A core outcome set for the treatment of pregnant women with pregestational diabetes: an international consensus study.

OBJECTIVE: To develop a core outcome set (COS) for randomised controlled trials (RCTs) evaluating the effectiveness of interventions for the treatment of pregnant women with pregestational diabetes mellitus (PGDM). DESIGN: A consensus developmental study. SETTING: International. POPULATION: Two hundred and five stakeholders completed the first round. METHODS: The study consisted of three components. (1) A systematic review of the literature to produce a list of outcomes reported in RCTs assessing the effectiveness of interventions for the treatment of pregnant women with PGDM. (2) A three-round, online eDelphi survey to prioritise these outcomes by international stakeholders (including healthcare professionals, researchers and women with PGDM). (3) A consensus meeting where stakeholders from each group decided on the final COS. MAIN OUTCOME MEASURES: All outcomes were extracted from the literature. RESULTS: We extracted 131 unique outcomes from 67 records meeting the full inclusion criteria. Of the 205 stakeholders who completed the first round, 174/205 (85%) and 165/174 (95%) completed rounds 2 and 3, respectively. Participants at the subsequent consensus meeting chose 19 outcomes for inclusion into the COS: trimester-specific haemoglobin A1c, maternal weight gain during pregnancy, severe maternal hypoglycaemia, diabetic ketoacidosis, miscarriage, pregnancy-induced hypertension, pre-eclampsia, maternal death, birthweight, large for gestational age, small for gestational age, gestational age at birth, preterm birth, mode of birth, shoulder dystocia, neonatal hypoglycaemia, congenital malformations, stillbirth and neonatal death. CONCLUSIONS: This COS will enable better comparison between RCTs to produce robust evidence synthesis, improve trial reporting and optimise research efficiency in studies assessing treatment of pregnant women with PGDM. TWEETABLE ABSTRACT: 165 key stakeholders have developed #Treatment #CoreOutcomes in pregnant women with #diabetes existing before pregnancy.

Skeletal findings in the first 12 months following initiation of glucocorticoid therapy for pediatric nephrotic syndrome.

UNLABELLED: Incident vertebral fractures and lumbar spine bone mineral density (BMD) were assessed in the 12 months following glucocorticoid initiation in 65 children with nephrotic syndrome. The incidence of vertebral fractures was low at 12 months (6 %) and most patients demonstrated recovery in BMD Z-scores by this time point. INTRODUCTION: Vertebral fracture (VF) incidence following glucocorticoid (GC) initiation has not been previously reported in pediatric nephrotic syndrome. METHODS: VF was assessed on radiographs (Genant method); lumbar spine bone mineral density (LS BMD) was evaluated by dual-energy X-ray absorptiometry. RESULTS: Sixty-five children were followed to 12 months post-GC initiation (median age, 5.4 years; range, 2.3-17.9). Three of 54 children with radiographs (6 %; 95 % confidence interval (CI), 2-15 %) had incident VF at 1 year. The mean LS BMD Z-score was below the healthy average at baseline (mean ± standard deviation (SD), -0.5 ± 1.1; p = 0.001) and at 3 months (-0.6 ± 1.1; p < 0.001), but not at 6 months (-0.3 ± 1.3; p = 0.066) or 12 months (-0.3 ± 1.2; p = 0.066). Mixed effect modeling showed a significant increase in LS BMD Z-scores between 3 and 12 months (0.22 SD; 95 % CI, 0.08 to 0.36; p = 0.003). A subgroup (N = 16; 25 %) had LS BMD Z-scores that were ≤-1.0 at 12 months. In these children, each additional 1,000 mg/m(2) of GC received in the first 3 months was associated with a decrease in LS BMD Z-score by 0.39 at 12 months (95 % CI, -0.71 to -0.07; p = 0.017). CONCLUSIONS: The incidence of VF at 1 year was low and LS BMD Z-scores improved by 12 months in the majority. Twenty-five percent of children had LS BMD Z-scores ≤-1.0 at 12 months. In these children, LS BMD Z-scores were inversely associated with early GC exposure, despite similar GC exposure compared to the rest of the cohort.

Skeletal findings in children recently initiating glucocorticoids for the treatment of nephrotic syndrome.

