Wimbledon champion Angelique Kerber became the latest big seed to tumble at the US Open after Slovakia's Dominika Cibulkova fought back to win their third round encounter 3-6, 6-3, 6-3 on Saturday.
Fourth seed Kerber, the 2016 US Open champion, followed the early exits of world No 1 Simona Halep and No 2 Caroline Wozniacki - the other two grand slam champions this season.
Fifth seed Petra Kvitova was also ousted, the two-time Wimbledon champion falling 7-5, 6-1 to rising Belarusian star Aryna Sabalenka.
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In all just three of the top 10 women made it through to the fourth round, although Kerber didn't blame a domino effect for her departure.
"I'm not looking around who was winning or who was losing," she said. "You have sometimes days where you are trying everything, but it's not really working as you wish."
Cibulkova, the 29th seed, moves on to face 2017 finalist Madison Keys, who shook off a slow start to beat Serbian Aleksandra Krunic 4-6, 6-1, 6-2.
Sabalenka will play Japan's Naomi Osaka, who crushed Aliaksandra Sasnovich 6-0, 6-0.
Sixth-seeded Caroline Garcia of France also departed, beaten 5-7, 6-4, 7-6 by Spain's Carla Suarez Navarro, and Czech teenager Marketa Vondrousova sprang a surprise, too, with a 7-6, 2-6, 7-6 victory over 13th-seeded Belgian Kiki Bertens.
Suarez Navarro, seeded 30th, next faces 2006 champion Maria Sharapova, who defeated 2017 French Open winner Jelena Ostapenko 6-3, 6-2.
Vondrousova, through to a Grand Slam third round for the first time, will play Ukraine's Lesia Tsurenko, who defeated Czech Katerina Siniakova 6-4, 6-0 after taking out Wozniacki in the second round.