GENERAL GYNECOLOGY Disease expression in women with hereditary angioedema Laurence Bouillet, MD, PhD; Hilary Longhurst, MA, MRCP, PhD; Isabelle Boccon-Gibod, MD; Konrad Bork, MD; Christophe Bucher, MD; Anette Bygum, MD; Teresa Caballero, MD, PhD; Christian Drouet, PhD; Henriette Farkas, MD, PhD; Christian Massot, MD; Erik W. Nielsen, MD, PhD; Denise Ponard, PharmD; Marco Cicardi, MD OBJECTIVE: Fluctuations in sex hormones can trigger angioedema at- tacks in women with hereditary angioedema. Combined oral contra- ceptive therapies, as well as pregnancy, can induce severe attacks. The course of angioedema may be very variable in different women. STUDY DESIGN: Within the PREHAEAT project launched by the European Union, data on 150 postpubertal women with hereditary angioedema were collected in 8 countries, using a patient-based questionnaire. RESULTS: Puberty worsened the disease for 62%. Combined oral con- traceptives worsened the disease for 79%, whereas progestogen-only pills improved it for 64%. During pregnancies, 38% of women had more attacks, but 30% had fewer attacks. Vaginal delivery was usually uncomplicated. Attacks occurred within 48 hours in only 6% of cases. Those more severely affected during menses had more symptoms dur- ing pregnancies, suggesting a hormone-sensitive phenotype for some patients. CONCLUSION: The course of angioedema in women with C1 inhibitor deficiency is affected by physiologic hormonal changes; consequently, physicians should take these into account when advising on management. Key words: angioedema, estrogens, pregnancies, puberty Cite this article as: Bouillet L, Longhurst H, Boccon-Gibod I, et al. Disease expression in women with hereditary angioedema. Am J Obstet Gynecol 2008;199:484.e1-484.e4. H ereditary angioedema (HAE) is a rare disease caused by C1 inhibitor (C1Inh) deficiency with an estimated prevalence between 1 in 10, 000 and 1 in 50,000. 1 This disease is characterized by episodic subcutaneous and submucosal edema. It is inherited in an autosomal dominant manner: consequently, both women and men can be affected. HAE attacks appear to depend on bradykinin release 2 and respond to an antagonist of bradykinin receptors. 3 It is known that HAE is influenced by the fluctuation of female hormones, but individual women vary greatly in their hormone sensitivity. Variations appear in frequency of angioedema symptoms according to the different female life stages of childhood, puberty, menses, pregnancies, and menopause. Reports have noted a close relationship between female hormones and angioedema. 4 Yip et al 5 published the case of a mother and her daughter whose HAE-related symp- toms appeared to be sex hormone de- pendent. Their first attack happened around puberty; angioedema worsened during premenstrual periods and when they took combined oral contraceptives. The report of a woman 6 with HAE and Turner’s syndrome is also very interest- ing: starting physiologic estrogen re- placement at the age of 34 years old, this woman experienced a worsening, both in the severity and in the frequency of angioedema attacks. McGlinchey et al 7 described a patient whose symptoms of HAE emerged after starting hormone re- placement therapy (HRT). Bork et al 8 re- ported that women with HAE had more severe disease than men, and that com- bined oral contraceptives or HRTs can exacerbate HAE: indeed, 63% of women with HAE taking these drugs reported new or worsened angioedema. The women studied had variable numbers of attacks and appeared to show different degrees of estrogen sensitivity. When a physician takes care of women with a HAE, some issues have to be ad- dressed: the choice of contraception, management of pregnancies and deliver- ies, and the selection of an effective pro- phylactic treatment without side effects. Danazol therapy is an effective prophy- lactic treatment for HAE, but it may be associated with side effects, especially for women. There is a lack of published lit- erature about clinical behavior and man- From the Department of Internal Medicine (Drs Bouillet, Boccon-Gibod, and Massot) and the Immunology Laboratory (Dr Drouet and Ms Ponard), Grenoble University Hospital, Grenoble, France; Barts and the London NHS Trust (Dr Longhurst), London, England, UK; Department of Dermatology (Dr Bork), Johannes Gutenberg University, Mainz, Germany; University Hospital (Dr Bucher), Zurich, Switzerland; the Department of Dermatology (Dr Bygum), Odense University Hospital, Odense, Denmark; University Hospital La Paz (Dr Caballero), Madrid, Spain; Third Department of Internal Medicine (Dr Farkas), Semmelweis University, Budapest, Hungary; the Department of Anesthesiology, Nordland Hospital, Bodo, and the University of Tromsø, Tromsø, Norway (Dr Nielsen); and Dipartimento di Medicina Interna (Dr Cicardi), Università degli Studi di Milano, University of Milan, Milan, Italy. Received April 25, 2007; revised April 9, 2008; accepted April 17, 2008. Reprints not available from the authors. This project was performed within the framework of the PREHAEAT project (QLG1-CT-2002- 01359) of the European Union and was supported by grants from the thematic action 5 of the French 2002 Programme Hospitalier de Recherche Clinique PHRC. 0002-9378/$34.00 • © 2008 Mosby, Inc. All rights reserved. • doi: 10.1016/j.ajog.2008.04.034 Research www. AJOG.org 484.e1 American Journal of Obstetrics & Gynecology NOVEMBER 2008