SUMMARY: Eighty children with nephrotic syndrome underwent lumbar spine densitometry and vertebral morphometry soon after glucocorticoid initiation. We found an inverse relationship between glucocorticoid exposure and spine areal bone mineral density (BMD) Z-score and a low rate of vertebral deformities (8%). INTRODUCTION: Vertebral fractures are an under-recognized complication of childhood glucocorticoid-treated illnesses. Our goal was to study the relationships among glucocorticoid exposure, lumbar spine areal BMD (LS BMD), and vertebral shape in glucocorticoid-treated children with new-onset nephrotic syndrome. METHODS: Lateral thoracolumbar spine radiography and LS BMD were performed in 80 children with nephrotic syndrome (median age 4.4 years; 46 boys) within the first 37 days of glucocorticoid therapy. Genant semiquantitative grading was used as the primary method for vertebral morphometry; the algorithm-based qualitative (ABQ) method was used for secondary vertebral deformity analysis. RESULTS: Six of the 78 children with usable radiographs (8%; 95% confidence interval 4 to 16%) manifested a single Genant grade 1 deformity each. All deformities were mild anterior wedging (two at each of T6, T7, and T8). Four of the 78 children (5%; 95% confidence interval 2 to 13%) showed one ABQ sign of fracture each (loss of endplate parallelism; two children at T6 and two at T8). Two of the children with ABQ signs also had a Genant grade 1 deformity in the same vertebral body. None of the children with a Genant or ABQ deformity reported back pain. An inverse relationship was identified between LS BMD Z-score and glucocorticoid exposure. CONCLUSIONS: Although we identified an inverse relationship between steroid exposure and LS BMD soon after glucocorticoid initiation for childhood nephrotic syndrome, there was only a low rate of vertebral deformities. The clinical significance of these findings requires further study.

Residual beta-cell function in children with IDDM: reproducibility of testing and factors influencing insulin secretory reserve.

Reproducibility of C-peptide secretion was assessed in 20 children (group 1) by their responses to two Sustacal- (a mixed liquid meal) stimulation tests performed 7-14 days apart. For the 12 C-peptide-positive children (basal C-peptide greater than or equal to 0.03 pmol/ml) there were no differences in the basal or stimulated values between tests 1 and 2. The effect of exogenous insulin on C-peptide secretion was assessed in 20 other children (group 2) by their responses to two Sustacal tests, one test without and one with soluble insulin (0.25 U/kg) injected subcutaneously before testing. Eleven children were C-peptide positive and had no differences in C-peptide response between tests 1 and 2. The results from test 1 in groups 1 and 2 were combined with those from 44 others undergoing a single Sustacal test (group 3, N = 84). There was a close correlation between basal and peak C-peptide concentrations in the 44 C-peptide-positive children (r = .88, P less than .001). Peak C-peptide concentrations correlated inversely with HbA1 (r = -.29, P less than .01), insulin dose in units per kilogram (r = -.40, P less than .001), and duration of diabetes (r = .33, P less than .001) and positively with age at onset of diabetes (r = .34, P less than .001). The C-peptide-positive children had reduced glucose response to Sustacal, lower HbA1 concentration, lower insulin requirement, later age of onset, and shorter duration of diabetes than children who were C-peptide negative.

Self-monitoring of blood glucose: how accurate are children with diabetes at reading chemstrip bG?

Accuracy of self-monitoring of blood glucose (SMBG) using Chemstrip bG (Bio-Dynamics, Indianapolis, Indiana) was studied in 90 randomly selected children with insulin-dependent diabetes mellitus (IDDM). For 28 children (mean age 8.3 +/- 3.6 yr) a parent routinely read the Chemstrip at home. The remaining 62 children (mean age 13.7 +/- 2.8 yr) read the Chemstrip themselves. Each child or parent analyzed 20 capillary blood samples using Chemstrips and answered a questionnaire on SMBG. The accuracy of SMBG of the group was high (mean correlation coefficient = 0.89 +/- 0.05), but consistency of measurement was variable (mean standard deviation = 1.90 +/- 0.57) and there was a general tendency to underread Chemstrips (mean y-intercept = 1.05 +/- 1.48; mean slope = 0.80 +/- 0.17). For each subject, 0-65% (mean of 34%) of readings were within 10% of the laboratory measurement, and 17-100% (mean 68%) within 20%. These results indicate that most subjects were fairly accurate in reading Chemstrips; however, analysis of accuracy is useful in identifying individuals who are inaccurate or inconsistent in SMBG. Continuing supervision of SMBG is necessary in children with IDDM.

