Impact of ART on pregnancies in California: an analysis of maternity outcomes and insights into the added burden of neonatal intensive care.

OBJECTIVE: We reviewed the occurrence of prematurity, low birth weight, multiple gestations, frequency of stillbirths and maternity care-associated variables including hospital stay and hospital charges of women conceiving using assisted reproductive technology (ART) or artificial insemination (AI) compared with women with a history of infertility who conceived naturally, and all other naturally conceived pregnancies in California at non-federal hospitals between 2009 and 2011. At a single center, infants born after ART/AI were compared with infants provided care in the normal nursery. STUDY DESIGN: Publically available inpatient data sets from the California Office of Statewide Health Planning and Development for years 2009-2011 using data from all California non-federal hospitals were used to determine the impact of ART on a variety of pregnancy-related outcomes and infant characteristics. Infant data from a single center was used to determine hospital charges for infants delivered over an 18-month period to compare the hospital and physician charges indexed to similar charges for infants admitted to the 'normal' newborn nursery. RESULT: Among ART/AI pregnancies, there was a 4-5-fold increase in stillbirths, compared with a 2-3-fold increase among women with infertility compared with other naturally conceiving women. ART/AI pregnancies underwent more cesarean sections (fourfold), and a near fourfold increase in the rate of preterm deliveries. Multiple gestations were increased 24-27-fold compared with naturally conceived pregnancies. Maternal hospital stay and hospital charges were increased among those undergoing ART/AI. Infant charges were increased multi-fold for singletons, twins and triplets delivered after ART/AI compared with naturally conceived infants. CONCLUSION: Multiple births, preterm births and a higher overall rate of fetal anomalies were found in California after ART/AI for 2009-2011. Cesarean section rates, longer length of maternal stay and hospital charges among women receiving ART/AI could be lowered if emphasis on elective single embryo transfers was a higher priority among providers. Charges for the care of infants delivered after ART/AI are substantially higher than among naturally conceived infants born late preterm or at term. Families seeking ART/AI need to be informed of the impact of these adverse pregnancy outcomes, including neonatal outcomes and charges for medical care for their infant(s), when considering ART/AI.

A pathway to insulin independence in newborns and infants with diabetes.

Permanent neonatal diabetes was previously assumed to require insulin injection or infusion for life. Recently, permanent neonatal diabetes resulting from mutations in the two protein subunits of the adenosine triphosphate-sensitive potassium channel (Kir6.2 and SUR1) has proven to be successfully treatable with high doses of sulfonylureas rather than insulin. Many patients with these mutations first develop hyperglycemia in the nursery or intensive care unit. The awareness of the neonatolgist of this entity can have dramatic effects on the long-term care and quality of life of these patients and their families. In this study, we present the experience of our center, highlighting aspects relevant to neonatal diagnosis and treatment.

Efficacy comparison between intraportal and subcapsular islet transplants in a murine diabetic model.

BACKGROUND: It is important to determine the efficacy of intraportal (IP) islet transplantation in comparison with other transplant sites. In this study, we sought to determine the optimal number of islets to achieve normoglycemia following transplantation into the liver versus the kidney using a mouse model. METHODS: Streptozotocin-induced diabetic mice (Balb/C) were transplanted with syngeneic islets via the IP versus renal subcapsular (SC) routes. The transplanted islet numbers were 0 to 800 (n = 3-5). We assessed the correlation between parameters and islet numbers, comparing IP versus SC groups. The parameters were: (1) percentage of normoglycemia; (2) postoperative days to normoglycemia; (3) mean blood glucose levels at various points from pretransplantation to the end of the study (postoperative day 28); (4) mean serum insulin; and (5) area under the curve of blood glucose levels after glucose injection. RESULTS: Two hundred islets yielded normoglycemia in renal subcapsular grafts, while 800 islets were the minimum required for normoglycemia with IP transplantation. The transplant efficacy in SC transplantation was 2 to 5 times greater than that of IP transplantation. The days to normoglycemia were significantly different between IP versus renal SC islets (13.25 +/- 4.38 days vs 4.50 +/- 0.81 days; P = .007). CONCLUSION: The efficacy of islet transplantation in murine diabetic models was significantly greater under the kidney capsule. Clinical islet transplantation could benefit from trials of alternative transplant sites.

Elevated total peripheral leukocyte count may identify risk for neurological disability in asphyxiated term neonates.

