Preeclampsia is a serious pregnancy-induced disorder unique to humans affecting 4.6% of pregnancies worldwide. Advances in the detection, prevention and treatment of preeclampsia have been poor due to our inadequate understanding of its pathogenesis. Here, we perform a multiomics study on early pregnancy placental biopsies (chorionic villus samples) from pregnancies that developed preterm and term preeclampsia compared to normotensive controls. Using an integrative statistical approach we discovered preterm preeclampsia was highly associated with lipoprotein metabolism whereas term preeclampsia was associated with inflammatory pathways and notch signaling. Melanophilin was identified as significantly reduced in early pregnancy placenta from term preeclampsia. Loss of melanophilin was required for syncytialization but excess loss disrupts syncytiotrophoblast function driving the production of antiangiogenic factors known to drive preeclampsia. Our study challenges the dogma that term preeclampsia is not associated with early placental pregnancy dysfunction and provides critical insight into the early pregnancy dysfunction underlying preeclampsia, opening up new avenues for predictive biomarker and preventative treatment discovery.