Postponing or eliminating red blood cell transfusions of very low birth weight neonates by obtaining all baseline laboratory blood tests from otherwise discarded fetal blood in the placenta.

BACKGROUND: Safely reducing the proportion of very low birth weight neonates (<1500 g) that receive a red blood cell (RBC) transfusion would be an advance in transfusion practice. STUDY DESIGN AND METHODS: We performed a prospective, single-centered, case-control, feasibility analysis, preparatory to designing a definitive trial. Specifically, we sought to determine whether we could obtain all baseline neonatal intensive care unit blood tests from the placenta, after placental delivery, thereby initially drawing no blood from the neonate. RESULTS: Ten cases where all baseline blood tests were drawn from the placenta, and 10 controls where all tests were drawn from the neonate, were closely matched for birth weight, gestational age, sex, and race. Early cord clamping was used for all 20. Over the first 18 hours the hemoglobin increased in nine cases versus two controls (p = 0.005). During the first 72 hours one case versus five controls qualified for and received an RBC transfusion. In the first week the cases received four transfusions and the controls received 16 (p = 0.02). None of the cases had an intraventricular hemorrhage (IVH) but four of the controls had a Grade 1 and two had a Grade 3 (p = 0.01). CONCLUSION: We speculate that this method is feasible and generally postpones the first RBC transfusion until beyond the period of peak vulnerability to IVH.

Signal generation in the New Zealand Intensive Medicines Monitoring Programme: a combined clinical and statistical approach.

The New Zealand Intensive Medicines Monitoring Programme (IMMP) undertakes prospective observational cohort studies on selected new drugs in the early postmarketing period using prescription-event monitoring (PEM) methodology with the purpose of identifying signals of previously unrecognised ADRs and establishing risk profiles for each drug. Events are reviewed by a physician and a relationship is established between each event and the drug. The events are then sorted into reactions and incidents. The latter are used to assist signal detection and control for bias. Rates for reports, reactions and incidents are used to assess the adequacy of reporting, signal detection and identification of confounders. Most signals are identified by clinical evaluation of the reports at a stage when statistical analyses are unlikely to have the power to detect them with confidence. The incident group is used for signal detection and controlling for bias. A low reporting rate indicates that certain types of event are unlikely to be reported. A systematic review of the original case reports at the site of collection provides the best opportunity for early signal detection. More resources need to be invested in the training and support of clinical evaluators. Categorising events into reactions and incidents gives added value to the data. Rates of reporting should be quoted with the results of cohort studies to facilitate assessment of their power to detect new signals.

Linking pharmacovigilance with pharmacogenetics.

The ability to identify individuals who are susceptible to adverse drug reactions (ADRs) has the potential to reduce the personal and population costs of drug-related morbidity. Some individuals may show an increased susceptibility to certain ADRs through genetic polymorphisms that alter their responses to various drugs. We wished to establish a methodology that would be acceptable to members of the general population and that would enable estimation of the risks that specific genetic factors confer on susceptibility to specific ADRs. Buccal swabs were selected as a minimally invasive method to obtain cells for DNA extraction. We wished to determine whether DNA of sufficient quantity and quality could be obtained to enable genotyping for two different polymorphic genes that code for enzymes that are widely involved in drug disposition. This article describes a small pilot study of methodology developed in the New Zealand Intensive Medicines Monitoring Programme (IMMP) to link prescription event monitoring (PEM) studies with pharmacogenetics. The methodology involves a nested case-control study design to investigate whether patients with genetic variants in P-glycoprotein (P-gp) and cytochrome P450 (CYP) 2C9 are more susceptible to psychiatric or visual disturbances following cyclo- oxygenase-2 inhibitor use (ADR signals identified in the IMMP database) than matched control patients taking the medication without experiencing any ADRs. It was concluded that the use of buccal swabs is acceptable to patients and provides DNA of sufficient quantity and quality for genotyping. Although no differences in the distribution of genotypes in the case and control populations were found in this small study, case-control studies investigating genetic risks for ADRs using drug cohorts from PEM studies are possible, and there are several areas where population-based studies of genetic risk factors for ADRs are needed. Examples are discussed where research in large populations is required urgently. These are: (i) genetic variations affecting P-gp function; (ii) variations affecting drugs metabolised by CYP2C9 and other polymorphic CYP enzymes; (iii) genetic variation in beta-adrenergic receptors and adverse outcomes from beta-adrenoceptor agonist therapy; and (iv) genetic variation in cardiac cell membrane potassium channels and their association with long QT syndromes and serious cardiac dysrhythmias. Such studies will help to identify factors that increase the risk of unwanted outcomes from drug therapy. They will also help to establish in what circumstances genotyping should be performed prior to commencing drug treatment and in tailoring drug treatment for individual patients.