Treatment of familial hypercholesterolemia in children and adolescents: effect of lovastatin. Canadian Lovastatin in Children Study Group.

OBJECTIVE: Familial hypercholesterolemia (FH), an inherited autosomal dominant disorder of lipoprotein metabolism, is associated with premature atherosclerosis. The recommended pediatric therapy consists of dietary intervention and, when necessary, treatment with bile acid-binding resins. However, compliance has been poor in many children. Therefore, our objectives were to determine the efficacy, safety, and tolerance of the short-term use of lovastatin, a 3-hydroxy 3-methylglutaryl coenzyme A reductase inhibitor, in the control of severe FH in a male pediatric population and to evaluate the dose-response relationship. METHODS: Sixty-nine male patients with FH 12.9 +/- 2.4 years of age (mean +/- SD) participated in this multicenter, randomized, double-blind trial. After a 4-week placebo period, the patients were allocated to four treatment groups (lovastatin 10, 20, 30, 40 mg/d) for 8 weeks. Plasma lipid and apolipoprotein (Apo) concentrations were measured every 2 weeks. Clinical and laboratory evidence of adverse events was monitored periodically throughout the study. RESULTS: All lovastatin doses reduced total cholesterol (-17% to -29%), low density lipoprotein cholesterol (-21% to -36%), and ApoB (-19% to -28%) concentrations. A dose-response relationship was seen, and between-group comparisons showed that results were significantly improved up to a dose of 30 mg/d. We observed a 7% increase in high-density lipoprotein cholesterol and a 4% increase in ApoA1 concentrations. The medication was well tolerated by all patients. No serious clinical adverse experience was reported. Lovastatin increased aspartate aminotransferase concentrations, but there was no evidence of a dose-response relationship, and no value exceeded two times the upper limit of normal. No significant change in alanine aminotransferase was observed. Three patients had marked (more than three times the upper limit of normal) asymptomatic elevations in their creatine kinase values, which returned spontaneously to normal, and no action was required regarding the drug.

Analysis of the collagens from the fetal membranes of diabetic mothers.

Changes in the basement membranes associated with the placenta and fetal membranes have been observed in diabetic women, but little is known about the underlying alterations at the biochemical level. Present studies are concerned with the amount, chain composition and carbohydrate content of the collagens from amniotic membranes of women with overt and gestational diabetes. Collagens were obtained from these membranes using pepsin digestion and differential salt precipitation. In comparison with controls, the amounts of the interstitial and type IV collagens remained unchanged while the type V samples showed a moderate increase. However, by the use of reduced pepsinization, a fraction containing primarily type VII collagen and some type VI showed a significant increase in the tissues from diabetics, especially those from overt patients. Slab gel electrophoresis of the latter fractions revealed increased amounts of type VII collagen chains. The collagens from diabetics showed only small and marginally significant increases in their carbohydrate content. These observations suggest that changes in the 'intermediate' collagens as a group may play a role in the connective tissue changes associated with diabetes.

Placental weight in diabetic pregnancies.

The placenta from 30 women with diabetes mellitus were examined and weighed at delivery. Nineteen of these were from women with overt and eleven from women with gestational diabetes. Eleven placentae from normal pregnancies served as controls. There was no difference between the mean +/- s.d. placental weight for the diabetic group and the control group (609 +/- 148 versus 591 +/- 93 g, NS). The mean placental weight ratios for the diabetic group and the control group were also similar (0.98 +/- 0.23 versus 0.89 +/- 0.15, NS). Moreover, there was no difference between the weights and weight ratios of placentae from women with overt (622 +/- 173 g, 1.02 +/- 0.27) and those with gestational diabetes (586 +/- 90 g, versus 0.90 +/- 0.13). Placental weights correlated with birthweights (r = 0.70, P less than 0.01) and with skinfold thickness measurements fo the infants (r = 0.40, P less than 0.05), but neither with gestational ages (r = 0.15, NS) nor with maternal glycosylated haemoglobin levels in the third trimester (r = 0.24, NS). Among the women with overt diabetes, placental weights were greater in those in White's class B and C than those in class D and R (689 +/- 143 versus 530 +/- 177 g; P less than 0.05). In general, placentae from well controlled diabetic patients were not heavier than those from normal pregnant women, although there was an increase in placental weight in White's class B and C, as compared with those in class D and R.

