Bengt-Erik Wiholm

Delivery outcome after the use of antidepressants in early pregnancy

AbstractObjectives: To investigate delivery outcome after the use of antidepressants in early pregnancy. Methods: Using an ongoing prospective recording of drug use in early pregnancy, 969 women were identified who reported the use of antidepressants: 531 used only SSRI (selective serotonin re-uptake inhibitor) drugs (mostly citalopram, 375 exposures), 423 used only other antidepressants, and 15 used both. Outcome was compared with all births in the population. Results: Women using these drugs were older and smoked more than three times as often as other women. There seemed to be an excess of high parity women. The frequency of multiple births was lower than expected, resulting from too few twin births in women who had used SSRI. Gestational duration among singletons was shorter but it did not affect infant survival and was similar after the use of SSRI or non-SSRI antidepressants, perhaps the result of uncompensated for confounding or related to the underlying disease. Infants were somewhat heavier than expected, notably after non-SSRI treatment. No increase was seen in congenital abnormalities, observable in the perinatal period. Conclusions: Based on this database, the use of antidepressants in early pregnancy does not seem to carry any significant risk for the infant that is detectable during the newborn period.

Drugs in the aetiology of agranulocytosis and aplastic anaemia

Abstract:  Agranulocytosis and aplastic anaemia are rare but serious conditions known to be caused by numerous drugs. Most of what is known or suspected about the aetiology is based on case reports, with only a few formal epidemiological studies that provide quantitative estimates of risk. Updated results have been obtained from a combined analysis of data from 3 case‐control studies that used similar methods: the International Agranulocytosis and Aplastic Anemia Study (IAAAS), conducted in Israel and Europe; a study conducted in the northeast US; and a study conducted in Thailand. Totals of 362 cases of agranulocytosis, 454 cases of aplastic anaemia and 6458 controls were included in the analyses. The IAAAS and Thai study were population‐based, providing estimates of the incidence of the 2 dyscrasias. The overall annual incidence of agranulocytosis in the ambulatory population was 3.4/106 in the IAAAS and 0.8/106 in Thailand; by contrast the incidence of aplastic anaemia was 2.0/106 in the IAAAS and 4.1/106 in Thailand. A total of 21 compounds were significantly associated with an increased risk of agranulocytosis in the IAAAS and US studies. Excess risks ranged from 0.06 to 13 cases/106 users/wk; the most strongly associated drugs were procainamide, anti‐thyroid drugs and sulphasalazine. An association with drugs that had previously been suspected was also seen in Thailand. The overall aetiologic fractions of agranulocytosis due to drug use were 62% in the IAAAS, 72% in the US and 70% in Thailand. Eleven drugs were significantly associated with an increased risk of aplastic anaemia, with excess risks ranging from 1.4 to 60 cases/106 users in a 5‐month period. The most strongly associated drugs were penicillamine, gold and carbamazepine. Aetiologic fractions were 27% in the IAAAS, 17% in the US and 2% in Thailand, which paralleled the prevalence of use of associated drugs in the 3 populations. The present results confirm that agranulocytosis is largely a drug‐induced disease, with similar proportions accounted for in 3 disparate geographic regions. By contrast, although many of the expected associations were observed for aplastic anaemia, most of the aetiology is not explained by drugs. For all associated drugs, the excess risks are sufficiently low that blood dyscrasias should not figure prominently in the balancing of risks and benefits.

Angio-oedema in relation to treatment with angiotensin converting enzyme inhibitors.

OBJECTIVE--To evaluate and describe the clinical course of angio-oedema reactions induced by angiotensin converting enzyme inhibitors. DESIGN AND METHODS--All reports of angio-oedema reactions associated with angiotensin converting enzyme inhibitors submitted to Swedish Adverse Reactions Advisory Committee were reviewed and the clinical courses summarised. Numbers of cases judged to be induced by angiotensin converting enzyme inhibitors were related to their annual usage, estimated from total sales of defined daily doses, as well as to the estimated number of new patients. All cases of angio-oedema associated with angiotensin converting enzyme inhibitors reported to the World Health Organisations international drug information system were also summarised. RESULTS--36 of the 38 reported cases in Sweden between 1981 and 1990 were judged to be related to angiotensin converting enzyme inhibitors. During 1981 through 1990, altogether 1309 cases of angio-oedema associated with angiotensin converting enzyme inhibitors were registered with the international drug information system. The incidence of reported cases of angio-oedema increased largely in parallel with the increased sales (usage) of angiotensin converting enzyme inhibitors. Of the 36 Swedish patients, 77% experienced the reaction within the first three weeks after starting treatment. 10 patients needed hospitalisation, two of whom had life threatening laryngeal obstruction. With one exception all 36 patients were free of symptoms within one week after discontinuing the drug. CONCLUSIONS--Angio-oedema induced by angiotensin converting enzyme inhibitors is a rare but potentially life threatening reaction, which in most instances occurs shortly after the start of treatment. Any patient in whom the reaction is suspected should have the treatment interrupted and, if necessary, be admitted for observation.

