A woman and a man were interviewed by police officers in charge of the murder after six children were transported to the hospital – where two of them died.
Neighbors said the adults were handcuffed while a fleet of ambulances and a helicopter were carrying the children to the victim.
Paramedics and the police went to a house at 7:30 am, fearing that some children had been poisoned.
Two boys aged 14 and 13 died after frantic attempts to resuscitate them.
Two girls aged seven months and three and two younger boys – ten and eleven – were doing well at Sheffield Children's Hospital.
Police confirmed that a 34-year-old woman and a 37-year-old man had been arrested for murder.
Forensic officers were examining a semi-bed with three beds in the Shiregreen area of the city.
Police refused to confirm reports that the victims were poisoned. Autopsies were to take place.
Neighbor Aaron Brunskill, 29, said there had been "about 20 police cars and four ambulances".
He added, "Then the air ambulance arrived. They just took kids.
Another neighbor said, "We often talk about their poisoning. It's too tragic to think about it.
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Teenagers told their boyfriend, "We do not go to school" a few minutes before the death
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Superintendent Paul McCurry stated that the force provided support to the children's relatives, as well as officers who responded to the 999 call.
Local MP Gill Furniss said the community was "deeply shaken".
She added, "My sincerest sympathies go to the dear ones of the children."