A previous study by Chaisavaneeyakorn et al
. reported significantly elevated MIF levels in the IVB plasma of Kenyan pregnant women compared to both peripheral and cord plasma 
. Similar results were obtained by Chaiyaroj et al
., who observed significantly higher MIF production by intervillous blood mononuclear cells (IVBMC) compared to peripheral blood mononuclear cells (PBMC), as well as high MIF level in placental plasma compared to paired peripheral plasma 
. Our finding confirms this observation in an Indian population as MIF was shown to be present at very high levels in the IVB plasma as compared with peripheral and cord plasma. This finding is not surprising given that MIF has been shown to play important roles during normal pregnancy 
and therefore, IVB MIF would be expected to be high.
We observed significantly higher IVB MIF levels in women with PM compared to PM− women. Similar findings were reported by Chaisavaneeyakorn et al
. who suggested that MIF may play a role in the pathogenesis of malaria 
. MIF is a pluripotent immune factor known to regulate both innate and adaptive immune responses to bacterial and parasitic infections. Several studies have demonstrated elevated levels of MIF in the peripheral or placental blood during malaria infections 
. MIF was shown to be induced in response to P. chabaudi
infection in mice and was implicated in the pathogenesis of malaria anemia 
. Awandare et al.
suggested that reduced MIF production may promote enhanced disease severity in children with P. falciparum
, implying that MIF may be required to clear a malaria infection. One of the roles of MIF is to inhibit the random migration of macrophages which has been demonstrated in vitro 
. We hypothesize that the increased MIF levels found in the placenta of malaria positive women is induced by the malaria parasites which tend to accumulate in the placenta 
and that this may help to retain macrophages in the placenta. MIF, together with other proinflammatory factors such as IFN-γ and TNF-α, may then activate these macrophages to clear and kill malaria parasites in the placenta.
It is generally accepted that about 50% or more of stillbirths in low and middle income countries are caused by maternal intrauterine infections (reviewed in 
). It has also been suggested that excessive proinflammatory immune responses may lead to adverse placental pathophysiology. These proinflammatory immune responses have been associated with the ensuing monocytic infiltration 
observed in malaria infected placentas and which has been associated with poor fetal outcomes such as LBW 
. In this study, higher levels of IVB MIF were associated with stillbirth deliveries and LBW babies irrespective of malaria infection status. To our knowledge, this is one of the first reports to demonstrate an association between elevated placental MIF levels and poor birth outcomes. Previous studies have shown that maternal peripheral serum MIF is associated with preterm delivery 
and preeclampsia 
. Two different explanations can be considered for the current findings. One possibility is that elevated levels of MIF may directly regulate some biological events related to stillbirth and LBW. For example, high levels of MIF (along with other factors such as TNF) can activate the inducible cyclooxygenase (COX)-2 pathway, leading to higher prostaglandin production and potentially other pathways that contribute to stillbirth and LBW. MIF was shown to directly stimulate the synthesis of COX-2 and the release of prostaglandin E2
in ectopic endometrial cells 
. Increased levels of prostaglandin E2
and prostaglandin F2α
induced by alcohol were shown to cause fetal death 
. Therefore, MIF may have a direct role in activating biological pathways that contribute to stillbirths and LBW. The second possibility is that elevated levels of MIF may be simply a marker for proinflammatory events occurring in the IVB and therefore, simply serve as a predictor of the events leading to the poor outcomes. A proinflammatory milieu is commonly observed in malaria infected placentas and this has been associated with poor fetal outcomes such as LBW 
. It is not surprising that this association was evident irrespective of placental malaria infection status because the elevated levels of MIF can occur due to many infectious agents and once MIF is activated beyond a particular threshold it is likely to trigger biological pathways that contribute to poor birth outcomes.
LBW is a hallmark of malaria during pregnancy with several studies demonstrating an increase in LBW babies delivered by PM+ women compared to PM- women. 
. A caveat of this study is the fact that we could not test for any differences in birth weight in these two groups since the percentage of low birth weight of infants born to PM− women was matched to that of PM+ women in the selection process. Therefore, the apparent lack of differences in birth weight in this study (mean birth weight <2500 g) is due to an enrolment artefact and might not have any generalizable bearing to this population.
In conclusion, this study demonstrates that intervillous MIF is significantly elevated in the presence of placental malaria. In addition, elevated intervillous MIF levels are associated with both stillbirth and low birth weight deliveries.