Immune response, phenotyping and molecular graft surveillance in kidney transplant recipients following severe acute respiratory syndrome coronavirus 2 vaccination.

BACKGROUND: Understanding immunogenicity and alloimmune risk following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in kidney transplant recipients is imperative to understanding the correlates of protection and to inform clinical guidelines. METHODS: We studied 50 kidney transplant recipients following SARS-CoV-2 vaccination and quantified their anti-spike protein antibody, donor-derived cell-free DNA (dd-cfDNA), gene expression profiling (GEP), and alloantibody formation. RESULTS: Participants were stratified using nucleocapsid testing as either SARS-CoV-2-naïve or experienced prior to vaccination. One of 34 (3%) SARS-CoV-2 naïve participants developed anti-spike protein antibodies. In contrast, the odds ratio for the association of a prior history of SARS-CoV-2 infection with vaccine response was 18.3 (95% confidence interval 3.2, 105.0, p < 0.01). Pre- and post-vaccination levels did not change for median dd-cfDNA (0.23% vs. 0.21% respectively, p = 0.13), GEP scores (9.85 vs. 10.4 respectively, p = 0.45), calculated panel reactive antibody, de-novo donor specific antibody status, or estimated glomerular filtration rate. CONCLUSIONS: SARS-CoV-2 vaccines do not appear to trigger alloimmunity in kidney transplant recipients. The degree of vaccine immunogenicity was associated most strongly with a prior history of SARS-CoV-2 infection.

Metabolomic insights into maternal and neonatal complications in pregnancies affected by type 1 diabetes.

AIMS/HYPOTHESIS: Type 1 diabetes in pregnancy is associated with suboptimal pregnancy outcomes, attributed to maternal hyperglycaemia and offspring hyperinsulinism (quantifiable by cord blood C-peptide). We assessed metabolomic patterns associated with risk factors (maternal hyperglycaemia, diet, BMI, weight gain) and perinatal complications (pre-eclampsia, large for gestational age [LGA], neonatal hypoglycaemia, hyperinsulinism) in the Continuous Glucose Monitoring in Women with Type 1 Diabetes in Pregnancy Trial (CONCEPTT). METHODS: A total of 174 CONCEPTT participants gave ≥1 non-fasting serum sample for the biorepository at 12 gestational weeks (147 women), 24 weeks (167 women) and 34 weeks (160 women) with cord blood from 93 infants. Results from untargeted metabolite analysis (ultrahigh performance LC-MS) are presented as adjusted logistic/linear regression of maternal and cord blood metabolites, risk factors and perinatal complications using a modified Bonferroni limit of significance for dependent variables. RESULTS: Maternal continuous glucose monitoring time-above-range (but not BMI or excessive gestational weight gain) was associated with increased triacylglycerols in maternal blood and increased carnitines in cord blood. LGA, adiposity, neonatal hypoglycaemia and offspring hyperinsulinism showed distinct metabolite profiles. LGA was associated with increased carnitines, steroid hormones and lipid metabolites, predominantly in the third trimester. However, neonatal hypoglycaemia and offspring hyperinsulinism were both associated with metabolite changes from the first trimester, featuring triacylglycerols or dietary phenols. Pre-eclampsia was associated with increased abundance of phosphatidylethanolamines, a membrane phospholipid, at 24 weeks. CONCLUSIONS/INTERPRETATION: Altered lipid metabolism is a key pathophysiological feature of type 1 diabetes pregnancy. New strategies for optimising maternal diet and insulin dosing from the first trimester are needed to improve pregnancy outcomes in type 1 diabetes.

Staged Endovascular and Surgical Management of a Mycotic Pseudoaneurysm After Pancreas Transplant.

