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3 year oldEmma Coronel Aispuro, 31, is accused of helping Guzmán run the Sinaloa drugs cartel and assisting in his prison escape in 2015, court records show.
She pleaded guilty to a range of charges including conspiracy to distribute illegal drugs.
Guzmán, 63, is currently serving a life sentence in Colorado for drug trafficking and money laundering.
Authorities say the Sinaloa cartel was the biggest supplier of drugs to the US.
Guzmán's trial in 2019 heard shocking revelations about his life, from drugging and raping girls as young as 13 to carrying out the cold-blooded murders of former cartel members and rivals.
Ms Coronel Aispuro, a former beauty queen, was arrested at Dulles International Airport in Washington DC in February and charged with conspiring to distribute 5kg or more of cocaine, 1kg or more of heroin, 500 grams or more of methamphetamine and 1,000kg or more of cannabis, as well as aiding and abetting.
Prosecutors are accusing her of helping Guzmán to traffic drugs between 2012 and 2014 by relaying messages, and then continuing to deliver messages while visiting him in a Mexican prison after his arrest in February 2014.
She is also accused of playing a key role in her husband's escape from prison in 2015.
Guzmán was sprung from Mexico's maximum-security Altiplano prison via an elaborate tunnel escape. His sons bought a property near the prison, and smuggled in a GPS watch, giving diggers his exact location. Guzmán escaped by riding a specially adapted small motorcycle through the tunnel.
Court documents said Ms Coronel Aispuro was allegedly involved in planning another prison escape for her husband before he was extradited to the US in January 2017.
Sources close to the case have told several news agencies, including AFP and the New York Times, that Ms Coronel Aispuro will plead guilty to at least some of the charges. She could face life in prison and be fined up to $10 million (£7.1 million).
Ms Coronel Aispuro is a dual US-Mexico citizen, a former beauty pageant winner, journalism student and the mother of twins with Guzmán. According to previous interviews given to US media, she first met him at a dance when she was 17 and he was 49.
She attended nearly every day of her husband's three-month trial in New York, during which she heard not only grim accounts of murder and rape, but also claims that he had spied on her and other mistresses.
She came under the media spotlight during that trial.
In one instance, she appeared to laugh during the tearful testimony of one of Guzmán's mistresses. On another day she and Guzmán wore similar velvet jackets, which many people interpreted as a show of solidarity.
She remained supportive of Guzmán throughout, saying at the end of the trial: "I don't know my husband as the person they are trying to show him as, but rather I admire him as the human being that I met, and the one that I married."
Guzmán came from a poor family in Sinaloa state, north-west Mexico. His organised crime business grew so big that he entered Forbes' 2009 list of the world's richest men at number 701, with an estimated worth of $1bn (£709m).
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