Early Identification of Primary Hypothyroidism in Neonates Exposed to Intralymphatic Iodinated Contrast: A Case Series.

Context: In neonates, iatrogenic hypothyroidism can result from topical or IV iodine exposure. Data on intralymphatic iodine exposure, risk factors for disease severity, and timing of hypothyroidism are limited. Case Descriptions: We report 4 cases of premature neonates with previously normal thyroid function tests (TFTs) who developed hypothyroidism after intralymphatic iodinated contrast. Patients 1 and 2, premature infants with complex medical histories, had chylous effusions and high-volume chest tube output requiring imaging with lymphangiograms on day of life (DOL) 97 and DOL 43, respectively. They developed severe, primary hypothyroidism with TSH of 335.7 mIU/mL (reference range, 1.7 to 9.1) on DOL 111 and TSH of 470.2 mIU/mL (reference range, 1.7 to 9.1) on DOL 68. Patient 3 had prenatally diagnosed fetal hydrops manifesting with chylous effusions and high-volume chest tube output. The infant underwent lymphangiography on DOL 90 and was noted to have an elevated TSH of 13.35 mIU/mL (reference range, 1.7 to 9.1) 4 days later with spot urine iodine of 1742 µg/L (normal, <200). Patient 4 had a lymphatic malformation and underwent sclerotherapy with doxycycline with intralymphatic iodine exposure on DOL 4 and was found to have a TSH of 16.7 µU/mL (reference range, 1.7 to 9.1) 3 days later with spot urine iodine of 228,712 µg/L (normal, <200). The TFT results for all patients improved after levothyroxine administration. Conclusion: Intralymphatic iodine should be considered a major risk factor in the development of iatrogenic primary hypothyroidism, especially in premature neonates soon after exposure. Close monitoring of TFTs is imperative to avoid potential long-term adverse outcomes in this population.

Hypothyroidism in Infants With Congenital Heart Disease Exposed to Excess Iodine.

Thyroid hormone is critical for neonatal brain development, and even transient hypothyroidism can cause adverse neurocognitive outcomes. Infants exposed to excess iodine are at risk of developing hypothyroidism, especially those with congenital heart disease (CHD), because they are routinely exposed to excess iodine from intravenous iodinated contrast media and topical antiseptics. The aim of the present study was to identify the proportion of neonates with CHD exposed to iodine who developed hypothyroidism and to identify the associated risk factors. This was a retrospective study of neonates undergoing cardiac catheterization at Boston Children's Hospital during a 3-year period, some of whom also underwent cardiac surgery. Hypothyroidism was defined as an elevated thyroid-stimulating hormone level (>20 mIU/L at 24 to 96 hours of age and >15 mIU/L at >96 hours of age by heel-stick sampling and >9.1 mIU/L at 1 to 20 weeks of age by serum testing). Multivariate logistic regression was performed to predict the odds of developing hypothyroidism. Hypothyroidism was diagnosed incidentally in 46 of 183 infants (25%) with CHD after iodine exposure. Controlling for baseline cardiac risk, postnatal age, and gestational age, we found a fourfold increase in odds of developing hypothyroidism in neonates with serum creatinine >0.9 mg/dL and a fourfold increase in those who underwent more than three procedures. Hypothyroidism in neonates with CHD exposed to excess iodine is associated with multiple procedures and impaired renal function. Routine serial monitoring of thyroid function in these neonates is warranted. Future studies should examine the association between hypothyroidism and neurocognitive function in this population.

RASopathies Are Associated With Delayed Puberty; Are They Associated With Precocious Puberty Too?

RASopathies, such as Noonan, Costello, and cardio-facio-cutaneous syndromes, are developmental disorders caused by mutations in rat sarcoma-mitogen-activated protein kinase pathway genes. Mutations that cause Noonan syndrome have been associated with delayed puberty. Here we report 4 patients with either Costello or cardio-facio-cutaneous syndrome who developed precocious puberty, suggesting complex regulation of the hypothalamic-pituitary-gonadal axis and the timing of puberty by the rat sarcoma-mitogen-activated protein kinase pathway. Additional study of the timing of puberty among patients with RASopathies is warranted to ascertain the incidence of delayed and precocious puberty in these conditions and to examine genotype-phenotype correlations, which may provide insight into pathways that regulate the timing of puberty.

Preoperative risk stratification of children with ovarian tumors.