Mycotic pseudoaneurysms are a rare, life-threatening complication after pancreas transplant. There have been limited reports of endovascular treatment of mycotic pseudoaneurysms in pancreas transplant recipients. Herein, we report on a case of a mycotic pseudoaneurysm from Pseudomonas aeruginosa after pancreas transplant. A 53-year-old male recipient underwent an uneventful simultaneous pancreas and kidney transplant. He was readmitted 48 days posttransplant with fevers and rigors. Pan-cultures were performed and broad-spectrum antibiotics were initiated. Imaging studies demonstrated a large mycotic pseudoaneurysm arising from the right common iliac artery adjacent to the arterial Y-graft anastomosis of the transplant pancreas. Endovascular stent placement was used to exclude the pseudoaneurysm prior to transplant pancreatectomy. During pancreatectomy, the lateral wall of the common iliac artery was found to be necrotic with significant exposure of the endovascular stent. After ligation and excision of the common iliac artery, a femorofemoral bypass was performed to revascularize the lower extremity. This case report highlights the advantage of a staged endovascular and surgical management strategy for complex mycotic pseudoaneurysms after pancreas transplant.

Stakeholders' perspectives on transplant metrics: the 2022 Scientific Registry of Transplant Recipients' consensus conference.

In July 2022, the Scientific Registry of Transplant Recipients (SRTR) hosted an innovative, multistakeholder consensus conference to identify information and metrics desired by stakeholders in the transplantation system, including patients, living donors, caregivers, deceased donor family members, transplant professionals, organ procurement organization professionals, payers, and regulators. Crucially, patients, caregivers, living donors, and deceased donor family members were included in all aspects of this conference, including serving on the planning committee, participating in preconference focus groups and learning sessions, speaking at the conference, moderating conference sessions and breakout groups, and shaping the conclusions. Patients constituted 24% of the meeting participants. In this report, we document the proceedings and enumerate 160 recommendations, 10 of which have been highly prioritized. SRTR will use the recommendations to develop new presentations of information and metrics requested by stakeholders to support informed decision-making.

Results of Two Cases of Pig-to-Human Kidney Xenotransplantation.

BACKGROUND: Xenografts from genetically modified pigs have become one of the most promising solutions to the dearth of human organs available for transplantation. The challenge in this model has been hyperacute rejection. To avoid this, pigs have been bred with a knockout of the alpha-1,3-galactosyltransferase gene and with subcapsular autologous thymic tissue. METHODS: We transplanted kidneys from these genetically modified pigs into two brain-dead human recipients whose circulatory and respiratory activity was maintained on ventilators for the duration of the study. We performed serial biopsies and monitored the urine output and kinetic estimated glomerular filtration rate (eGFR) to assess renal function and xenograft rejection. RESULTS: The xenograft in both recipients began to make urine within moments after reperfusion. Over the 54-hour study, the kinetic eGFR increased from 23 ml per minute per 1.73 m2 of body-surface area before transplantation to 62 ml per minute per 1.73 m2 after transplantation in Recipient 1 and from 55 to 109 ml per minute per 1.73 m2 in Recipient 2. In both recipients, the creatinine level, which had been at a steady state, decreased after implantation of the xenograft, from 1.97 to 0.82 mg per deciliter in Recipient 1 and from 1.10 to 0.57 mg per deciliter in Recipient 2. The transplanted kidneys remained pink and well-perfused, continuing to make urine throughout the study. Biopsies that were performed at 6, 24, 48, and 54 hours revealed no signs of hyperacute or antibody-mediated rejection. Hourly urine output with the xenograft was more than double the output with the native kidneys. CONCLUSIONS: Genetically modified kidney xenografts from pigs remained viable and functioning in brain-dead human recipients for 54 hours, without signs of hyperacute rejection. (Funded by Lung Biotechnology.).

Safety and Efficacy of Drug Eluting Stents for Treatment of Transplant Renal Artery Stenosis.

