Y, Ouma C, et al.: Role of monocyte-acquired hemozoin in suppression of macrophage migration inhibitory factor in children with severe malarial anemia. Infect Immun. 2007; 75(1): 201–210. PubMed Abstract | Publisher Full Text | Free Full Text

[16] 16. Jain V, McClintock S, Nagpal AC, et al.: Macrophage migration inhibitory factor is associated with mortality in cerebral malaria patients in India. BMC Res Notes. 2009; 2: 36. PubMed Abstract | Publisher Full Text | Free Full Text

[17] 17. Singh PP, Lucchi NW, Blackstock A, et al.: Intervillous macrophage migration inhibitory factor is associated with adverse birth outcomes in a study population in Central India. PLoS One. 2012; 7(12): e51678. PubMed Abstract | Publisher Full Text | Free Full Text

[18] 18. Salih MM, Mohammed AH, Mohmmed AA, et al.: Monocytes and macrophages and placental malaria infections in an area of unstable malaria transmission in eastern Sudan. Diagn Pathol. 2011; 6: 83. PubMed Abstract | Publisher Full Text | Free Full Text

[19] 19. Batran SE, Salih MM, Elhassan EM, et al.: CD20, CD3, placental malaria infections and low birth weight in an area of unstable malaria transmission in Central Sudan. Diagn Pathol. 2013; 8: 189. PubMed Abstract | Publisher Full Text | Free Full Text

[20] 20. Bayoumi NK, Bakhet KH, Mohmmed AA, et al.: Cytokine profiles in peripheral, placental and cord blood in an area of unstable malaria transmission in eastern Sudan. J Trop Pediatr. 2009; 55(4): 233–7. PubMed Abstract | Publisher Full Text

[21] 21. Bayoumi NK, Elhassan EM, Elbashir MI, et al.: Cortisol, prolactin, cytokines and the susceptibility of pregnant Sudanese women to Plasmodium falciparum malaria. Ann Trop Med Parasitol. 2009; 103(2): 111–7. PubMed Abstract | Publisher Full Text

[22] 22. Alim A, E Bilal N, Abass AE, et al.: Complement activation, placental malaria infection, and birth weight in areas characterized by unstable malaria transmission in central Sudan. Diagn Pathol. 2015; 10(1): 49. PubMed Abstract | Publisher Full Text | Free Full Text

[23] 23. Chandrasiri UP, Randall LM, Saad AA, et al.: Low antibody levels to pregnancy-specific malaria antigens and heightened cytokine responses associated with severe malaria in pregnancy. J Infect Dis. 2014; 209(9): 1408–17. PubMed Abstract | Publisher Full Text

[24] 24. Malik EM, Atta HY, Weis M, et al.: Sudan Roll Back Malaria Consultative Mission: Essential Actions to Support the Attainment of the Abuja Targets. Sudan RBM Country Consultative Mission Final Report. Geneva: Roll Back Malaria Partnership; 2004. Reference Source

[25] 25. Bulmer JN, Rasheed FN, Francis N, et al.: Placental malaria. I. Pathological classification. Histopathology. 1993; 22(3): 211–218. PubMed Abstract | Publisher Full Text

[26] 26. Bulmer JN, Rasheed FN, Morrison L, et al.: Placental malaria. II. A semi-quantitative investigation of the pathological features. Histopathology. 1993; 22(3): 219–225. PubMed Abstract | Publisher Full Text

[27] 27. Chaisavaneeyakorn S, Moore JM, Othoro C, et al.: Immunity to placental malaria. IV. Placental malaria is associated with up-regulation of macrophage migration inhibitory factor in intervillous blood. J Infect Dis. 2002; 186(9): 1371–5. PubMed Abstract | Publisher Full Text

[28] 28. Chaiyaroj SC, Rutta AS, Muenthaisong K, et al.: Reduced levels of transforming growth factor-beta1, interleukin-12 and increased migration inhibitory factor are associated with severe malaria. Acta Trop. 2004; 89(3): 319–327. PubMed Abstract | Publisher Full Text

[29] 29. Lucchi NW, Peterson DS, Moore JM: Immunologic activation of human syncytiotrophoblast by Plasmodium falciparum. Malar J. 2008; 7: 42. PubMed Abstract | Publisher Full Text | Free Full Text

[30] 30. Young A, Thomson AJ, Ledingham M, et al.: Immunolocalization of proinflammatory cytokines in myometrium, cervix, and fetal membranes during human parturition at term. Biol Reprod. 2002; 66(2): 445–449. PubMed Abstract | Publisher Full Text

[31] 31. Ietta F, Todros T, Ticconi C, et al.: Macrophage migration inhibitory factor in human pregnancy and labor. Am J Reprod Immunol. 2002; 48(6): 404–409. PubMed Abstract | Publisher Full Text

[32] 32. Todros T, Bontempo S, Piccoli E, et al.: Increased levels of macrophage migration inhibitory factor (MIF) in preeclampsia. Eur J Obstet Gynecol Reprod Biol. 2005; 123(2): 162–166. PubMed Abstract | Publisher Full Text

[33] 33. Jüttner S, Bernhagen J, Metz CN, et al.: Migration inhibitory factor induces killing of Leishmania major by macrophages: dependence on reactive nitrogen intermediates and endogenous TNF-alpha. J Immunol. 1998; 161(5): 2383–90. PubMed Abstract

[34] 34. Eltayeb R, Bilal NE, Abass A, et al.: Dataset 1. Raw dataset for Eltayeb et al., 2015 ‘Macrophage migration inhibitory factor and placental malaria infection in an area characterized by unstable malaria transmission in Central Sudan’. F1000Research. 2015. Data Source

Macrophage migration inhibitory factor and placental malaria infection in an area characterized by unstable malaria transmission in central Sudan

Abstract

Keywords

Background

Material and methods

Giemsa-stained blood smears for light microscopy

ELISA for measuring MIF levels

Statistical analysis

Ethics

Results

Table 1. Basic characteristics of the pregnant women (n = 151) included in the study at Medani Hospital, Sudan.

Table 2. Factors associated with placental malaria among pregnant women at Medani Hospital, Sudan using univariate and multivariate analyses.

Figure 1. Maternal and umbilical cord macrophage migration inhibitory factor levels and placental malaria infection.

Table 3. Factors associated with maternal and cord MIF in pregnant women at Medani Hospital, Sudan using linear regression analyses.

Table 4. Factors associated with maternal hemoglobin and birth weight levels at Medani Hospital, Sudan using linear regression analyses.

Discussion

Conclusion

Data availability

Author contributions

Competing interests

Grant information

Acknowledgement

Supplementary materials

References

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