Evaluation of an affinity chromatographic procedure for the determination of glycosylated hemoglobin (HbA1).

An affinity chromatographic method for the determination of glycosylated hemoglobin (HbA1) was evaluated. The procedure was shown to be precise, the within- and between-assay coefficients of variation being less than 5%. It was also shown to correlate well with electrophoresis (r = 0.968) and ion-exchange chromatography (r = 0.916). An inverse relationship was shown to exist between increasing temperature and HbA1 levels measured by affinity chromatography. A statistically significant difference was found for samples run at 20 degrees C and 25 degrees C respectively, suggesting that the method should be run in a temperature-controlled environment. The affinity procedure was also shown not to be affected by the type of anticoagulant, the concentration of hemoglobin in the hemolysate, and acetylation.

Randomized controlled trial of very early continuous distending pressure in the management of preterm infants.

Application of continuous distending pressure at birth (very early CDP) should stabilize the immature airways and reduce the severity of respiratory distress syndrome (RDS) in preterm infants. Eighty-two preterm infants of less than 32 weeks gestation were randomly assigned at birth to early treatment group (TG), in which CDP of 6 cm water pressure was applied at birth by the nasopharyngeal route (NP-CDP), or to control group (CG), in which CDP was applied when indicated for established criteria (pO2 less than 50 mmHg in FiO2 greater than 0.5). Characteristics of the infants in the two groups were comparable. No statistically significant difference between the two groups was found in the incidence of RDS. The course of RDS, and oxygen and ventilatory requirements also did not appear to be changed. In blood gas parameters of most of the time frames, no significant difference was found between the two groups when the results were analyzed according to the assigned group. When the results were analyzed separately for the infants who developed RDS, infants in TG appear to have fared worse from the therapy in terms of oxygenation, as indicated by significantly higher FiO2 (P less than 0.01) and lower a/A (P less than 0.01) values on the third day of the course of RDS, as compared to infants in CG. The incidence of complications was comparable in the two groups. Four infants from TG (9.3%) and one from CG (2.6%) died (P = NS). We conclude that VECDP by nasopharyngeal route does not reduce the incidence of RDS and does not appear to improve the outcome and may worsen the severity of RDS when compared to application of CDP for established criteria.

Residual beta-cell function in children with type 1 diabetes: measurement and impact on glycemic control.

We studied residual beta-cell function in 84 children with IDDM to assess (1) relationship between basal and stimulated C-peptide concentrations; (2) reproducibility of testing (Group 1, n = 20); (3) the effect of exogenous insulin on test interpretation (Group II, n = 20); and (4) impact on metabolic control. Sustacal (a mixed liquid meal) was utilized as the test stimulus. In C-peptide positive subjects (n = 44) there was a strong correlation between basal and peak C-peptide concentrations (r = 0.88, p less than 0.001). In Group 1 subjects, Sustacal proved to be a highly reproducible test stimulus producing identical results on two tests 7-14 days apart. The results of the tests were not affected by the administration of subcutaneous regular insulin prior to the second test in Group II. Peak C-peptide correlated inversely with HbA1, insulin dose, and disease duration (r = -0.29, -0.40, and -0.33 respectively, p less than 0.05) and positively with age (r = 0.34, p less than 0.05). We conclude that Sustacal is a highly reproducible stimulus to residual beta-cell function in IDDM and is not affected by exogenous insulin. This residual insulin secretion has a small but significant effect on glycemic control.

Subclinical diabetes mellitus in the BB rat.

