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
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 year 1. 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 parity 5. Malaria is associated with adverse pregnancy outcomes such as anemia 6 and LBW 7, and it is the main cause of maternal mortality 8.
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 LBW 11.
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 diseases 12. 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 malaria 17. 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 parasite 24.
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 3cm 3 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 pigment 25. 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 follows 26: 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).
Figure 1. Maternal and umbilical cord macrophage migration inhibitory factor levels and placental malaria infection.
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
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.
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/.
Copyright: © 2015 Eltayeb R et al.
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).
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 negative 17. 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 infection 17. 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 infection 17. 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 plasma 28. Increased secretion of MIF by syncytiotrophoblasts was observed previously using an in vitro system 29. Generally MIF has been shown to play important roles during normal pregnancy 30, as well as in preterm delivery 31 and preeclampsia 32 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 parasites 25. 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 major 33.
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 weight 7.
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
The data referenced by this article are under copyright with the following copyright statement: Copyright: © 2015 Eltayeb R et al.
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). http://creativecommons.org/publicdomain/zero/1.0/
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.d102039 34
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.
Funding Statement
The author(s) declared that no funding was involved in supporting this work.
[version 1; referees: 2 approved]
Supplementary materials
Data collection questionnaire.
Questionnaire was applied by a medical professional to participants in the study. ANC: antenatal care; HB: haemoglobin; WT: weight
.
References
- 1. WHO: World Malaria Report 2012. Geneva, Switzerland: World Health Organization;2013. Reference Source [Google Scholar]
- 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. 10.1086/315449 [DOI] [PubMed] [Google Scholar]
- 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] [Google Scholar]
- 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. 10.1186/1475-2875-13-232 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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. 10.1186/1756-3305-4-88 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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. 10.1016/j.trstmh.2005.02.008 [DOI] [PubMed] [Google Scholar]
- 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. 10.1186/1475-2875-12-172 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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. 10.3855/jidc.1282 [DOI] [PubMed] [Google Scholar]
- 9. Miller LH, Baruch DI, Marsh K, et al. : The pathogenic basis of malaria. Nature. 2002;415(6872):673–9. 10.1038/415673a [DOI] [PubMed] [Google Scholar]
- 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. 10.1016/S0002-9440(10)63761-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Umbers AJ, Aitken EH, Rogerson SJ: Malaria in pregnancy: small babies, big problem. Trends Parasitol. 2011;27(4):168–75. 10.1016/j.pt.2011.01.007 [DOI] [PubMed] [Google Scholar]
- 12. Calandra T, Roger T: Macrophage migration inhibitory factor: a regulator of innate immunity. Nat Rev Immunol. 2003;3(10):791–800. 10.1038/nri1200 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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. 10.1095/biolreprod64.4.1200 [DOI] [PubMed] [Google Scholar]
- 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. 10.1095/biolreprod60.6.1299 [DOI] [PubMed] [Google Scholar]
- 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. 10.1128/IAI.01327-06 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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. 10.1186/1756-0500-2-36 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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. 10.1371/journal.pone.0051678 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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. 10.1186/1746-1596-6-83 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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. 10.1186/1746-1596-8-189 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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. 10.1093/tropej/fmn062 [DOI] [PubMed] [Google Scholar]
- 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. 10.1179/136485909X385045 [DOI] [PubMed] [Google Scholar]
- 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. 10.1186/s13000-015-0275-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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. 10.1093/infdis/jit646 [DOI] [PubMed] [Google Scholar]
- 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 [Google Scholar]
- 25. Bulmer JN, Rasheed FN, Francis N, et al. : Placental malaria. I. Pathological classification. Histopathology. 1993;22(3):211–218. 10.1111/j.1365-2559.1993.tb00110.x [DOI] [PubMed] [Google Scholar]
- 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. 10.1111/j.1365-2559.1993.tb00111.x [DOI] [PubMed] [Google Scholar]
- 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. 10.1086/344322 [DOI] [PubMed] [Google Scholar]
- 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. 10.1016/j.actatropica.2003.10.010 [DOI] [PubMed] [Google Scholar]
- 29. Lucchi NW, Peterson DS, Moore JM: Immunologic activation of human syncytiotrophoblast by Plasmodium falciparum. Malar J. 2008;7:42. 10.1186/1475-2875-7-42 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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. 10.1095/biolreprod66.2.445 [DOI] [PubMed] [Google Scholar]
- 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. 10.1034/j.1600-0897.2002.01152.x [DOI] [PubMed] [Google Scholar]
- 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. 10.1016/j.ejogrb.2005.03.014 [DOI] [PubMed] [Google Scholar]
- 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] [Google Scholar]
- 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 [DOI] [PMC free article] [PubMed]