BACKGROUND: Transplant renal artery stenosis (TRAS) after renal transplantation is a common cause of graft dysfunction and failure. Endovascular intervention in the form of percutaneous transluminal angioplasty (PTA) and stenting has rapidly become the dominant treatment modality for the TRAS. There is a paucity of clinical data on the use of drug-eluting stent (DES) for TRAS. We investigated the outcomes of patients with clinically significant TRAS undergoing DES placement. METHODS: A retrospective review of patients with clinically significant TRAS undergoing PTA with DES placement from June 2014 to April 2021 was conducted. Patients treated for TRAS exhibited uncontrolled hypertension and/or unexplained allograft dysfunction. Patient demographics, procedural details, and follow-up outcomes were collected. Primary endpoints were the in-stent primary patency and graft survival. Secondary endpoints were freedom from reintervention, primary-assisted patency, and access-related complications. RESULTS: Thirteen TRAS in 12 patients with graft function alteration were treated with DES. The median age was 57 years (interquartile range (IQR), 48-63 years), and 9 (70%) patients were male. The median follow-up was 9 months (IQR, 4-52 months). The most common comorbidity was hypertension (100%), coronary artery disease (83%), and diabetes. The median time from deceased donor transplant to intervention was 5.8 months (IQR, 3.5-6.7 months). TRAS was most commonly found at the juxta-ostial segment (77%). The procedure was performed with carbon dioxide angiography with minimal amount of iodinated contrast (median, 3 mL) under local anesthesia in 9 (69%), and general anesthesia in 4 (31%) patients. The median stent diameter was 4.5 mm (IQR, 4-5 mm), and the median stent length was 15 mm (IQR, 15-18 mm). No intraoperative complications occurred. The rates of stenosis-free primary patency of the DES and graft survival were 76% and 100%, respectively. All 3 reinterventions for restenosis resulted from the kinking of the transplant renal artery proximal to the DES, which were treated by extending the stent more proximally 1-2 mm into the external iliac artery. There were no access-related complications. The median time to reintervention was 0.9 months (range, 0.23-2 months). Freedom from reintervention and primary-assisted patency were 76% and 100%, respectively. CONCLUSIONS: Our study demonstrates that DES is a safe and effective treatment modality in patients with TRAS at short to mid-term follow-up. As all reinterventions after DES were performed due to kinking of the transplant renal artery proximal to the stent, bridging of the DES 1-2 mm into the external iliac artery is recommended.

Intraoperative Verapamil Fails to Reduce Delayed Graft Function in Donation After Circulatory Death Renal Allografts.

BACKGROUND: The shortage of transplantable organs has led to increased utilization of kidneys that may be particularly vulnerable to ischemia-reperfusion injury (IRI) and delayed graft function (DGF). Kidneys from donation after circulatory death (DCD) donors have additional IRI from donor procurement that results in increased risk of DGF. Verapamil may reduce IRI in kidney allografts when given at the time of organ reperfusion. This study sought to determine if intraoperative administration of verapamil (Ver) could reduce the risk of DGF in DCD kidney transplants. METHODS: A single-center retrospective matched cohort study was performed of 93 Ver (-) kidney transplant recipients compared with 93 Ver (+) kidney transplant recipients, matched by donor age, Kidney Donor Profile Index, and DCD status. Covariates that could impact DGF risk were evaluated by univariate and multivariate logistic regression analyses. RESULTS: The Ver (-) and Ver (+) matched cohorts did not have any significant differences in the demographic covariates. There was no difference in DGF rate between the Ver cohorts in either the overall study population or within the DCD subgroup. There was a trend toward reduced DGF in the Ver (+) cohort for cold ischemia time (CIT) ≤24 h, but this failed to achieve statistical significance. On multivariate analysis, only CIT was found to be independently associated with DGF. CONCLUSIONS: Intraoperative verapamil failed to reduce DGF risk in DCD kidney allografts. Limitations to this study include nonrandomization for the intraoperative administration of verapamil and the mean CIT >24 h in the study population. Only CIT was an independent prognosticator for DGF on multivariate analysis in a cohort matched for DCD status, consistent with prior studies.

Caregiver exposure to hepatitis C virus following transplantation with hepatitis C viremic donor organs: A case series.