OBJECTIVE: The present study investigated the relationship between neurologic outcome and total circulating white blood cell (WBC) and absolute neutrophil counts (ANCs) in the first week of life in term infants with hypoxic-ischemic encephalopathy (HIE). STUDY DESIGN: Long-term neurologic outcome at 18 months was measured retrospectively in 30 term neonates with HIE using the Pediatric Cerebral Performance Category Scale (PCPCS) score with outcomes dichotomized as either good or poor. We then compared white blood cell and ANC levels during the first 4 days of life and magnetic resonance imaging (MRI) obtained within the first month life between the two PCPCS groups. MRI was quantified using a validated scoring system. RESULTS: Neonates with good long-term outcomes had significantly lower MRI scores (indicating lesser injury) than neonates with poor outcomes. More importantly, neonates with poor outcomes had significantly higher WBC and ANC levels as early as12 h after birth and up to 96 h after birth compared to those with good outcomes. These data suggest that elevated peripheral neutrophil counts in the first 96 h of life may signal or predict adverse long-term outcome. CONCLUSIONS: Our findings suggest that elevated peripheral neutrophil counts in the first 96 h of life in term infants with HIE may contribute to abnormal neurodevelopmental outcome.

Dynamic production of hypoxia-inducible factor-1alpha in early transplanted islets.

More than half of transplanted beta-cells undergo apoptotic cell death triggered by nonimmunological factors within a few days after transplantation. To investigate the dynamic hypoxic responses in early transplanted islets, syngeneic islets were transplanted under the kidney capsule of balb/c mice. Hypoxia-inducible factor-1alpha (HIF-1alpha) was strongly expressed at post-transplant day (POD) 1, increased on POD 3, and gradually diminished on POD 14. Insulin secretion decreased on POD 3 in association with a significant increase of HIF-1alpha-related beta-cell death, which can be suppressed by short-term hyperbaric oxygen therapy. On POD 7, apoptosis was not further activated by continually produced HIF-1alpha. In contrast, improvement of nerve growth factor and duodenal homeobox factor-1 (PDx-1) production resulted in islet graft recovery and remodeling. In addition, significant activation of vascular endothelial growth factor in islet grafts on POD 7 correlated with development of massive newly formed microvessels, whose maturation is advanced on POD 14 with gradual diminution of HIF-1alpha. We conclude that (1) transplanted islets strongly express HIF-1alpha in association with beta-cell death and decreased insulin production until adequate revascularization is established and (2) early suppression of HIF-1alpha results in less beta-cell death thereby minimizing early graft failure.

Beneficial effects of nerve growth factor on islet transplantation.

OBJECTIVE: Development of the Edmonton protocol was a pivotal contribution to clinical islet transplantation (ITx). Persistent limitations to ITx include insufficient supply and posttransplant functional failure of islets. In this study, nerve growth factor (NGF) was used to enhance both cultured and transplanted beta-cell function, thus achieving prolonged graft survival. METHODS: Fluorescence microscopy with ethidium bromide and SYTO green staining was used to evaluate balb/c mouse islet viability. Islets were syngeneically transplanted under the kidney capsule of recipients with streptozotocin-induced diabetes. Intraperitoneal glucose tolerance was used to test posttransplant function. RESULTS: Improved viability was found in murine islets cultured for 48 hours in 500 ng/mL NGF (P < .05). A submarginal islet mass (260 islet equivalents/recipient) was used for ITx. The NGF-culture resulted in prolonged islet survival (24.7 days vs 5.5 days without NFG culture, n = 6). Intravenous injection of NGF (6 mug) on the day of transplant and postoperative days (POD) 1 + 2 prolonged islet survival from 4.1 days (no treatment) to 13.2 days (n = 6). Glucose tolerance testing performed at posttransplant day 4 showed improvement at 60 and 120 minutes in recipients treated intravenously with NGF (blood glucose of 95 +/- 15 vs 210 +/- 78 and 57 +/- 6 vs 176 +/- 70 mg/dL, respectively). CONCLUSION: NGF may improve beta-cell function and result in prolonged survival of both cultured and transplanted islets.

Graphical user interface for a neonatal parenteral nutrition decision support system.

We developed and implemented a decision support system for prescribing parenteral nutrition (PN) solutions for infants in our neonatal intensive care unit. We employed a graphical user interface to provide clinical guidelines and aid the understanding of the interaction among the various ingredients that make up a PN solution. In particular, by displaying the interaction between the PN total solution volume, protein, calcium and phosphorus, we have eliminated PN orders that previously would have resulted in calcium-phosphorus precipitation errors.

