Pitfalls in the design and analysis of paediatric clinical trials: a case of a ‘failed’ multi-centre study, and potential solutions

Aim: To increase awareness of possible pitfalls in the design and analysis of a multi-centre randomized clinical trial and to give an overview of alternative study designs and their consequences for power analyses in case of limited availability of trial participants

In utero exposure to coumarins and cognition at 8 to 14 years old

Objective. To assess the cognitive abilities in school-aged children who have been exposed to coumarins in utero. Background. Coumarin derivatives are an effective option for anticoagulant therapy in pregnant women. However, case reports describe anomalies of the fetal central nervous system after in utero exposure to coumarins. It is unclear whether prenatal exposure has an effect on cognitive functioning later in childhood. Methods. The exposed cohort consisted of 291 children from mothers who were prospectively registered because of coumarin treatment during pregnancy. The nonexposed cohort included 253 age-matched peers. An IQ was estimated using subtests of the Weschler Intelligence Scale for Children-Revised. Educational achievement was examined with tests for reading, spelling, and arithmetic. In addition, schoolteachers were asked to judge performance on language and arithmetic. The observers were not aware of the exposure status of the child. Results. No differences in mean IQ were found between the exposed and nonexposed cohort (mean difference: -1.1; 95% confidence interval [CI]: -3.2-1.1), but an IQ score below 80 was found in 11 children in the exposed compared with 3 children in the nonexposed cohort (odds ratio [OR] = 3.1; CI: 0.8-11.6). Regarding the tests for educational achievement, exposed children as a group performed as well as nonexposed controls. Exposed boys, in comparison with nonexposed boys, showed a higher frequency of poor performance on reading (OR = 2.9; CI: 1.1-7.4) and spelling (OR = 2.5; CI: 1.0-6.0). Conclusion. Cognitive functioning in coumarin-exposed children does not differ from nonexposed controls, but a minority of children seem to be prone to the potential negative effects of coumarins during pregnancy

In utero exposure to coumarins and cognition at 8 to 14 years old

Objective. To assess the cognitive abilities in school-aged children who have been exposed to coumarins in utero. Background. Coumarin derivatives are an effective option for anticoagulant therapy in pregnant women. However, case reports describe anomalies of the fetal central nervous system after in utero exposure to coumarins. It is unclear whether prenatal exposure has an effect on cognitive functioning later in childhood. Methods. The exposed cohort consisted of 291 children from mothers who were prospectively registered because of coumarin treatment during pregnancy. The nonexposed cohort included 253 age-matched peers. An IQ was estimated using subtests of the Weschler Intelligence Scale for Children-Revised. Educational achievement was examined with tests for reading, spelling, and arithmetic. In addition, schoolteachers were asked to judge performance on language and arithmetic. The observers were not aware of the exposure status of the child. Results. No differences in mean IQ were found between the exposed and nonexposed cohort (mean difference: -1.1; 95% confidence interval [CI]: -3.2-1.1), but an IQ score below 80 was found in 11 children in the exposed compared with 3 children in the nonexposed cohort (odds ratio [OR] = 3.1; CI: 0.8-11.6). Regarding the tests for educational achievement, exposed children as a group performed as well as nonexposed controls. Exposed boys, in comparison with nonexposed boys, showed a higher frequency of poor performance on reading (OR = 2.9; CI: 1.1-7.4) and spelling (OR = 2.5; CI: 1.0-6.0). Conclusion. Cognitive functioning in coumarin-exposed children does not differ from nonexposed controls, but a minority of children seem to be prone to the potential negative effects of coumarins during pregnancy

Adherence to a guideline for coumarins in pregnancy

OBJECTIVE: To asses the adherence in daily clinical practice to a guideline for anticoagulation during pregnancy. METHODS: The Dutch anticoagulation clinics developed a pregnancy guideline for anticoagulant therapy in order to avoid foetal exposure to coumarins between the 6th and 9th week of gestation. Anticoagulation was studied in 282 prospectively-registered pregnant women, who were treated by 26 different anticoagulation clinics. RESULTS: The guideline was adhered to in 93% of treated women. Conforming to the guideline, the majority of patients commenced anticoagulation with heparin in the first trimester (n = 81) or started treatment from the second trimester onwards (n = 168). At the time of conception, 31 anticoagulated women were on coumarin treatment. In 13 of these patients (42%), coumarins were withdrawn before the 6th gestational week. In two pregnant women coumarin therapy started unintentionally during the first trimester of gestation. CONCLUSION: The present study shows that the guideline under study is useful in daily clinical practice. A careful instruction of women of child-bearing age who need medication remains important

Intravenous immunoglobulin versus observation in childhood immune thrombocytopenia:A randomized controlled trial

Management of children with newly diagnosed immune thrombocytopenia (ITP) consists of careful observation or immunomodulatory treatment. Observational studies suggest a lower risk of chronic ITP in children after intravenous immunoglobulin (IVIg) treatment. In this multicenter randomized trial, children aged 3 months-16 years with newly diagnosed ITP, platelet counts ≤20 × 109/L and mild to moderate bleeding were randomly assigned to receive either a single infusion of 0.8 g/kg IVIg or careful observation. Primary outcome was development of chronic ITP, at time of study initiation defined as a platelet count < 150 × 109/L after 6 months. Two hundred and six children were allocated to receive IVIg (n=102) or careful observation (n=104). Chronic ITP occurred in 18.6% in the IVIg group and in 28.9% in the observation group (relative risk [RR] 0.64; 95% confidence interval [CI] 0.38-1.08). Platelet counts < 100 × 109/L at 12 months (current definition of chronic ITP) were observed in 10% children in the IVIg group and in 12% in the observation group (RR 0.83; 95% CI 0.38-1.84). Complete response rates in the first three months were significantly higher in the IVIg group. IgG- Fc receptor IIb genetic variations were associated with early complete response in both groups. Grade 4-5 bleeding occurred in 9% in the observation group versus 1% in the IVIg group. IVIg treatment at diagnosis in children with ITP did not result in a lower rate of chronic ITP. In the IVIg group higher early complete response rates and less bleeding events were observed. This trial was registered at www.trialregister.nl as NTR 1563