Direct-acting antiviral (DAA) therapeutics have ushered in an era in which transplanting organs from donors infected with hepatitis C virus (HCV+) into recipients without (HCV-) is an increasingly common practice. Rare but potentially life-threatening events have been reported in recipients of HCV+ organs. Since 2018 at our institution, 182 HCV- patients have received HCV+ donor organs. Here, we retrospectively reviewed cases in which recipients' family member caregivers reported sustaining needlestick exposures at home following discharge of the transplant recipient from the hospital. Caregiver needlestick exposures were passively reported in three cases of HCV+ into HCV- transplants (1.64% of such cases at our center). In all instances, the exposed individuals were aiding in diabetic management and the exposure occurred via lancets or insulin needles. In one case, the recipient viral load was undetectable at the time of the exposure but in the other two, recipients were viremic, putting their family members at risk to contract HCV infection. Surveillance for the exposed individuals was undertaken and no transmissions occurred. For centers performing HCV+ into HCV- transplants, it is important that informed consent includes discussion of potential secondary risks to family members and caregivers. Further, protocols for postexposure surveillance and for the acquisition of DAA treatment in the event of a secondary transmission should be in place.

Clinical and Financial Implications of 2 Treatment Strategies for Donor-derived Hepatitis C Infections.

Transplanting hepatitis C viremic donor organs into hepatitis C virus (HCV)-negative recipients is becoming increasingly common; however, practices for posttransplant direct-acting antiviral (DAA) treatment vary widely. Protracted insurance authorization processes for DAA therapy often lead to treatment delays. METHODS: At our institution, 2 strategies for providing DAA therapy to HCV- recipients of HCV+ transplants have been used. For thoracic organ recipients, an institution-subsidized course of initial therapy was provided to ensure an early treatment initiation date. For abdominal organ recipients, insurance approval for DAA coverage was sought once viremia developed, and treatment was initiated only once the insurance-authorized supply of drug was received. To evaluate the clinical impact of these 2 strategies, we retrospectively collected data pertaining to the timing of DAA initiation, duration of recipient viremia, and monetary costs incurred by patients and the institution for patients managed under these 2 DAA coverage strategies. RESULTS: One hundred fifty-two transplants were performed using HCV viremic donor organs. Eighty-nine patients received DAA treatment without subsidy, and 62 received DAA treatment with subsidy. One patient who never developed viremia posttransplant received no treatment. Subsidizing the initial course enabled earlier treatment initiation (median, 4 d [interquartile range (IQR), 2-7] vs 10 [IQR, 8-13]; P < 0.001) and shorter duration of viremia (median, 16 d [IQR, 12-29] vs 36 [IQR, 30-47]; P < 0.001). Institutional costs averaged $9173 per subsidized patient and $168 per nonsubsidized patient. Three needlestick exposures occurred in caregivers of viremic patients. CONCLUSIONS: Recipients and their caregivers stand to benefit from earlier DAA treatment initiation; however, institutional costs to subsidize DAA therapy before insurance authorization are substantial. Insurance authorization processes for DAAs should be revised to accommodate this unique patient group.

Impact of the 2014 kidney allocation system changes on trends in A2/A2B into B kidney transplantation and organ procurement organization reporting of donor subtyping.

The current kidney allocation system (KAS) preferentially allocates kidneys from blood type A2 or A2B (A/A2B) donors to blood type B candidates. We used national data to evaluate center-level performance of A2/A2B to B transplants, and organ procurement organization (OPO) reporting of type A or AB donor subtyping, in 5-year time periods prior to (2009-2014) and following (2015-2019) KAS implementation. The number of centers performing A2/A2B to B transplants increased from 17 pre-KAS to 76 post-KAS, though this still represents only a minority of centers (7.3% pre-KAS and 32.6% post-KAS). For high-performing centers, the median net increase in A2/A2B to B transplants was 19 cases (range -2-72) per center in the 5 years post-KAS. The median net increase in total B recipient transplants was 21 cases (range -17-119) per center. Despite requirements for performance of subtyping, in 2019 subtyping was reported on only 56.4% of A/AB donors. This translates into potential missed opportunities for B recipients, and even post-KAS up to 2322 A2/A2B donor kidneys may have been allocated for transplantation as A/AB. Further progress must be made both at center and OPO levels to broaden implementation of A2/A2B to B transplants for the benefit of underserved recipients.

