The 2008 American League MVP had been voted in as the starter at second base in fan voting. His wife is due in August with the couple's first child.
"After consulting with [Red Sox manager Terry Francona], Theo [Epstein], Phyllis Merhige of Major League Baseball and my wife, Kelli, I have decided to withdraw from this year's All-Star Game in St. Louis. I will instead stay in Boston with my wife as we tend to a serious family health matter," Pedroia said in a statement released by Major League Baseball.
The last club to put four infielders in the All-Star Game was the 2002 New York Yankees, with first baseman Jason Giambi, second baseman Alfonso Soriano, shortstop Derek Jeter and third baseman Robin Ventura.
"I'm extremely humbled by this opportunity," Pena said. "What I like is the fact that I was chosen by my own manager. That's what means the most to me. I want to experience the whole thing. I'm thrilled."
Maddon chose Pena over Rangers second baseman Ian Kinsler, left off the All-Star team despite excellent statistics.
Pena was leading the league with 24 homers. He will take part in the Home Run Derby on Monday night, rounding out an AL field that also includes Minnesota's Joe Mauer, Detroit's Brandon Inge and Texas' Nelson Cruz.
"I would have to believe that anyone leading the league in hitting home runs normally belongs in the All-Star Game," Maddon said. "The fact he hadn't been on the team yet was bothering me just a little bit."
Swinging for the Busch Stadium fences from the National League will be four powerful first basemen: St. Louis' Albert Pujols, Philadelphia's Ryan Howard, Milwaukee's Prince Fielder and San Diego's Adrian Gonzalez.
Maddon said Toronto's Aaron Hill will start at second base in place of Pedroia.
Information from The Associated Press was used in this report.