Nonsteroidal anti‐inflammatory drug use in relation to major upper gastrointestinal bleeding

In a study in the United States, Sweden, and Hungary, 335 cases of gastric bleeding without predisposing factors were compared with 670 control subjects, and 239 cases of duodenal bleeding were compared with 489 control subjects. For aspirin taken at least every other day during the week before the onset of bleeding (regular use), the relative risk of gastric bleeding was 4.4 (95% confidence interval [CI], 2.9 to 6.7); for occasional use, it was 3.3 (95% CI, 2.1 to 5.0). For ibuprofen, the corresponding estimates were 1.0 (95% CI, 0.4 to 2.6) and 1.1 (95% CI, 0.5 to 2.4). For naproxen, the estimate for regular use was 4.0 (95% CI, 1.5 to 11). The estimates for any use of piroxicam (crude estimate), indo‐methacin, and diclofenac during the week before onset were 18 (95% CI, 4.1 to 83), 1.6 (95% CI, 0.4 to 5.9), and 0.9 (95% CI, 0.2 to 4.2), respectively. The corresponding relative risks of duodenal bleeding were 7.1 (95% CI, 4.2 to 12) and 2.2 (95% CI, 1.3 to 3.7) for the regular and occasional use of aspirin, 2.4 (95% CI, 0.5 to 11) and 0.8 (95% CI, 0.3 to 2.0) for ibuprofen, 12 (95% CI, 2.8 to 54) and 9.9 (95% CI, 2.3 to 44) for naproxen, 17 (95% CI, 3.6 to 79) for any use of piroxicam (crude estimate), and 1.7 (95% CI, 0.2 to 14) for any use of indomethacin. There was a significant trend in the risk of gastric bleeding with increasing dose of regular aspirin use (p = 0.002). The relative risk estimates for the regular use of 325 mg or less were significantly elevated for both gastric and duodenal bleeding at 3.1 and 6.4, respectively.

The risk of acute major upper gastrointestinal bleeding among users of aspirin and ibuprofen at various levels of alcohol consumption

Objective:Major upper gastrointestinal bleeding (UGIB) is the most important adverse effect of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs). Alcoholic beverages also precipitate UGIB. This analysis was conducted to evaluate whether the deleterious effects of NSAIDs are further increased among drinkers.Methods:An interview-based, case-control study was conducted in the U.S. and Sweden; 1224 patients hospitalized with acute major UGIB due to newly occurring peptic ulcer or gastritis were compared to 2945 neighbor controls.Results:Compared with those who drank less than one drink/wk, the relative risk of acute UGIB increased with increasing alcohol consumption, rising to 2.8 among those who drank ≥21 drinks/wk. Among current drinkers, the relative risk of acute UGIB due to the use of aspirin was raised at all levels of alcohol consumption; the estimate for aspirin taken at least every other day (regular use) at doses of >325 mg among all current drinkers combined was 7.0; for regular use at lower doses, the corresponding estimate was 2.8, and for any occasional use, it was 2.4. All estimates were statistically significant. Data for ibuprofen were more limited, but the relative risk estimates did not appear to vary consistently with level of alcohol consumption. For regular use (all doses combined), the estimate among all drinkers combined was significantly elevated, at 2.7; occasional ibuprofen use was not associated with UGIB (1.2). There were insufficient data to evaluate other NSAIDs according to alcohol consumption.Conclusions:The findings suggest that acute UGIB is similarly associated with the use of the two most common nonprescription NSAIDs, aspirin and ibuprofen, at all levels of alcohol consumption. As heavy alcohol intake independently increases the risk, the incidence of UGIB is highest among persons who are both heavy drinkers and users of aspirin or ibuprofen.

Metformin-associated lactic acidosis in Sweden 1977-1991.

SummarySince the withdrawal of phenformin in 1978, the use of metformin has increased from 13,500 to 22,00 patient years/year. During the period 1977–91 a total of 18 cases of metformin — associated acidosis was reported, of which 16 had lactic acidosis.The incidence of reported acidosis and lactic acidosis decreased from 1.50 cases per 10,000 patient years in 1977–81 to 0.24 cases per 10,000 patient years 1987–91, probably due to lower doses doses and reduced usage in the very old. All the reports described patients with several other concomitant diseases, mainly cardiovascular and renal, when the acidosis was diagnosed.It is important continuously to re-evaluate metformin therapy and to stop treatment at the onset of impaired renal or cardiovascular function.