Best practice recommendations for the use of hepatitis C viremic donor organs for hepatitis C virus naïve recipients.

The combination of the transplant organ deficit, the increase in HCV nucleic acid positive donors (HCV NAT+), and the development of direct-acting antiviral agents (DAAs) has resulted in a rapid increase in HCV NAT+ organ transplants into HCV naïve recipients. Early clinical experience with HCV NAT+ donor organs has shown promising outcomes; however, best practices are lacking to guide transplant programs during all phases of patient care. Transplant programs developing protocols for the utilization of HCV NAT+ organs will need a multidisciplinary team to address all aspects of pre-transplant and post-transplant patient care. Reports of fibrosing cholestatic hepatitis in HCV NAT+ organ transplant recipients receiving delayed DAA initiation highlight the need for the transplant community to develop safe and effective protocols. A failure to do so will inevitably lead to the erosion of public trust from cases of missed or inadequately treated donor-derived HCV infections. Herein, we provide best practice guidelines for the utilization of HCV NAT+ organs into HCV-negative recipients based on literature review and expert opinion from the faculty of the ASTS Standards and Quality Committee.

Association of maternal lipid profile and gestational diabetes mellitus: A systematic review and meta-analysis of 292 studies and 97,880 women.

BACKGROUND: Gestational Diabetes Mellitus (GDM) is the most prevalent metabolic disorder during pregnancy, however, the association between dyslipidaemia and GDM remains unclear. METHODS: We searched Medline, Scopus, Web of Science, Cochrane, Maternity and Infant Care database (MIDIRS) and ClinicalTrials.gov up to February 2021 for relevant studies which reported on the circulating lipid profile during pregnancy, in women with and without GDM. Publications describing original data with at least one raw lipid [triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), or very low-density lipoprotein cholesterol (VLDL-C)] measurement were retained. Data extraction was performed using a piloted data extraction form. The protocol was registered with PROSPERO (CRD42019139696). FINDINGS: A total of 292 studies, comprising of 97,880 pregnant women (28232 GDM and 69,648 controls) were included. Using random-effects meta-analysis models to pool study estimates, women with GDM had significantly higher (by 20%) TG levels, with a pooled weighted mean difference between GDM and non-GDM pregnancies of 0.388 mM (0.336, 0.439, p < 0.001). Further analyses revealed elevated TG levels occur in the first trimester and persist afterwards. Meta-regression analyses showed that differences in TG levels between women with GDM and healthy controls were significantly associated with age, BMI, study continent, OGTT procedure, and GDM diagnosis criteria. INTERPRETATION: Elevated lipids, particularly, TG, are associated with GDM.

Pancreas transplantation from hepatitis C viremic donors to uninfected recipients.

Despite utilization of hepatitis C viremic organs for hepatitis C naïve recipients (HCV D+/R-) in other solid organ transplants, HCV viremic pancreata remain an unexplored source of donor organs. This study reports the first series of HCV D+/R- pancreas transplants. HCV D+/R- had shorter waitlist times compared to HCV D-/R-, waiting a mean of 16 days from listing for HCV-positive organs. HCV D+/R- had a lower match allocation sequence than HCV D-/R-, and this correlated with receipt of organs with a lower Pancreas Donor Risk Index (PDRI) score. All HCV D+/R- had excellent graft function with a mean follow-up of 438 days and had undetectable HCV RNA levels by a mean of 23 days after initiation of HCV-directed therapy. The rates of infectious complications, reoperation, readmission, rejection, and length of stay were not impacted by donor HCV status. A national review of potential ideal pancreas donors found that 37% of ideal HCV-negative pancreas allografts were transplanted, compared to only 5% of ideal HCV-positive pancreas allografts. The results of the current study demonstrate the safety of accepting HCV-positive pancreata for HCV-naïve recipients and advocates for increased utilization of ideal HCV-positive pancreas allografts.

