**8. Future promising interventions**

**6. HAE in pregnancy**

142 A Comprehensive Review of Urticaria and Angioedema

symptoms [66].

**7. HAE in childhood**

drug approved in other countries [55].

The influence of pregnancy on the course of the HAE is variable. Some patients can experi‐ ence fewer attacks while others experience them more frequently [9]. There are a few case series about pregnancy and delivery in HAE, which include few patients. Therefore, the approach and management of pregnancies is debated. In a recently published study, 125 pregnancies in 61 patients were analyzed and 59.2% of the patients reported a mild increase in HAE symptoms, 14% reported no symptoms, and the symptoms of 40% of the patients were sustained in a similar severity and frequency throughout the pregnancy. A HAE diagnosis was known before gestation in 30.7% of the pregnancies. Long‐term prophylaxis was used in nine pregnancies including one with epsilon‐amino‐caproic acid, two with tranexamic acid, two with anabolic steroids (temporary usage for 8 and 12 weeks in two male‐confirmed fetuses), and four with plasma‐derived C1‐inh concentrates. None of the babies experienced side effects from these drugs. Most of the deliveries were vaginal (88%) with cesarean sections required in 15 patients. Ten patients did not receive prophylaxis and one of them experienced mild symptoms during delivery and was treated with a plasma‐derived C1‐inh concentrate. After vaginal delivery without prophylaxis, a few patients developed mild local edema [63]. Similar observations were also reported by other authors [64, 65]. In another study, none of the patients who received prophylactic treatment before cesarean sections experienced any

In conclusion, the course of HAE varies from patient to patient in pregnancy. Although the frequency and severity of episodes can increase in some patients, others may not have any symptoms. Patients who have had severe or more frequent episodes during this pregnancy or a previous pregnancy or have additional risk factors are recommended to have a vaginal delivery with a prophylactic plasma‐derived C1‐inh concentrate before delivery [63]. In addi‐ tion, plasma‐derived C1‐inh should be accessible during delivery and hospitalization [63].

Episodes of angioedema and abdominal pain can begin in childhood; however, an accurate diagnosis is often delayed leading to the administration of inadequate or incorrect therapies and even to death [55, 67]. Moreover, life‐threatening laryngeal edema can be the first clinical presentation [67, 68]. Therefore, it is crucial to scan the entire family, including children, in a newly diagnosed patient. In this way, the disease can be detected and serious angioedema

A consensus of treatment strategies in pediatric patients with HAE was reported in 2007 [69]. Afterwards, a German group covered the treatment options in pediatric patients and addressed the problem that previous consensus reports could not meet the needs of indi‐ vidual countries because of different approved drugs. Therefore, they suggested treatment strategies for German‐speaking countries and pointed out that in every country physicians should consider the approved treatment options in their country before choosing an off‐label

attacks can be prevented through prophylactic or therapeutic modalities [55].

Preventing angioedema episodes in HAE patients is still an important problem since there are limited options comprising oral‐attenuated androgens, which have various side effects leading to dose limitations and plasma‐derived C1‐inh, which is administered intravenously and therefore not practical [70, 71]. Additionally, on‐demand treatment of acute episodes has the risk of laryngeal angioedema and leads to a reduction in the quality of life since the angio‐ edema attacks continue to occur [72–74]. Given these problems, new practical safe and effec‐ tive treatment options to prevent acute episodes are necessary.

Avoralstat is a newly developed oral plasma kallikrein inhibitor for which studies are ongo‐ ing. In the recently published first in‐human study, the authors observed that the amount of the drug sufficient to inhibit the plasma kallikrein (400 mg every 8 h) was well tolerated [75].

There is no curative treatment for HAE. Amerantunga et al. argued that HAE can be consid‐ ered a metabolic liver disease and as in other metabolic liver disorders liver transplantation and hepatocyte transformation can be curative options [76, 77]. However, these treatments have surgical risks and need long‐term immunosuppression [77]. They also asserted that although liver‐based gene therapies are not practical, they can be the alternative curative options where a recombinant virus as a vector can infect the hepatocytes leading to the pro‐ duction of the targeted protein [77].

Another future concern is to prevent the development of HAE with prenatal genetic diag‐ nosis before implantation occurs [78]. Although it seems to be reasonable, the strategy has some limitations. First of all, in some parents, the mutations causing the disease cannot be determined, and in one quarter of the patients, the disease is caused by de novo mutations. Furthermore, because of the hormonal stimulation during in vitro fertilization, it can possibly lead to angioedema attacks. Lastly, there is a risk of having mild influenced offspring [78]. Therefore, patients need intensive genetic counseling before such a therapy.

#### **9. Conclusion**

In summary, HAE is a rare life‐threatening disease with highly variable clinical presentations. Physicians and the public are not familiar with the disease. There are still unknown features of the disease and delay in diagnosis or misdiagnosis leading to inaccurate treatment. It is, however, crucial to recognize the disease to prevent mortality and morbidity. Therefore, more comprehensive studies are needed to describe the disease, and social work is essential to increase the awareness.
