Gender‐specific decline in perioperative allergic reactions in Norway after withdrawal of pholcodine
Authors: Lars Berg Malvik, Gerrit Hendrik De Pater, Geir Olav Dahle, Anne Berit Guttormsen
Journal: Allergy (2021)

There is a known gender difference in immunological diseases. Women are overrepresented both during fertile years and to a lesser degree before menarche and after menopause, suggesting both genetic and hormonal mechanisms.1 Perioperative allergy and anaphylaxis are rare events and, therefore, challenging to study. In the recent NAP6 studies, the incidence of a severe perioperative reaction is estimated to be 1 in 10 000, and the authors suspected a higher true incidence based on some incomplete case reports not included in their work.1, 2 Mertes et al.3, 4 have demonstrated a female predominance, and Florvaag et al.5 hypothesize possible cross-sensitization with quaternary ammonium ion-containing compounds and the use of such compounds in cosmetics, as a possible explanation. The Norwegian Network for Anaphylaxis under Anesthesia (NARA) has published several studies describing perioperative hypersensitivity reactions in Norway. The effect of the withdrawal of a pholcodine containing cough syrup was evident, with a significant decline in the number of reports and IgE sensitization from 2007 to 2009.6 The purpose of this study was to investigate the influence of gender on the decline in perioperative hypersensitivity reports. We analyzed 1,379 reports from 1997 to 2017, based on standardized reports of patient characteristics, clinical presentation, and laboratory investigations. Severity of the reaction was for additional analyses converted into “Mild” (1–2) and “Severe” (3–5) based on a modified Ring and Messmer scale. Age-group splits were constructed according to the Norwegian national average age of menarche at 13 years and menopause at 51 years. Of the 1,379 reported cases, 461 were men and 918 were women. Median age was 42 years (range 0–89 years). Muscle relaxants were used in 1,023 patients (74.2%). There was a female predominance in all age-groups but more pronounced in women of 14 to 51 years old. There was no significant difference in reaction severity between men and women, men being reported with 51.2% “Mild” reaction and 40.8% “Severe” (remainder missing), while in women 49.2% had a “Mild” and 42.4% had a “Severe” reaction (p = .52). There was no clinically relevant gender difference in the increase in serum tryptase for the different grades of severity (Table 1). From 1997 to 2007, there was a mean of 76 reports per year, and after an initial yearly increase in number of reports following the establishment of the registry, there was a mean of 87 yearly reports from 2001 to 2007. After 2007, the mean number of reports fell to 61, with stable reporting from 2009. There was no change in the case-reporting procedures during the timeframe of this study. The gender difference was significant in both periods of stable reporting. From 2001 to 2007, there was a 72% female predominance (p < .01), and from 2009 to 2017, 60% were women (p < .01) (Figure 1). The allergic phenotype is influenced by sex hormones, where estrogen acts as both anti- and pro-inflammatory, while testosterone and progesterone are anti-inflammatory.7-14 Finding a female predominance in perioperative hypersensitivity is not surprising. The degree to which women are overrepresented prior to the withdrawal of pholcodine is more pronounced than in similar reports.3, 15 A registry analysis by Saager et al.16 showed a more modest gender difference in the United States where pholcodine is not available. After withdrawal of pholcodine from the Norwegian market, we observed a decline in the number of reports from about 90 to 60 per year. Most of this reduction had taken place among women. If this gender-specific decline in reports is attributable to the withdrawal of Pholcodine, a possible explanation could be differences in patterns of consumption between men and women. From sales numbers, Florvaag estimated that about 40% of the Norwegian population has been exposed to pholcodine.5 The syrup was sold over the counter until 2007, and we have no information about different patterns of use. If not explained by behavioral mechanisms, there may be a gender difference in the way immunoglobulin-producing cell lines react to antigens. The nature of this difference could constitute an interesting theme of future research. We did not find any gender difference in total IgE. There was no significant difference in absolute or relative serum tryptase levels, but conclusions based on this finding are problematic as we do not know exactly at what time blood was drawn relative to the debut of the reaction. However, there is no reason to believe that this would be selective to either gender. There was no difference in the clinical severity of the reaction between men and women; this is in line with similar biochemical findings. Hox et al.12 have shown in a mouse model that female mice had more severe reactions when exposed to an allergic stimulus, a finding not supported by our data. Their study investigates the influence of a single hormone, which may offer one explanation. We did not measure serum level of hormones in our patients, and we have no information on contraceptive use. The proportion of reported reactions that took place during cesarean section is not known. Surgery at term pregnancy could constitute a particularly challenging hormonal event, but the inherent risks of the procedure could also represent a bias as it represents an important pharmacological and physiological stress to the patient, which could be misinterpreted as an allergic reaction. Women are overrepresented in the database of the Norwegian Network for Anaphylaxis under Anesthesia, accounting for two thirds of reported cases. After the withdrawal of pholcodine from the Norwegian market, the gender difference has become less pronounced. The reduction in reports was more pronounced in women aged 14–51 years old than in other patient groups. If attributable to the withdrawal of pholcodine, this finding could represent an interesting theme for further research. The authors would like to thank Dr. Erik Florvaag for his input in the process of writing this paper. The authors declare there are no funders. The authors declare that there are no conflicts of interest. The authors declare eligibility for author listing. Lars Berg Malvik contributed to conceptualization, formal analysis, visualization, original draft preparation, and review and editing. Gerrit Hendrik De Pater contributed to data curation, validation, and review and editing. Geir Olav Dahle contributed to validation, and review and editing. Anne Berit Guttormsen contributed to supervision, and review and editing. 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