The medical expenses can be five times as high for twins and up to 20 times as high for triplets and other multiple births, said the report in the American Journal of Obstetrics and Gynecology.
The tally included all medical expenses for the mothers from 27 weeks before birth until 30 days afterward, combined with the medical costs of infant care for the first year.
The total healthcare cost was around $21,000 per delivery with singletons, $105,000 with twins, and over $400,000 with triplets or more, said the study.
Researchers said their approach was the first to account for the comprehensive cost associated with multiple pregnancies by estimating all-cause medical expenses over the time period from early pregnancy to the children's first birthdays.
For women who had single births, the majority of the overall costs were for maternal care (60 percent).
For women with multiple births, the bulk of the expenses (70 percent for twins and 85 percent for multiples) went to caring for the infants, who were more likely to have health problems and to endure longer hospitalizations than the single children.
The higher costs also were attributable to more common use of cesarean section for delivery and maternal complications with multiple births.
The research was based on nearly 440,000 births among US women aged 19-45 from 2005 to 2010.
A total of 97 percent (424,880) of births were singletons, 2.85 percent (12,482) were twins and 0.13 percent (562) were triplets or more.
The study described multiple births as a major public health concern and called for strategies to reduce the risk in women undergoing in vitro fertilization by limiting the number of embryos implanted in the womb.