Review: Special Considerations in Treating Hereditary Angioedema in Women

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Hereditary angioedema (HAE) is a rare disease characterized by recurrent, self-limiting episodes of severe swelling of the skin and mucous membranes in the gastrointestinal tract and upper airway. Episodes usually begin in childhood or adolescence and become more frequent after puberty. Attacks in the airway can be life-threatening.

HAE types I and II are caused by mutations in the C1NH gene—type I is due to C1 inhibitor deficiency and type II is due to C1 inhibitor dysfunction. These types are also marked by abnormal levels of complement protein. HAE type III is characterized by normal C1 inhibitor and normal complement protein levels and usually begins in adulthood.

Massachusetts General Hospital's Elizabeth Yakaboski, MD, clinical fellow at the Allergy and Clinical Immunology Unit, Aleena Banerji, MD, director of the Drug Allergy Program and clinical director of Allergy and Clinical Immunology, and Tina Motazedi, MD, clinical fellow at the Allergy and Clinical Immunology Unit, recently reviewed special considerations for clinicians who care for women with HAE. Their paper, which is drawn mainly from research on HAE type I, appears in Allergy and Asthma Proceedings.

Contraception

Progestin-only oral contraceptives are recommended for routine and emergency contraception and may even lessen attacks. Conversely, estrogen-containing oral contraceptives can trigger a first HAE episode and exacerbate attacks in established HAE. Intrauterine devices are well tolerated, but rescue treatment should be available at the time of insertion in case of an HAE attack.

Pregnancy

Women with HAE face uncertainty with each pregnancy. In HAE type I, the frequency of attacks during pregnancy generally increases in one-third of patients, decreases in one-third and remains unchanged in one-third. Moreover, the clinical course of the first pregnancy does not necessarily predict that of subsequent pregnancies.

Long-term prophylaxis against HAE episodes is not universally recommended in pregnancy and is often driven by patient preference. Plasma-derived C1 inhibitor is the first-choice agent because it is FDA-approved. The literature supports the use of recombinant C1 inhibitor for short-term prophylaxis as well as treatment of HAE attacks in pregnancy.

If C1 inhibitor is unavailable, fresh frozen plasma can be used for short-term prophylaxis and acute treatment during pregnancy. Either fresh frozen plasma or tranexamic acid can be used for long-term prophylaxis. Tranexamic acid crosses the placenta but studies of its use during human pregnancy are lacking. Still, guidelines of the U.S. Hereditary Angioedema Association, published in JACI: In Practice, say physicians should be knowledgeable about its use and how to monitor for adverse effects.

Attenuated androgens (e.g., danazol, stanozolol, oxandrolone) are contraindicated during pregnancy because they may affect fetal development.

Labor and Delivery

Cesarean section is more likely than vaginal delivery to induce an HAE attack. For women who must undergo cesarean delivery, short-term prophylaxis is needed, ideally with C1 inhibitor. Epidural anesthesia is preferred to intubation and general anesthesia, given the risk of laryngeal HAE attacks.

The incidence of HAE attacks during vaginal delivery is relatively low. Whether to use short-term prophylaxis with C1 inhibitor during vaginal delivery is a shared decision between the provider and the patient; it is not routinely recommended.

Breastfeeding

Lactation increases the frequency of HAE attacks. Subcutaneous or intravenous plasma-derived C1 inhibitor is recommended for women who need long-term prophylaxis, but either plasma-derived or recombinant C1 inhibitor can be used for treatment. Tranexamic acid and anabolic acids are secreted into breast milk and are contraindicated.

The review also touches on special considerations for women with HAE in regards to menstruation, in vitro fertilization, genetic testing of first degree relatives including children, menopause and female reproductive cancers.

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