BACKGROUND: The appropriate operative approach to pediatric patients with ovarian tumors must balance real risk of malignancy with maximal preservation of reproductive potential. We evaluate preoperative risk of malignancy in order to more precisely guide treatment, so as to err on the side of ovarian preservation if at all possible. METHODS: We retrospectively reviewed the records of all patients undergoing surgical intervention for ovarian tumors at a single institution. The primary endpoint was ovarian malignancy. RESULTS: Of 502 patients who underwent surgery for ovarian tumors, 44 (8.8%) had malignancies. Malignancy rate (95% confidence interval) was low for cystic lesions <9cm (0.0%, 0.0-2.9%) and for tumor marker-negative heterogeneous lesions <9cm (2.3%, 0.4-12.1%). High-risk profiles for malignancy included tumor marker-positive heterogeneous lesions (66.7%, 35.4-87.9%) and solid tumors ≥9cm (69.2%, 16.2-40.3%). Intermediate risk tumors included cystic tumors ≥9cm (6.8%, 3.5-20.7%), tumor marker-negative heterogeneous lesions ≥9cm (31.2%, 18.0-48.6%), and solid tumors <9cm (11.1%, 4.4-25.3%). CONCLUSIONS: We developed a decision strategy to help determine who may and may not require an ovarian-sparing approach, which warrants prospective application and validation. Ultimately, the decision to pursue an oncologic surgery with oophorectomy and staging (as opposed to fertility-preserving surgery) should be made after individualized discussion involving the surgeon, patient, and family.

Poor adherence to staging guidelines for children with malignant ovarian tumors.

PURPOSE: Historically, surgical staging practices for pediatric malignant ovarian tumors mirrored adult guidelines. In 2004, the Children's Oncology Group (COG) developed guidelines specific to pediatric patients with ovarian germ cell tumors. We sought to characterize the operative management of pediatric ovarian lesions and adherence to COG surgical staging guidelines. METHODS: We conducted a single institution, retrospective study of pediatric patients who underwent surgical intervention for ovarian lesions between 1995 and 2012. The primary outcome was adherence to COG staging guidelines. RESULTS: Among 502 patients, 44 (8.8%) had malignant ovarian tumors. Two patients (2/44, 4.5%) underwent correct surgical staging. Therefore, 95.5% (42/44) underwent incorrect surgical staging by omitting recommended maneuvers (surgical understaging) or performing clinically unnecessary surgical staging steps (surgical overstaging). Of the 42 patients with incorrect surgical staging, 85.7% (36/42) were surgically overstaged and 76.2% (32/42) were surgically understaged. In the entire cohort, 12 (27.3%) patients had complete staging procedures, including 10 surgically overstaged patients (10/12, 83.3%). Staging practices were not significantly different before and after the release of the 2004 COG guidelines. CONCLUSION: Incorrect surgical staging of pediatric ovarian malignancies is commonplace. These data stress the need for greater education among all surgeons caring for children with malignant ovarian tumors.

Germinoma with malignant transformation to nongerminomatous germ cell tumor.

The authors describe the case of a young girl with suprasellar germinoma. Six weeks after this diagnosis, just prior to initiation of therapy, serum and CSF marker analysis revealed sudden and marked elevation of alpha-fetoprotein, indicating transformation of her germinoma to a nongerminomatous germ cell tumor. She underwent chemotherapy and radiation therapy per the national treatment approach for the new diagnosis, with subsequent return of her serum and CSF tumor markers to normal levels. To the authors' knowledge, this is the first case in the English-language literature of a nongerminomatous germ cell tumor resulting from conversion of germinoma at the original site of presentation.

A randomized clinical trial to evaluate optimal treatment for unexplained infertility: the fast track and standard treatment (FASTT) trial.

OBJECTIVE: To determine the value of gonadotropin/intrauterine insemination (FSH/IUI) therapy for infertile women aged 21-39 years. DESIGN: Randomized controlled trial. SETTING: Academic medical center associated with a private infertility center. PATIENT(S): Couples with unexplained infertility. INTERVENTION(S): Couples were randomized to receive either conventional treatment (n=247) with three cycles of clomiphene citrate (CC)/IUI, three cycles of FSH/IUI, and up to six cycles of IVF or an accelerated treatment (n=256) that omitted the three cycles of FSH/IUI. MAIN OUTCOME MEASURE(S): The time it took to establish a pregnancy that led to a live birth and cost-effectiveness, defined as the ratio of the sum of all health insurance charges between randomization and delivery divided by the number of couples delivering at least one live-born baby. RESULT(S): An increased rate of pregnancy was observed in the accelerated arm (hazard ratio [HR], 1.25; 95% confidence interval [CI], 1.00-1.56) compared with the conventional arm. Median time to pregnancy was 8 and 11 months in the accelerated and conventional arms, respectively. Per cycle pregnancy rates for CC/IUI, FSH/IUI, and IVF were 7.6%, 9.8%, and 30.7%, respectively. Average charges per delivery were $9,800 lower (95% CI, $25,100 lower to $3,900 higher) in the accelerated arm compared to conventional treatment. The observed incremental difference was a savings of $2,624 per couple for accelerated treatment and 0.06 more deliveries. CONCLUSION(S): A randomized clinical trial demonstrated that FSH/IUI treatment was of no added value.

Medicare's national coverage decisions, 1999-2003: quality of evidence and review times.