A call to action: Feasible strategies to reduce the discard of transplantable kidneys in the United States.

Changes to the United States kidney allocation system targeted at reducing organ discard have failed to improve organ utilization. High Kidney Donor Profile Index kidneys continue to be discarded at high rates as a result of the regulatory and financial barriers to widespread utilization of these organs. However, there are potential changes to clinical practice that could improve organ utilization. Expediting the time from initial offer to final organ acceptance would reduce cold ischemic time and should improve utilization. Implementation of procurement biopsy standards to avoid biopsy of low risk organs may prevent organ discards due to inaccurate data or excessive cold ischemia time. Further, standardization of procurement biopsy pathological interpretation coupled with electronic accessibility would enable early acceptance of difficult to transplant organs. These changes to allocation practice patterns are vital given proposals to expand the geographic sharing of deceased donor kidneys. Implementation of new allocation policies must be evaluated to ensure they result in higher transplant rates and acceptable post-transplant outcomes.

A Feasibility Study of Paired Continuous Glucose Monitoring Intrapartum and in the Newborn in Pregnancies Complicated by Type 1 Diabetes.

AIM: To describe the continuous glucose monitoring (CGM) profiles of type 1 diabetes (T1D) offspring in the early neonatal period and its association with maternal intrapartum glucose control. METHODS: A prospective observational study of T1D pregnant women and their neonatal offspring. Women had a CGM sensor inserted 2-3 days before delivery. Infants had a masked CGM sensor inserted as soon as possible after delivery. Maternal glycemic outcomes were time-in-target (70-140 mg/dL [3.9-7.8 mmol/L]), hyperglycemia >140 mg/dL (7.8 mmol/L), and mean CGM glucose during the 24 h preceding delivery. Neonatal outcomes included lowest recorded blood glucose concentration, and CGM measures (glucose <47 mg/dL [2.6 mmol/L], time-in-target (47-144 mg/dL [2.6-8.0 mmol/L]), glucose standard deviation [SD]) during the first 72 h of life. RESULTS: Data were available for 16 mother-infant pairs. Mothers had a mean age (SD) 32.3 (4.3) years, T1D duration 17.6 (6.8) years, first antenatal glycated hemoglobin 7.4 (0.8)% (57 [8.5] mmol/mol). In the 24 h preceding delivery, mothers spent mean (SD) 72 (20)% time-in-target (70-140 mg/dL [3.9-7.8 mmol/L]), 19 (15)% time >140 mg/dL (7.8 mmol/L), and 9 (9)% time <70 mg/dL (3.9 mmol/L) with mean (SD) CGM glucose 113 (9) mg/dL (6.3 [0.7] mmol/L). Fifteen infants (93.8%) had ≥1 blood glucose concentration <47 mg/dL (2.6 mmol/L), and five had ≥1 blood glucose concentration <18 mg/dL (1.0 mmol/L). The mean infant CGM glucose on days 1, 2, and 3 of life was 63 (14), 67 (13), 76 (11) mg/dL (3.5 [0.8], 3.7 [0.7], and 4.2 [0.6] mmol/L). Four infants (25%) spent >50% time with CGM glucose levels <47 mg/dL (2.6 mmol/L) on day 1. CONCLUSIONS: CGM detected widespread neonatal hypoglycemia, even among mothers with good intrapartum glucose control.

Adaptability of Closed Loop During Labor, Delivery, and Postpartum: A Secondary Analysis of Data from Two Randomized Crossover Trials in Type 1 Diabetes Pregnancy.

