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Despite the worldwide success of vaccination, newborns remain vulnerable to infections. While neonatal vaccination has been hampered by maternal antibody-mediated dampening of immune responses, enhanced regulatory and tolerogenic mechanisms, and immune system immaturity, maternal pre-natal immunization aims to boost neonatal immunity via antibody transfer to the fetus. However, emerging data suggest that antibodies are not transferred equally across the placenta. To understand this, we used systems serology to define Fc features associated with antibody transfer. The Fc-profile of neonatal and maternal antibodies differed, skewed toward natural killer (NK) cell-activating antibodies. This selective transfer was linked to digalactosylated Fc-glycans that selectively bind FcRn and FCGR3A, resulting in transfer of antibodies able to efficiently leverage innate immune cells present at birth. Given emerging data that vaccination may direct antibody glycosylation, our study provides insights for the development of next-generation maternal vaccines designed to elicit antibodies that will most effectively aid neonates. • NK cell-activating antibodies are selectively transferred across the placenta • Digalactosylated Fc glycans are preferentially transferred across the placenta • Digalactosylated antibodies bind more effectively to FcRn and FCGR3A • Although immature, neonatal NK cells are highly responsive to immune complexes Antibodies with a specific glycan modification and with the ability to activate NK cells are selectively transferred across the placenta to the neonate. [ABSTRACT FROM AUTHOR]