In 1998 Medicare amended its procedures for making national coverage decisions for new technologies in an attempt to make the process more transparent and evidence based. We examined the quality of evidence for sixty-nine technologies reviewed by Medicare since then. Determinations by the Centers for Medicare and Medicaid Services (CMS) have generally been consistent with the strength of evidence. Good clinical evidence from rigorous studies is usually lacking for the technologies Medicare considers, although in most cases the CMS covers with conditions if there is at least fair evidence that benefits outweigh harms. Decisions referred to the external Medicare Coverage Advisory Committee (MCAC) have averaged eight months longer than non-MCAC decisions.

Reducing acute adverse outcomes in youths with type 1 diabetes: a randomized, controlled trial.

OBJECTIVE: Both acute and chronic complications of diabetes account for a disproportionate percentage of US health care expenditures. Despite improvements in diabetes care, the incidence of adverse events in children with type 1 diabetes remains high, particularly for youths with poor glycemic control. Cost-effective intervention programs designed to reduce complications are needed. This study evaluated a low-intensity, nonmedical intervention using a case manager (called a "Care Ambassador"), with and without the supplementation of psychoeducational modules, designed to monitor and encourage routine diabetes care visits to reduce short-term adverse outcomes and improve glycemic control in youths with type 1 diabetes. METHODS: We performed a 2-year prospective, randomized clinical trial in 299 youths with type 1 diabetes, aged 7 to 16 years, comparing 3 treatment programs (Care Ambassador [CA], Care Ambassador plus psychoeducational modules [CA+], and standard multidisciplinary diabetes care [SC]). The study was conducted in a large metropolitan US city from April 1997 through April 2000. Number of medical visits, frequency of hypoglycemic events, hospital/emergency department (ED) utilization, and glycosylated hemoglobin A1c were assessed during follow-up. RESULTS: During the 2-year study period, both the CA and CA+ groups had significantly more routine visits (mean [standard deviation]: 7.3 [2.06] and 7.5 [2.02], respectively) compared with the SC group (5.4 [2.62]). The CA+ intervention group had significantly reduced rates of short-term adverse outcomes compared with the other 2 groups; 25% fewer total hypoglycemic events, 60% fewer severe hypoglycemic events, and 40% fewer hospitalizations and ED visits. "High-risk" youths in the CA+ group (baseline glycosylated hemoglobin A1c > or =8.7%) were 3.4-fold (1.57-7.41) more likely to improve their glycemic control compared with those at high risk in the other 2 groups. CONCLUSIONS: For youths with type 1 diabetes, the CA and CA+ interventions increased visit frequency. Youths in the CA+ intervention had reduced rates of hypoglycemia and hospital/ED utilization with estimated annual cost savings of 80 000 dollars to 90 000 dollars. The CA+ intervention compared with the other 2 groups improved glycemic control in "high-risk" youths. Nonmedical case management incorporating psychoeducational modules seems to be a cost-effective approach to improving outcomes in youths with diabetes.

Do HEDIS measures reflect cost-effective practices?

PURPOSE: Whether the Health Plan Employer Data and Information Set (HEDIS) performance measures for managed care plans encourage a cost-effective use of society's resources has not been quantified. Our study objectives were to examine the cost-effectiveness evidence for the clinical practices underlying HEDIS 2000 measures and to develop a list of practices not reflected in HEDIS that have evidence of cost effectiveness. DATA SOURCES: Two databases of economic evaluations (Harvard School of Public Health Cost-Utility Registry and the Health Economics Evaluation Database) and two published lists of cost-effectiveness ratios in health and medicine. STUDY SELECTION: For each of the 15 "effectiveness of care" measures in HEDIS 2000, we searched the data through 1998 for cost-effectiveness ratios of similar interventions and target populations. We also searched for important interventions with evidence of cost-effectiveness (<$20,000 per life-year [LY] or quality-adjusted life year [QALY] gained), which are not included in HEDIS. All ratios were standardized to 1998 dollars. The data were collected and analyzed during fall 2000 to summer 2001. DATA EXTRACTION: Cost-effectiveness ratios reporting outcomes in terms of cost/LY or cost/QALY gained were included if they matched the intervention and population covered by the HEDIS measure. DATA SYNTHESIS: Evidence was available for 11 of the 15 HEDIS measures. Cost-effectiveness ranges from cost saving to $660,000/LY gained. There are numerous non-HEDIS interventions with some evidence of cost effectiveness, particularly interventions to promote healthy behaviors. CONCLUSIONS: HEDIS measures generally reflect cost-effective practices; however, in a number of cases, practices may not be cost effective for certain subgroups. Data quality and availability as well as study perspective remain key challenges in judging cost effectiveness. Opportunities exist to refine existing measures and to develop additional measures, which may promote a more efficient use of societal resources, although more research is needed on whether these measures would also satisfy other desirable attributes of HEDIS.