To determine whether pregnancy provides an improved milieu for fetal/neonatal pancreas/islet transplantation, we studied neonatal pancreatic implants into non-obese diabetic (NOD) female mice during early gestation. We monitored maternal glycemic status, birthweight of the offspring, and graft histology to assess the efficacy of transplantation. One hundred and thirteen twelve-week-old NOD female mice were randomized into four groups as follows: (1) non-pregnant NOD mice received a sham operation; (2) non-pregnant NOD mice received neonatal pancreatic transplants; (3) pregnant NOD mice received a sham operation; and (4) pregnant NOD mice received neonatal pancreatic transplants. Pancreas segments from 3 neonatal NOD mice were placed via an incision 1 to 2 mm distal to the ear-skull junction of each of the recipients. Maternal blood glucose and glycated hemoglobin were determined between days 18 and 20 after the surgery. Pups were weighed within 5 to 6 hours after delivery. Pregnant NOD that received transplants (n = 29) had lower glucose and glycated hemoglobin (GHb) than sham operated pregnant controls (n = 26) (4.9 +/- 0.05 versus 9.0 +/- 5.0 mmol/L, p < 0.001 for glucose and 2.0 > or = 0.2 versus 3.0 > or = 1.2%, p < 0.008 for GHb) at 18 to 20 days of gestation. Controlling for litter size showed a decrease in birthweight for offspring of transplant recipients versus offspring of pregnant controls (1.59 +/- 0.08 versus 1.65 +/- 0.08 g, p < 0.002). Histological scoring of transplanted tissue at day 21 indicated that the lymphocytic infiltration in the pregnant group was significantly less than the control group (2.9 +/- 1.2 versus 4.9 +/- 0.2, p < 0.0001). We conclude that the pregnant NOD mouse provides a useful transplant model, that pregnancy provides an opportunity to increase beta-cell mass with transplanted tissue, and that pancreatic transplantation decrease birthweight and macrosomia in the offspring of NOD mice.