Vertonghen had been hoping to start the game on home soil, but he is struggling with a muscle problem and will now have to wait until after the upcoming international break.
Midfielder Erik Lamela is also a doubt due to a thigh issue, but the Argentinean has an outside chance of featuring this weekend. Goalkeeper Hugo Lloris continues to sit on the sidelines, with the club captain undergoing surgery on his dislocated elbow earlier this week.
His absence means, Paulo Gazzaniga continues in goal for the fifth game in a row.
Spurs find themselves 11th in the Premier League table, and they need to improve their league form if they are to mount a top-four challenge. Pochettino’s men have failed to win any of their last four league matches with defeats to Brighton and Liverpool putting them under severe pressure.
The north London outfit last won a league game in September, while their tally for the season stands at just three. They were pegged back by Everton last time out, and Sheffield United will fancy their chances of leaving London with a result.
The Blades are up to sixth after a four-match unbeaten run in which they have conceded just one goal.
Their 3-0 win over Burnley last time out was a massive statement, while they also beat Arsenal towards the end of October.
Chris Wilder’s side boast the joint-best defensive record in the league this term, conceding just eight goals so far.
Defender John Egan will need to pass a late fitness test in order to play, but apart from that, Wilder has a fully-fit squad to choose from.
The pair last met in 2015 in the Carabao Cup, with Spurs progressing over two legs in the end. United’s last win at Spurs came in November 1991, when they won 1-0 in the old First Division.