Extracorporeal membrane oxygenation for perioperative support in neonatal and pediatric cardiac transplantation.

Currently there is a lack of consensus on guidelines in the clinical application of extracorporeal membrane oxygenation (ECMO) in neonatal and pediatric cardiac transplantation patients. In this context, given the limited data presently available through the Extracorporeal Life Support Organization (ELSO) Registry, we conducted a preliminary survey to specifically evaluate the practice of using ECMO as a bridge to cardiac transplantation or as posttransplantation therapy for failure to wean from cardiopulmonary bypass or graft failure. We received responses to our questionnaire from 95 of 118 (81%) centers located in the U.S.A. and abroad. Of the 95 centers that responded, 36 were performing neonatal/pediatric cardiac transplants, with 29 centers reporting the concomitant use of ECMO to support cardiac transplant patients. There was wide variability in the responses from the 29 centers to a selected list of relative ECMO contraindications. However, only 7 centers had specific ECMO entry criteria for cardiac transplant patients. Fifteen of the 29 centers provided relevant data on cardiac transplant patients including the proportions of neonatal (11 of 37) and pediatric (63 of 217) patients requiring ECMO; neonatal (2 of 5) and pediatric (16 of 27) patients surviving to transplant; and neonatal (1 of 5) and pediatric (12 of 27) patients surviving to hospital discharge. These findings confirm the important role of ECMO in providing perioperative support in neonatal and pediatric cardiac transplantation patients. However, the lack of consensus among centers contributes to uncertainty in the decision making process to offer ECMO and to utilize ECMO effectively in this high risk population. We recommend that institution-specific information be collected, either using the ELSO Registry (or by a similar multicentric database) to develop specific guidelines for ECMO applications in cardiac transplant patients, and to carefully monitor and follow up EMCO treated patients to further evaluate the efficacy of this limited resource.

Growth and neurodevelopmental outcome of infants undergoing heart transplantation.

The purpose of this study was to examine the long-term growth and developmental outcome of infants undergoing heart transplantation. We studied weight, length, and head circumference from birth to 12 months after surgery in 110 infant recipients less than 6 months of age. Forty-eight early transplant recipients (0 to 30 days) were compared with 62 late transplant recipients (31 to 180 days). Late transplant recipients showed less growth in all parameters at the time of transplant. However, by 6 months after transplantation, there were no differences between the two groups. Growth in 20 infants, now 3 to 7 years old, appears normal. Neurodevelopmental outcome was evaluated prospectively in 57 infants. Four months after transplantation, 11 infants (19%) had abnormal neurologic examinations, with generalized hypotonia (64%) being the most common finding. The Bayley Scale of Infant Development was administered to 48 of 57 infants. The Mental Developmental Index averaged 87 (+/- 21) and the Psychomotor Developmental Index averaged 90 (+/- 21). Of 140 infants who have undergone heart transplantation, transient postoperative seizures occurred in 23 survivors (21%) and 10 nonsurvivors (33%). Our findings suggest that growth, neurologic outcome, and development are normal in the majority of infants who undergo transplantation before 6 months of age.

Anticoagulation therapy advisor: a decision-support system for heparin therapy during ECMO.

We present a case study describing our development of a mathematical model to control a clinical parameter in a patient--in this case, the degree of anticoagulation during extracorporeal membrane oxygenation (ECMO) support. During ECMO therapy, an anticoagulant agent (heparin) is administered to prevent thrombosis. Under- or over-coagulation can have grave consequences. To improve control of anticoagulation, we developed a pharmacokinetic-pharmacodynamic (PK-PD) model that predicts activated clotting times (ACT) using the NONMEM program. We then integrated this model into a decision-support system, and validated it with an independent data set. The population model had a mean absolute error of prediction for ACT values of 33.5 seconds, with a mean bias in estimation of -14.3 seconds. Individualization of model-parameter estimates using nonlinear regression improved the absolute error prediction to 25.5 seconds, and lowered the mean bias to -3.1 seconds. The PK-PD model is coupled with software for heuristic interpretation of model results to provide a complete environment for the management of anticoagulation.

Maprotiline poisoning in a child.

A 6-year-old girl presented with tonic-clonic seizures and generalized convulsions lasting several minutes. A serum drug screen revealed maprotiline, and the estimated intake was 12 mg/kg. Despite initial neurologic impairment on discharge, follow-up 6 months later showed normal neurologic function in the patient. This report describes that case and discusses the toxicity associated with maprotiline and its management.