Hereditary Angioedema during Pregnancy: History
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Kristen Park
,
Andrew Yeich
,
Timothy Craig

Hereditary angioedema (HAE) is a genetic condition that is characterized by recurrent episodes of swelling in various subcutaneous and mucosal tissues, including the skin, upper respiratory system, and gastrointestinal tract. The prevalence of HAE is estimated to be 1:30,000–80,000, and approximately 200,000 people are estimated to be affected by HAE worldwide.

  • hereditary angioedema
  • HAE
  • HAE-1
  • HAE-2 pregnancy

1. Introduction

There are two major types of hereditary angioedema (HAE) that exist: HAE-1 is characterized by a C1 inhibitor protein (C1-INH) deficiency and is the most common type, and HAE-2 is due to dysfunctional C1-INH. There is also a third type classified as HAE-nC1-INH, which is when HAE occurs despite the presence of normal C1-INH. This is thought to be due to other mutations affecting the pathway involving C1-INH [1][2]. However, given the limited data due to the rarity of this type, it will not be discussed in this research.
The pathophysiology of HAE has been well described in the literature despite the condition’s relatively recent characterization. The key mutation found in patients with HAE revolves around C1-INH, which belongs to the superfamily of serine protease inhibitors and is encoded by the SERPING1 gene. C1-INH regulates the complement system but more importantly, it is also a major regulator for the contact activation system in humans. This system, which is also known as the intrinsic clotting pathway, is important for activating procoagulant and proinflammatory reactions. In HAE, the symptom presentation is mainly due to C1-INH’s role in the latter reaction. Additional components of this proinflammatory pathway include coagulation factor XIIa and its active form of factor XII, plasma kallikrein as well as its active form of prekallikrein, and high molecular weight kininogen (HMWK), which produces bradykinin. The main function of C1-INH in this pathway is to inhibit the activation of factor XIIa and plasma kallikrein. Factor XIIa is necessary for converting prekallikrein into its active form, plasma kallikrein. Plasma kallikrein then goes on to activate the conversion of HMWK into bradykinin. By inactivating factor XIIa, this prevents the activation of prekallikrein into plasma kallikrein. Subsequently, the inhibition of this process causes decreased conversion of HMWK to bradykinin. Thus, C1-INH functions to decrease bradykinin levels and the resulting excessive angioedema caused by inflammation [3][4]. By applying this pathway to HAE, mutations in the SERPING1 gene result in either low levels of functioning C1-INH (HAE-1) or dysfunctional C1-INH (HAE-2), leading to an excess of bradykinin and overactivation of bradykinin B2 receptors [4]. This ultimately triggers increased vascular permeability and vasodilation, causing the various clinical features seen in HAE, such as cutaneous angioedema, abdominal swelling and pain, and upper airway edema. Due to this possibility of laryngeal edema, which has been associated with one death for every 20 HAE patients, the management of HAE is crucial in preventing mortality caused by life-threatening asphyxiation [5][6].
There is no cure available for HAE; however, rescue medications, short-term prophylaxis (STP), and long-term prophylaxis (LTP) therapies are available to mitigate and decrease the frequency of attacks via targeting of the intrinsic clotting pathway components discussed earlier [7]. Rescue medications, also called on-demand therapies, are used during an acute attack to mitigate increasing severity and include ecallantide (kallikrein inhibitor), icatibant (bradykinin B2 receptor antagonist), plasma-derived C1-INH (pdC1-INH), and recombinant human C1-INH (rhC1-INH). STP therapies are often used prior to medical and dental procedures, which have been associated with triggering HAE attacks due to associated inflammation. These include pdC1-INH, rhC1-INH, fresh frozen plasma, and attenuated androgens. The first line choice prior to a procedure is currently the intravenous form of pdC1-INH, while the remaining are the second line. Lastly, LTP therapies are used on a routine basis to prevent attacks and include subcutaneous (SC) and intravenous (IV) pdC1-INH, lanadelumab (human monoclonal antibody targeting plasma kallikrein), berotralstat (kallikrein inhibitor), danazol (attenuated androgen), and tranexamic acid (antifibrinolytic) [8][9][10].