Quality criteria for early signals of possible adverse drug reactions

The main function of the World Health Organisations International Collaborative Programme on Drug Monitoring is to provide a reliable early warning of possible health hazards caused by medicines. Described here is an attempt to devise criteria that would produce a well-founded early signal of an adverse reaction on the basis of reports sent in by national collaborating centres and combined in the WHO database. To reduce the frequency of spurious associations (false-positive signals) it is suggested that publication be delayed until a few case-histories meeting the suggested criteria have been sent in. The criteria were tested retrospectively against early published case-reports on drug-associated agranulocytosis. 19 suspected associations were examined and a signal in the database was defined by there being three or more cases containing stipulated information about the patient and the treatment. The WHO database had reports on all the associations, suggested criteria for a signal being met in 15 instances. This signal was present when the first case was published in 7 instances and within three months of first publication in 1. Moreover, in 3 instances where publication came first the cases presented had been collected by a national drug monitoring centre. The WHO databank has the potential to provide doctors and scientists with signals which then should be evaluated in detail.

Epidemiology of adverse reactions to carbamazepine as seen in a spontaneous reporting system

A survey was made of 505 reports on 713 adverse reactions to carbamazepine submitted to the Swedish Adverse Drug Reactions Advisory Committee from 1965–1987. For the period after 1972, the relation between the reports and sales statistics could be investigated. The total incidence of reported adverse reactions to carbamazepine was 4.5 per million defined daily doses (DDD), corresponding to 2.7 per million prescribed daily doses (PDD). Most often reported were skin reactions (48%), but reports on haematological (12%) and hepatic disorders (10%) were also frequent. Virtually all hepatic disorders and severe skin reactions, as well as the majority (60%) of the haematological reactions, occurred within the first 2 months of treatment. In view of the very low incidence of reported serious blood dyscrasias, such as pancytopenia (0.04/million PDD) and agranulocytosis (0.06/million PDD), continuous haematological monitoring seems to be of little value. The elderly appear to be at increased risk of developing blood dyscrasias and liver reactions, and alcohol abusers seem to represent a high‐risk group for developing serious skin reactions.

Dyspnoea, asthma, and bronchospasm in relation to treatment with angiotensin converting enzyme inhibitors.

Abstract Objective: To evaluate the occurrence of asthma and dyspnoea precipitated or worsened byangiotensin converting enzyme inhibitors. Design: Summary of reports of adverse respiratory reaction in relation to treatment with angiotensin converting enzyme inhibitors that were submitted to Swedish Adverse Drug Reactions Advisory Committee and to World Health Organisations international drug information system until 1992. Sales of angiotensin converting enzyme inhibitors in Sweden were also summarised. Subjects: Patients receiving angiotensin converting enzyme inhibitors who reported adverse respiratory reactions. Main outcome measures: Clinical characteristics of adverse reactions of asthma, bronchospasm, and dyspnoea. Results: In Sweden 424 adverse respiratory reactions were reported, of which most (374) were coughing. However, 36 patients had averse drug reactions diagnosed as asthma, bronchospasm, or dyspnoea. In 33 of these cases the indication for treatment with angiotensin converting enzyme inhibitors was hypertension, in only three heart failure. The respiratory symptoms occurred in about half of the patients within the first two weeks of treatment, and about one third needed hospitalisation or drug treatment. Dyspnoea symptoms occurred in conjunction with other symptoms from the airways or skin in 23 out of the 36 cases. In the WHO database there were 318 reports of asthma or bronchospasm, 516 reports of dysponea, and 7260 reports of cough in relation to 11 different angiotensin converting enzyme inhibitors. Conclusion: Symptoms of airway obstruction in relation to treatment with angiotensin converting enzyme inhibitors seem to be a rare but potentially serious reaction generally occurring within the first few weeks of treatment.

Concepts in risk-benefit assessment. A simple merit analysis of a medicine?

SummaryThe term ‘benefit-risk ratio’ is often used as a general term linked to the use of a medicine. To balance risk and benefit is, however, a very complex exercise. For most medicines the benefits are limited to a few indications and for an individual patient there is usually only a single benefit sought but the potential risks are multiple.Perceptions of risks versus benefits are influenced to a great extent by the context in which they occur. Thus, perception of risk may be different to actual risk. In the end in any given situation, the acceptable risk-to-benefit balance is an individual judgement on the part of the patient or the prescriber.For newer medicines, where there is likely to be limited experience, conser-vative estimates of the overall merit seem preferable so that the prescriber will use the drug critically. Subsequently, re-evaluation of the risk-to-benefit balance is necessary as greater knowledge of efficacy and adverse effects is acquired.It is possible to provide a general ‘principle of threes’ structure for a merit assessment based upon the concepts of seriousness, duration and incidence as related to disease indication, disease amelioration by a medicine, and the adverse effects ascribed to the medicine. This allows a rapid first comparison of medicines for a given indication.In using this general conceptual model in a transparent fashion for a given hypothesis and context, it is possible to identify the essential data used and assumptions involved that make up a merit statement. The quality and value, particularly of risk data, is problematic. Risk perception is an issue that needs to be clearly identified alongside a merit analysis. A simple merit assessment should pave the way for more focused studies.