The spontaneously diabetic BB Wistar rat is a well recognized animal model for the study of insulin-dependent diabetes mellitus (IDDM). Previously we have noted hyperglycemia and insulitis in BB rats without clinical diabetes. 121 rats were studied prospectively. 43 (36%) were normal and 64 (52%) developed IDDM suspected by the presence of glycosuria and acute weight loss, and confirmed with pancreatic histology. In the remaining 14 (12%) animals, pancreatic histology was also abnormal, varying from mild insulitis only to moderate insulitis and beta-cell degranulation. Since these rats gained weight normally, had no glycosuria, or hyperglycemia they were designated as having subclinical diabetes. At death, their plasma-insulin concentrations and the amount of extracted pancreatic insulin was intermediate between that of the normal and diabetic group (p less than 0.001). We have identified a group of rats with pancreatic features of diabetes but no clinical expression. Further investigation of this syndrome may reveal clinical, immunological or histological features which protect these animals from the development of overt disease.

Factors affecting insulin antibody binding in children with insulin-dependent diabetes mellitus.

We measured insulin antibody binding in 2 groups of patients: Study 1, 32 children with newly diagnosed IDDM before onset of insulin therapy, and, in 20 of these, 10 days, 1, 3, and 6 months after beginning therapy; and Study 2, 35 children with long-standing IDDM, 20 of whom had free insulin concentrations measured before, and for 2 hours following subcutaneous injection of 0.25 U/kg regular insulin. Almost 35% of new onset subjects had insulin antibody binding above control levels. In those studied prospectively, binding increased significantly with time. Pre-treatment binding did not correlate with later insulin antibody binding nor metabolic control. In Study 1 we have confirmed previous studies showing abnormally high insulin antibody binding in children with IDDM pre-treatment. We have been unable to demonstrate a relationship between this binding and that found 6 months after initiation of therapy. In Study 2, we have shown that insulin antibody binding is not related to either the level of metabolic control or the rate of rise of free insulin levels in children with IDDM.

Dietary triggers of insulin-dependent diabetes in the BB rat.

Environmental "triggers" (including viruses, toxins and dietary factors) have been implicated in the pathogenesis of insulin-dependent diabetes mellitus. Data have suggested a possible role for cow's milk protein (CMP) as a trigger of diabetes. To study this further, 86 BB rats were divided into 2 groups during the weaning period (days 13-25): Group A received rat chow without CMP; Group B, rat chow with 1% CMP added. Each group was subdivided afterwards into 2: Groups A1 and B1 received chow without CMP; Groups A2 and B2, chow with CMP. Animals weaned with chow containing CMP (B1 and B2) had a higher incidence of diabetes (66%) than those weaned without (A1 and A2; 29%, p less than 0.001). The incidence in both B1 and B2 was significantly greater than in either A1 or A2 (p less than 0.05). The highest incidence of diabetes occurred in male rats weaned on rat chow with CMP (90%), the incidence being significantly higher than female rats weaned with (43%) or without CMP (18%) and males weaned without CMP (39%). Thus, it appears that (a) the presence of cow's milk protein in the diet increases the incidence of diabetes in the BB rat; (b) the critical time for exposure to CMP appears to be the weaning period; and (c) male rats appear to be more susceptible to the development of diabetes than female rats, when exposed to this trigger. This supports the hypothesis that dietary triggers may play an important role in the expression of diabetes in the susceptible host and that its prevalent action occurs early in life.

Growth failure after treatment of pediatric brain tumors.

OBJECTIVES: Primary brain tumors are the most common solid tumors that occur in childhood. With improved management of these tumors, there are more survivors with long-term sequelae of radiation and chemotherapy including growth failure. The aim of this study was to assess growth prospectively in children with nonpituitary-related primary brain tumors. METHODS: Forty-one children 3.1 to 13.8 years of age diagnosed consecutively between 1989 and 1992 with a primary nonpituitary-related brain tumor were studied. RESULTS: Of 34 prepubertal children, 14 (41%) were diagnosed as having growth hormone (GH) deficiency. All 14 children were treated with cranial irradiation. During the first year from completion of brain tumor therapy, the annual height velocity of those children confirmed subsequently as being GH-deficient was 3.06 +/- 1.19 cm compared with 5.29 +/- 2.21 cm for those who were not GH-deficient. During the second year, the annual height velocity was 3.29 +/- 1.14 cm per year for the GH-deficient group compared with 5.48 +/- 1.24 cm per year for the non-GH-deficient group. All children with GH deficiency received cranial irradiation and chemotherapy. Two of 34 children developed precocious puberty. Primary hypothyroidism was diagnosed in 6 of 41 children (12%). CONCLUSION: We conclude that GH deficiency and primary hypothyroidism are common after cranial irradiation and chemotherapy for nonpituitary-related brain tumors. Linear growth appears to reflect GH status accurately in children with brain tumors. Precise auxologic evaluation is simple and noninvasive and may reflect more accurately GH status than provocative GH testing. These findings reflect the need for prospective growth monitoring of children with nonpituitary-related brain tumors treated with cranial irradiation and chemotherapy. Early diagnosis of GH deficiency facilitates early initiation of GH therapy and optimization of final height.