2. HAE during Pregnancy and Lactation

To identify the published data regarding HAE and pregnancy/lactation, Google Scholar and PubMed search engines were used. Keywords including “pregnancy AND hereditary angioedema,” “lactation AND hereditary angioedema,” and “gestation AND hereditary angioedema” were used. Additional references were found by searching the references of these published reports. Altogether, this search yielded 40 relevant references, which included 10 review articles, 7 consensus articles, and 23 clinical cases.
Approximately 90% of patients have their first HAE attack before age 20 [11]. Although most pregnant patients will have hopefully been diagnosed prior to pregnancy, examples of HAE first presenting during pregnancy have been reported [12][13]. However, a diagnosis in such cases can be complicated by a physiologic decrease in C1-INH during pregnancy. This may be due to an increase in plasma volume [14][15]. If found to have low C1-INH levels, pregnant patients with suspected HAE should undergo additional testing, such as genetic testing or postpartum testing, to avoid false positives to potentially prevent and avoid subsequent complications of the disease [16][17].
HAE is inherited in an autosomal dominant manner, with incomplete penetrance and variability in the genetics and phenotype [18][19]. Thus, pregnant patients with HAE should be offered genetic counseling pertaining to the condition, which includes education on the inheritance pattern, discussion of the expected disease course in the future newborn if transmitted, and potential diagnostic screening of other family members [17][20][21]. Prenatal diagnosis of HAE is not routinely conducted, most likely due to recent characterization of the disease and the risks associated with prenatal diagnosis via chorionic villus or amniotic fluid sampling, which carries a 0.5–1% unintended abortion risk [22]. Meanwhile, measuring C1-INH in a newborn may not yield accurate levels, as there is a physiologic decrease during the first year of life until the neonate’s contact and complement system mature [23][24][25]. However, given the autosomal inheritance pattern of HAE, it should be assumed that neonates with a parent positive for HAE have a 50% chance of being affected by the condition. Confirmatory testing with biochemical assays should be delayed until after 12 months of age; however, genetic testing can be performed at any age, including in the fetus. Children with HAE will typically experience their first attack during puberty, although the severity and degree of the symptoms may be variable. Some patients may even remain asymptomatic throughout their entire life. For this reason, parents are often hesitant to determine the diagnosis during the prenatal period as well as in the newborn period. It is up to parents to determine whether this testing should be conducted [26]. In low-income countries, especially those that do not have access to HAE medications or require a limited family size, prenatal diagnosis may help parents with decision-making. However, there are currently no clear guidelines addressing these situations.
The risk factors that help to predict HAE severity during pregnancy are not clearly identified. Maternal age, fetus gender, and HAE attacks during previous pregnancies have not been found to be associated with an increased likelihood of attacks during pregnancy [27][28][29][30][31]. However, pregnancy-associated mechanical trauma and the discontinuation of prophylactic HAE treatments have been associated with a higher attack frequency [32][33]. One study has associated an earlier onset of HAE during childhood with a worse disease course during pregnancy, although more data is needed to explore this relationship [33]. Studies have also hypothesized that symptoms may increase during pregnancy if carrying a fetus with an HAE mutation, implying a possible shared supply of the C1-INH protein between the mother and the fetus [17][31][33]. One particular retrospective analysis found an association between lower maternal C1-INH levels in pregnancies with a fetus positive for HAE, but this relationship did not correlate with more severe symptoms in the mothers [34].
The relationship between pregnancy and HAE symptom control has not been thoroughly examined and understood. Despite a large, published case series on the topic reporting worsening attack rates in the majority of pregnancies, there still remains conflicting evidence [17][28][29][32][33][34][35][36][37]. Many of these studies used differing endpoints to assess the severity of the disease, which may be responsible for the varying outcomes [20]. Attacks during pregnancy are more likely to occur in the abdominal region compared to pre-pregnancy [29][33][34][37]. This may be due to mechanical stress, a common trigger for HAE, from fetal movement and uterus enlargement [33]. Lower extremity swelling is also common [35]. There is mixed evidence regarding which trimester of pregnancy is most correlated with HAE symptoms [29][32][33][34][35][36][37][38][39][40][41].
Involving a clinical provider specialized in HAE during a pregnant patient’s perinatal care is highly recommended, in addition to geneticists and high-risk OB/GYN specialists. Close monitoring should be performed in such patients for at least 72 h following delivery [2][17][33][42]. Out of 89% of mothers with HAE enrolled in the PREHEAT study (Novel methods for predicting, preventing, and treating attacks in patients with hereditary angioedema), 6% experienced postpartum HAE attacks within 48 h of delivery [17][32][33]. Other case series have reported more frequent attacks in the immediate weeks following delivery, with some referencing puerperal abdominal attacks in particular [31] and others noting the presence of more vulvar symptoms [11][33][39][43][44][45].
Breastfeeding is not contraindicated and is even encouraged in mothers with HAE [17]. However, some may experience an increased frequency of abdominal attacks during the lactation period [33]. One retrospective study suggested a relationship between increased prolactin levels and abdominal attacks [46]. If more studies support this relationship, discontinuation of breastfeeding may be an option to decrease the frequency of HAE attacks. However, given the numerous benefits of breastfeeding to the neonate, it is highly recommended to initiate LTP during the lactation period rather than discontinue breastfeeding [33].
Pregnant HAE patients experience spontaneous vaginal delivery at a similar rate to the general population [33][47]. In addition, the PREHEAT study reported 12% of participants with HAE underwent cesarean delivery, while the general population average was 16% [32]. Animal models have shown that excess bradykinin may even stimulate uterine contractions [48]. Although HAE can lead to increased frequency and severity of attacks during pregnancy, the association between HAE and spontaneous abortion is not clear. One observational study associated HAE with higher rates of spontaneous abortions and earlier deliveries [49]. However, other studies found no difference compared to the controls [32][33][34].

This entry is adapted from the peer-reviewed paper 10.3390/futurepharmacol3030037

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