Successful treatment with octreotide of spontaneous chylothorax in a premature infant.

A 2-month-old premature infant developed a spontaneous chylothorax. Medical therapy (chest tube drainage, parenteral alimentation) and thoracic duct ligation at 103 days of age had no effect. Drainage ceased during an octreotide infusion. The effusion recurred after octreotide was stopped, and responded completely to a longer course of therapy. Octreotide offers a substantial advantage over current medical management to some babies with spontaneous chylothorax.

Use of the New Zealand Intensive Medicines Monitoring Programme to study the levonorgestrel-releasing intrauterine device (Mirena).

PURPOSE: To demonstrate how the Intensive Medicines Monitoring Programme (IMMP) can be used to monitor adverse events associated with an intrauterine device, using the levonorgestrel-releasing intrauterine device (Mirena) as an example. METHODS: A long-term prospective observational cohort study using Prescription Event Monitoring (PEM) is currently being undertaken in women using Mirena in New Zealand. This report describes the method used and reports the early results for those women who used the device between March 1998 and March 2001. Adverse events were recorded by inserting doctors and general practitioners on registration forms and systematic follow-up questionnaires. RESULTS: Between March 1998 and March 2001, the IMMP received 3519 registration forms for insertions in 3452 women. 'Difficult insertion' was the most frequently reported event (3.6% of all insertions). Approximately, 2% of the Mirena insertions were carried out under GA and there were three uterine perforations (0.9 per 1000 insertions) in the total cohort. To date, follow-up questionnaires have been processed for 495 patients. The response rate for these was 83%. CONCLUSION: As adapted in the IMMP, PEM is an effective tool for the early post-marketing surveillance of an intrauterine device in real life clinical practice.

Disturbance of vision by COX-2 inhibitors.

In this review, 35 cases of acute, reversible, sometimes severe, disturbances of vision closely associated with the use of celecoxib or rofecoxib are described. These were identified from three different databases using strict selection criteria. The events included temporary blindness, visual field defect, scotoma, teichopsia, blurred vision, decreased vision and abnormal vision. The reactions had a mean onset time of 9.5 days and recovery occurred within 3 days following withdrawal of the drug. The reactions do not appear to be related to age, gender, dose, or indication for use. The incidence of reported cases is estimated to be not less than 5 per 10,000 patients. Possible mechanisms for this type of reaction are described. The most likely appears to be the result of interference with the retinal blood supply through reduced production of prostanoids. Genetic polymorphisms that affect drug metabolism or uptake could be risk factors and are discussed along with suggestions for research.

Activation of pain by sumatriptan.

OBJECTIVE: To demonstrate that sumatriptan may induce activation or aggravation of pain at sites of inflammation caused by trauma or disease. METHODS: Case reports from the national pharmaco vigilancecenters of 2 countries, The Netherlands and New Zealand, are presented. These reports come from programs that use 2 methodologies to monitor drugs for adverse reactions: spontaneous reporting and a prospective observational cohort study. The potential mechanisms for pain production by sumatriptan are discussed in detail. RESULTS: Thirteen case reports of activation of pain by sumatriptan following injury and 8 associated with inflammatory diseases are presented. Most patients had one or more positive rechallenges. This type of reaction occurred at a higher rate with the subcutaneous formulation than with the oral preparation. Pain mostly was severe but short-lasting; pain was prolonged in some patients with inflammatory disease. CONCLUSIONS: A strong association has been demonstrated between the use of sumatriptan and the production of pain at sites of inflammation, and there is a plausible pharmacological mechanism for this reaction. Pain activation may be a class effect of the selective serotonergic agonists used in the treatment of migraine.