Long-term insulin independence following allogenic islet transplant and childbirth

Introduction: Pregnancy post allo-islet transplant (IT) is generally discouraged due to presumed risks to mother, fetus and graft. There are 4 published cases of childbirth in allo-IT recipients, all of which required insulin during pregnancy or within 2 years (y) post-partum (PP). Here we report the first known case of long-term, uninterrupted insulin independence post allo-IT and childbirth. Method: A 35 y/o Caucasian female with T1D since age 18y, complicated by hypoglycemia and diabetic eye disease (DED), received 3 ITs. Pre-IT, C-peptide was undetectable and daily insulin use was 41 units/d (0.62 units/kg/d) with A1c of 7.3%. Islets were infused intraportally (total islet dose: 849,265 IEQ; 12,751 IEQ/kg). Immunosuppression consisted of basiliximab/daclizumab, etanercept, tacrolimus (TAC) and sirolimus (SIRO), with intermittent MMF. Patient (pt) became insulin free. At Y5, A1c was 5.7% and stimulated c-peptide of 5.59 ng/ml. At age 41y (6y post-IT), pt conceived with ovarian stimulation. Pre-conception, SIRO was discontinued and TAC was increased. Azathioprine (AZA) was added during the 1st trimester. OGTT and immune studies were performed at 7, 15 and 25 wks of gestation and 24 wks PP. This report summarizes observations through 13.5y post-IT and 7y PP. Results: Throughout pregnancy, 1st morning BG was 99±14 mg/dl and A1c was maintained between 5.1-5.3% without insulin. Glyburide was started at 20 wks to achieve target fasting BG<105 mg/dl. At 15 and 25 wks, plasma glucose (PG) 2-hrs post 75g OGTT was 149 and 138 mg/dl, with peak C-peptide responses of 12.5 and 8.85 ng/ml; respectively. Blood pressure, renal function and DED were stable. At 36 wks, pt vaginally delivered a healthy 6.0lb baby girl without complication. The infant received 3 days of UV light therapy for hyperbilirubinemia, but was otherwise in good health. At 24 wks PP (7y post-IT), pt remained off insulin with A1c of 5.5% and normal OGTT response (2-hr PG=149 mg/dl; peak C-peptide=8.46 ng/ml). Glyburide was discontinued 6-mo PP due to hypoglycemia. In the years PP, pt has maintained uninterrupted insulin independence and A1c < 6.5%. Mildly elevated FBG were observed starting ~1y PP (113-133 mg/dl) and prompted resuming oral diabetes medication. Between Y9.5-10 post-IT, AZA was discontinued and low dose SIRO re-started. At Y13.5 post-IT, immunosuppression includes low dose SIRO (< 2.0 ng/ml) and TAC (3.7 ng/ml). Pt remains off insulin and on metformin and linagliptin with an A1c of 6.1% and no hypoglycemia. Pre-existing DED continues with slow, progressive loss of vision in the left eye. Per pt, the child, now almost 7y, is in good health. Conclusion: This is the 1st reported case of uninterrupted, long-term insulin independence for 13.5y post-IT and 7y PP with only oral DM medication support. While pregnancy in T1D and immunosuppression remains high risk, this suggests that successful childbirth post-IT can be safely achieved without significantly compromising graft function. NIH Grant U42R16607 (Southern California Islet Cell Resources Center). NIH Grant M01 RR-43 (General Clinical Research Center). Beckman Research Institute of the City of Hope. References: 1. Schive SW, Scholz H, Sahraoui A, Kloster-Jensen K, Hafsahl G, Korsgren O, Foss A, Jenssen TG. Graft function 1 year after pregnancy in an islet-transplanted patient. Transpl Int. 2015 Oct;28(10):1235-9. doi: 10.1111/tri.12596. Epub 2015 May 11. PMID: 25903157. 2. Assalino M, Podetta M, Demuylder-Mischler S, Francini K, Pernin N, Randin JP, Bosco D, Andres A, Berney T. Successful pregnancy and delivery after simultaneous islet-kidney transplantation. Am J Transplant. 2018 Aug;18(8):2075-2078. doi: 10.1111/ajt.14884. Epub 2018 May 10. PMID: 29673064. 3. Rickels MR, Markmann E, Naji A. Successful pregnancies after islet transplantation for type 1 diabetes. Am J Transplant. 2019 Jan;19(1):298-299. doi: 10.1111/ajt.14972. Epub 2018 Jul 13. PMID: 29920931; PMCID: PMC6364294. 4. Birrell K, Ali M, Shaw J, MacDougall M, Williams S, Napier C. Pregnancy following islet cell transplantation in a woman with type 1 diabetes and autoimmune Addison’s disease. Endocrine Abstracts (2022) 86 P221. doi: 10.1530/endoabs.86.P221