Tight glucose control during labor and delivery is recommended for pregnant women with type 1 diabetes. This can be challenging to achieve using the current treatment modalities. The automated nature of closed loop and its ability to adapt to real-time glucose levels make it well suited for use during labor, delivery, and the immediate postpartum period. We report observational data of participants from two randomized crossover trials who chose to continue using closed loop during labor, delivery, and postpartum. Labor was defined as the 24 h before delivery and postpartum as the 48 h after delivery. The glucose target range during pregnancy was 3.5-7.8 mmol/L (63-140 mg/dL) and 3.9-10 mmol/L (70-180 mg/dL) after delivery. Twenty-seven (84.4%) of the potential 32 trial participants used closed loop through labor, delivery, and postpartum. Use of closed loop was associated with 82.0% (interquartile range [IQR] 49.3, 93.0) time-in-target range during labor and delivery and a mean glucose of 6.9 ± 1.4 mmol/L (124 ± 25 mg/dL). Closed loop performed well throughout vaginal, elective, and emergency cesarean section deliveries. Postpartum, women spent 83.3% (IQR 75.2, 94.6) time-in-target range (3.9-10.0 mmol/L [70-180 mg/dL]), with a mean glucose of 7.2 ± 1.4 mmol/L (130 ± 25 mg/dL). There was no difference in maternal glucose concentration between mothers of infants with and without neonatal hypoglycemia (6.9 ± 1.6 mmol/L and 6.8 ± 1.1 mmol/L [124 ± 29 mg/dL and 122 ± 20 mg/dL] respectively; P = 0.84). Automated closed-loop insulin delivery is feasible during hospital admissions for labor, delivery, and postpartum. Larger scale studies are needed to evaluate its efficacy compared with current clinical approaches as well as understand how women and healthcare providers will adopt this technology.

Day-and-Night Closed-Loop Insulin Delivery in a Broad Population of Pregnant Women With Type 1 Diabetes: A Randomized Controlled Crossover Trial.

OBJECTIVE: Despite advances in technology, optimal glucose control remains elusive and neonatal complications remain ubiquitous in type 1 diabetes (T1D) pregnancy. Our aim was to examine the safety, efficacy, and longer-term feasibility of day-and-night closed-loop insulin delivery. RESEARCH DESIGN AND METHODS: We recruited 16 pregnant women (mean [SD]: age 32.8 [5.0] years, T1D duration 19.4 [10.2] years, HbA1c 8.0% [1.1], and BMI 26.6 [4.4] kg/m2) to an open-label, randomized, crossover trial. Participants completed 28 days of closed-loop and sensor-augmented pump (SAP) insulin delivery separated by a washout period. Afterward, participants could continue to use the closed-loop system up to 6 weeks postpartum. The primary end point was the proportion of time with glucose levels within the target range (63-140 mg/dL). RESULTS: The proportion of time with glucose levels within target was comparable during closed-loop and SAP insulin delivery (62.3 vs. 60.1% [95% CI -4.1 to 8.3]; P = 0.47). Mean glucose and time spent hyperglycemic >140 mg/dL also did not differ (131.4 vs. 131.4 mg/dL [P = 0.85] and 36.6 vs. 36.1% [P = 0.86], respectively). During closed-loop, fewer hypoglycemic episodes occurred (median 8 [range 1-17] vs. 12.5 [1-53] over 28 days; P = 0.04) and less time at <63 mg/dL (1.6 vs. 2.7%; P = 0.02). Hypoglycemia <50 mg/dL (0.24 vs. 0.47%; P = 0.03) and low blood glucose index (1.0 vs. 1.4; P = 0.01) were lower. Less nocturnal hypoglycemia (2300-0700 h) during closed-loop therapy (1.1 vs. 2.7%; P = 0.008) and a trend toward higher overnight time in target (67.7 vs. 60.6%; P = 0.06) were found. CONCLUSIONS: Closed-loop insulin delivery was associated with comparable glucose control and significantly less hypoglycemia than SAP therapy. Larger, longer-duration multicenter trials are now indicated to determine clinical efficacy of closed-loop insulin delivery in T1D pregnancy and the impact on neonatal outcomes.

