The present study found that malaria infection altered the investigated cytokines (IL-4, IL-6, IL-10, IL-17A and INF-γ), with elevated levels of antibodies to recombinant antigens in Sudanese maternal, placental and neonatal plasma. The high levels of the pregnancy non-specific antibodies detected in primipara peripheral compared to parous can be explained by the high malaria transmission in the study area. The presence of non-specific, non-protective Ig may delay or interfere with the acquisition of memory B cells .
In the current study, the levels of IL-4 and IL-10 were elevated but the levels of IL-6 and IL-17 were reduced in the plasma of the maternal peripheral, placental and umbilical cord blood samples of the PM infected mothers in comparison to the non-infected group. Moreover, the maternal peripheral level of IL-17A and the placental and neonate IFN-γ levels were not significantly different due to the infection. Several previous studies have shown elevated levels of type 2 anti-inflammatory cytokines IL-10 and IL-4 in the malaria-infected group [12, 13, 15, 23, 25, 30, 31]. Conversely, the present results were different from the previous findings in an area with unusable malaria transmission in Sudan, where higher levels of IL-4 and IL-10 in the non-infected group was reported . The findings of the increased IL-6 levels in non-infected women is in agreement with the results of other studies [11, 16, 32, 33].
Interestingly, the level of cytokines in the maternal peripheral samples among the investigated groups was significantly correlated with the levels in the placental and umbilical cord samples. Nevertheless, plasma from the umbilical cord (except for the maternal peripheral IL-17A levels) contained significantly lower concentrations of the investigated cytokines in comparison to the peripheral and placental plasma in both study groups (PM infected and non-infected groups). Kabyemela et al. , in Tanzania, and Ibitokou , in Benin, reported similar levels of IFN-γ between the investigated groups. The results of the present study corroborate the findings of a previous study that reported higher levels of IFN-γ in infected placentas , and a study from Cameron that found an increase in maternal IFN-γ and IL-17-A levels in non-infected controls . The elevated detection levels of IFN-γ in the investigated samples may be due to the ability of the innate immune response to produce IFN-γ to clear the parasite, probably as the first line of defense against both peripheral and placental infection . It has been suggested that the differences in cytokine responses associated with malaria infection have a gravidity-based pattern .
Infiltration of immune cells in the placental intervillous spaces, due to the sequestration of P falciparum IEs, disrupting Th1 and Th2 cytokines balance in both placental and peripheral blood [22, 34]. Contradictory findings about impairment of cellular immune responses against malaria in pregnancy and PM have been described [12, 13, 15, 17, 21, 25, 35, 36]. However, the differences in the cytokine profiles between these studies may be attributed to variations in the cytokine measurement methods used and the malaria endemicity in different study areas, as well as differences in the diagnostic techniques and the study population.
In the present study, among the cytokines assessed, IL-4 and IL-10 were elevated and significantly correlated (P <0.001) in the plasma of the three types of blood samples that were investigated; no correlation was found between the maternal peripheral levels of IL-10 and IFN-γ (P=0.448). IL-17A was positively correlated with IL-6, but no correlation was found between the IFN-γ in the plasma of the three types of samples. IFN-γ and IL-17-A are both effector helper T cells, and IL-17A can facilitate regulation of inflammatory cytokine production by accelerating specific inflammation via the recruitment and activation of immune cells. IL-6 is both a target of IL-17 and a differentiation factor for Th17 cells that led to an increase in IL-17 . Agudelo et al.  observed a significant correlation between IL-4 and IL-10 in the placental samples, but not in the peripheral blood, and levels of maternal IL-10 and IFN-γ were positively correlated. Moreover,  reported high expression of IFN-γ, TNF and IL-10 in the placental tissues and peripheral blood samples, and placental IL-4 in the infected women in comparison to the non-infected group. Due to the high expression associated with PM infection, it has been suggested that the IL-10 level in peripheral blood to be used as biomarker of placental inflammation related to PM  or as an immunosuppressive factor .
The antibody levels were negatively correlated with the IL-6 and IFN-γ levels in the present study. Chandragiri et al.  also reported a negative correlation between the same cytokines and non-pregnancy-specific variant surface antigens (VSA) in women with severe malaria in areas characterized by unstable malaria transmission in Sudan.
The present study found that IL-6 and IFN-γ had significant effects on birth weight and the maternal haemoglobin level, accompanied by the negative correlation of IL-4 and IL-10 in the plasma of the three types of samples investigated. It has been documented that there is a disturbance of cytokine equilibrium in malaria during pregnancy, and PM may be involved in many pathological disorders; it may also have negative consequences, such as LBW and reduced maternal haemoglobin level [38-40].
While the levels of IL-17A in the placental and umbilical cord samples were significantly positively correlated with birth weight and maternal haemoglobin, no significant correlation was found with the IL-17A levels in the maternal peripheral samples. The roles of IFN-γ and IL-10 in the malaria-infected women with maternal anaemia and baby birth weight was controversially documented in a reviewed by Seitz et al. . Although Djontu et al.  reported no significant association between IL-6 level, maternal haemoglobin and baby birth weight, an elevated level of IL-6 was associated with anaemia in another study .
Similar to the current study’s findings, an association was reported between maternal haemoglobin and IL-17A levels and the peripheral plasma level of IFN-γ. It has been suggested that both cytokines provide protection against infection . Furthermore, elevated levels of IL-17 with high levels of IL-4, IL-12 and IFN-γ were associated with haemoglobin loss in malaria recovered semi-immune mice . Fitri et al.  reported that an imbalance between IL-17 and IL- 10 caused low fetal weight in Plasmodium berghei infection in mice.
Disturbance of proinflammatory cytokines and the inflammatory disorder of iron haemostasis led to the development of malarial anaemia . Elevated levels of circulating IL-6, which play a vital role in T cells differentiation and immune response polarization, have been strongly related to reduced haemoglobin concentration in reticulocytes.
There are limitations to this study to be addressed. The study did not investigate the antibodies related to the pregnancy-specific antigens, particularly VAR2CSA, to determine their correlation with the cytokine response associated with infection. The study was conducted in a setting of other common infections during pregnancy which could influence variations in antibodies and / or cytokine levels, not checking for the presence of other infections is another limitation.