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"Priscilla and I are happy to share we're expecting another baby girl!" Zuckerberg, 32, wrote in a post that included photos of the couple when they were children.
They are already parents to their 15-month-old daughter Maxima, whom they call Max.
Zuckerberg also wrote about the difficulties that Chan, a pediatrician, had getting pregnant.
"After our difficult experience having Max, we weren't sure what to expect or whether we'd be able to have another child," he wrote. "When Priscilla and I first found out she was pregnant again, our first hope was that the child would be healthy. My next hope was that it would be a girl. I cannot think of a greater gift than having a sister and I'm so happy Max and our new child will have each other."
Zuckerberg concluded his post writing, "We are all better people because of the strong women in our lives -- sisters, mothers and friends. We can't wait to welcome our new little one and do our best to raise another strong woman."