The relationship of metabolic control to growth and pubertal development in children with insulin-dependent diabetes.

Growth and pubertal development were studied in 122 children aged 13.4 +/- 2.9 yr (mean +/- SD) with IDDM of 6.1 +/- 3.8 yr duration. Height and weight, pubertal status, insulin dose (u/kg), frequency of insulin administration and HbA1 were measured every 3 months for a minimum period of 1 yr for each child. The mean and distribution of height and height velocity percentiles were normal for boys and girls. The mean weight percentile for boys was increased (62 +/- 27, p less than 0.01), but was normal for girls. The mean and distribution of weight velocity percentiles were normal for both sexes. The mean and distribution of age of onset of Tanner 2 in both boys (11.9 +/- 1.4 yr) and girls (11.2 +/- 1.3) was normal, as was the age of menarche (13.2 +/- 1.2 yr). The mean HbA1 level was 11.1 +/- 2.0% (normal less than 7.5%). There was no correlation of mean HbA1 levels (calculated from 4 or more measurements for each child) with height velocity or with weight velocity percentiles or with mean height or weight percentiles. These results indicate that diabetic control, as reflected by HbA1 levels, was not a major determinant of growth in this group of children with IDDM, who displayed normal growth patterns and pubertal development despite a wide range of HbA1 levels. Normal growth may not reflect optimal metabolic control but "average" control.

Interference of fetal hemoglobin and labile glycosylated hemoglobin with measurements of glycosylated hemoglobin.

We examined the effect of fetal hemoglobin and labile glycosylated hemoglobin on a number of diverse methods used to measure glycosylated hemoglobin. Samples were supplemented with various amounts of cord blood to give proportions of fetal hemoglobin ranging from 1 to 20% of total hemoglobin concentration. Procedures in which the separation of hemoglobin A1 from the major hemoglobin A fraction is based on differences in ionic properties (cation-exchange chromatography and electrophoresis) are subject to interference by fetal hemoglobin, whereas procedures that base the quantitation on other properties (colorimetry and affinity column chromatography) are not. The same procedures that are affected by the presence of fetal hemoglobin are also subject to interference by labile glycosylated hemoglobin. We conclude that the affinity chromatographic and colorimetric methods may give a more nearly accurate determination of glycosylated hemoglobin.

Secular change in birthweight of Asian babies born in Birmingham.

We have studied changes in the birthweight of Asian babies born alive at this hospital between 1968 and 1978. In 1978 Pakistani babies were 139 g heavier but Indian babies only 25 g heavier than 10 years earlier. Contributing to these changes were significantly fewer short mothers and primiparae among Pakistanis, and non-significant increases in gestational age and intrauterine growth (that is, weight centile after allowing for gestational age, parity, and maternal height). Among Indians there were significant increases in maternal height and gestational age, but parity was reduced and intrauterine growth did not increase. In both groups there were fewer teenage mothers, but whereas among Pakinstanis birth intervals of less than one year were less common, there was no such reduction among Indian mothers. The secular change suggests that genetic factors are unlikely to be the major reason why Pakistani babies born in Birmingham are lighter than European babies, and that environmental factors play an important role. Efforts to increase birthweight need to consider both the mothers' physical environment during pregnancy and prepregnancy factors influencing growth in childhood, age at first pregnancy, and birth interval. The study shows a need to describe an 'Asian' population with details of their sub-ethnic structure. The sub-ethnic and secular differences further suggest that a single 'Asian' standard for birthweight and intrauterine growth may be inappropriate; the use of international reference data with which all infants may be compared is preferable.