Continuous glucose monitoring in pregnant women with type 1 diabetes (CONCEPTT): a multicentre international randomised controlled trial.

BACKGROUND: Pregnant women with type 1 diabetes are a high-risk population who are recommended to strive for optimal glucose control, but neonatal outcomes attributed to maternal hyperglycaemia remain suboptimal. Our aim was to examine the effectiveness of continuous glucose monitoring (CGM) on maternal glucose control and obstetric and neonatal health outcomes. METHODS: In this multicentre, open-label, randomised controlled trial, we recruited women aged 18-40 years with type 1 diabetes for a minimum of 12 months who were receiving intensive insulin therapy. Participants were pregnant (≤13 weeks and 6 days' gestation) or planning pregnancy from 31 hospitals in Canada, England, Scotland, Spain, Italy, Ireland, and the USA. We ran two trials in parallel for pregnant participants and for participants planning pregnancy. In both trials, participants were randomly assigned to either CGM in addition to capillary glucose monitoring or capillary glucose monitoring alone. Randomisation was stratified by insulin delivery (pump or injections) and baseline glycated haemoglobin (HbA1c). The primary outcome was change in HbA1c from randomisation to 34 weeks' gestation in pregnant women and to 24 weeks or conception in women planning pregnancy, and was assessed in all randomised participants with baseline assessments. Secondary outcomes included obstetric and neonatal health outcomes, assessed with all available data without imputation. This trial is registered with ClinicalTrials.gov, number NCT01788527. FINDINGS: Between March 25, 2013, and March 22, 2016, we randomly assigned 325 women (215 pregnant, 110 planning pregnancy) to capillary glucose monitoring with CGM (108 pregnant and 53 planning pregnancy) or without (107 pregnant and 57 planning pregnancy). We found a small difference in HbA1c in pregnant women using CGM (mean difference -0·19%; 95% CI -0·34 to -0·03; p=0·0207). Pregnant CGM users spent more time in target (68% vs 61%; p=0·0034) and less time hyperglycaemic (27% vs 32%; p=0·0279) than did pregnant control participants, with comparable severe hypoglycaemia episodes (18 CGM and 21 control) and time spent hypoglycaemic (3% vs 4%; p=0·10). Neonatal health outcomes were significantly improved, with lower incidence of large for gestational age (odds ratio 0·51, 95% CI 0·28 to 0·90; p=0·0210), fewer neonatal intensive care admissions lasting more than 24 h (0·48; 0·26 to 0·86; p=0·0157), fewer incidences of neonatal hypoglycaemia (0·45; 0·22 to 0·89; p=0·0250), and 1-day shorter length of hospital stay (p=0·0091). We found no apparent benefit of CGM in women planning pregnancy. Adverse events occurred in 51 (48%) of CGM participants and 43 (40%) of control participants in the pregnancy trial, and in 12 (27%) of CGM participants and 21 (37%) of control participants in the planning pregnancy trial. Serious adverse events occurred in 13 (6%) participants in the pregnancy trial (eight [7%] CGM, five [5%] control) and in three (3%) participants in the planning pregnancy trial (two [4%] CGM and one [2%] control). The most common adverse events were skin reactions occurring in 49 (48%) of 103 CGM participants and eight (8%) of 104 control participants during pregnancy and in 23 (44%) of 52 CGM participants and five (9%) of 57 control participants in the planning pregnancy trial. The most common serious adverse events were gastrointestinal (nausea and vomiting in four participants during pregnancy and three participants planning pregnancy). INTERPRETATION: Use of CGM during pregnancy in patients with type 1 diabetes is associated with improved neonatal outcomes, which are likely to be attributed to reduced exposure to maternal hyperglycaemia. CGM should be offered to all pregnant women with type 1 diabetes using intensive insulin therapy. This study is the first to indicate potential for improvements in non-glycaemic health outcomes from CGM use. FUNDING: Juvenile Diabetes Research Foundation, Canadian Clinical Trials Network, and National Institute for Health Research.