Preferred Therapy for Patients with Hereditary Angioedema during Pregnancy

Abstract

Hereditary angioedema (HAE) is a rare, inherited disease caused by a deficiency (HAE-1) or lack of functional (HAE-2) C1 inhibitor protein. The symptoms present with mucocutaneous swelling of various organ systems, such as the respiratory and gastrointestinal systems, which can manifest as stridor and abdominal pain, respectively. HAE can present with increased frequency and severity of attacks during the pregnancy and lactation period. This is thought to be due to hormonal changes, which may trigger HAE attacks. The management of this condition in pregnant and lactating patients can be challenging for providers due to disease rarity and the lack of data regarding the management of this specific population. This review aims to provide insights for HAE management regarding rescue therapy, short-term prophylaxis, and long-term prophylaxis via the consolidation of the current literature and various international consensus guidelines. Furthermore, this review discusses when to initiate treatment and at what frequency and dosing, as well as the possible side effects that may occur as a result of therapy.

1. Introduction

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 [1,2]. 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 [3]. There are two major types of 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 [4,5]. However, given the limited data due to the rarity of this type, it will not be discussed in this review.

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 [1,6]. 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 [6]. 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 [7,8].

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 [9]. 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) [10,11,12].

HAE attacks can often be spontaneous and without an identifiable trigger; however, there have been some common triggers that have been identified. The triggers include but are not limited to emotional stress, physical injuries, strenuous activity, medical procedures, dental work, estrogen-containing medications, ACE inhibitors, and hormonal changes [13]. Females are disproportionately affected by HAE given that hormones, specifically increased estrogen, can trigger HAE attacks. Pregnancy, which is characterized by a hypercoagulable and high-estrogen state, has been shown to be associated with an increase in HAE attacks. In addition, increased prolactin, which is seen during the lactation period, has also been associated with increased frequency and severity of attacks [14,15,16,17]. Given the rarity of the disease and a lack of objective data, it can be challenging for physicians and other clinical providers to manage pregnant or lactating patients with HAE. Despite this, there have been many therapeutic advances for HAE patients within recent years, but there still remains a lack of consolidated guidance regarding pregnant and lactating patients with HAE at this time. Our objective for this literature review is to identify manuscripts, consensus documents, and current guidelines regarding the management of pregnant and/or lactating patients with HAE and provide recommendations regarding therapies that are safe to use in these populations.

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 [18]. Although most pregnant patients will have hopefully been diagnosed prior to pregnancy, examples of HAE first presenting during pregnancy have been reported [19,20]. 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 [21,22]. 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 [23,24].

HAE is inherited in an autosomal dominant manner, with incomplete penetrance and variability in the genetics and phenotype [25,26]. 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 [17,24,27]. 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 [28]. 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 [29,30,31]. 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 [32]. 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 [33,34,35,36,37]. However, pregnancy-associated mechanical trauma and the discontinuation of prophylactic HAE treatments have been associated with a higher attack frequency [14,38]. 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 [38]. 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 [24,37,38]. 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 [39].

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 [14,24,34,35,38,39,40,41,42]. Many of these studies used differing endpoints to assess the severity of the disease, which may be responsible for the varying outcomes [17]. Attacks during pregnancy are more likely to occur in the abdominal region compared to pre-pregnancy [35,38,39,42]. This may be due to mechanical stress, a common trigger for HAE, from fetal movement and uterus enlargement [38]. Lower extremity swelling is also common [40]. There is mixed evidence regarding which trimester of pregnancy is most correlated with HAE symptoms [14,35,38,39,40,41,42,43,44,45,46].

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 [5,24,38,47]. 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 [14,24,38]. Other case series have reported more frequent attacks in the immediate weeks following delivery, with some referencing puerperal abdominal attacks in particular [37] and others noting the presence of more vulvar symptoms [18,38,44,48,49,50].

Breastfeeding is not contraindicated and is even encouraged in mothers with HAE [24]. However, some may experience an increased frequency of abdominal attacks during the lactation period [38]. One retrospective study suggested a relationship between increased prolactin levels and abdominal attacks [51]. 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 [38].

Pregnant HAE patients experience spontaneous vaginal delivery at a similar rate to the general population [38,52]. In addition, the PREHEAT study reported 12% of participants with HAE underwent cesarean delivery, while the general population average was 16% [14]. Animal models have shown that excess bradykinin may even stimulate uterine contractions [53]. 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 [54]. However, other studies found no difference compared to the controls [14,38,39].

3. Long-Term Prophylaxis

LTP serves to reduce the frequency and severity of HAE attacks. However, LTP does not guarantee the complete prevention of attacks, and, for this reason, rescue treatment should also be available to patients. Given the hormonal changes that occur during pregnancy, pregnant women are more likely to experience frequent and severe HAE attacks. Thus, LTP should be discussed with all female patients anticipating pregnancy to subsequently improve the quality of life during pregnancy and throughout the lactation period. In addition, LTP should highly be considered in cases of frequent and/or severe attacks or when attacks are triggered by mood changes or stressors [55]. Overall, shared decision-making is recommended to establish the need for LTP. Patients with LTP should be educated on how to self-administer the medication. They should also be monitored for efficacy and side effects associated with the treatment [1]. In addition, it should be noted that despite being on LTP, all patients must have at least two doses of rescue therapy available for breakthrough attacks.

Although no clinical studies exist regarding the safety and efficacy of LTP during pregnancy and lactation, there have been multiple expert consensus panels that have published recommendations regarding management during pregnancy and lactation. The USA Hereditary Angioedema Medical Advisory Board and World Allergy Organization (WAO) both published consensus guidelines recommending LTP in patients according to their individual needs and tolerance to various medications [5,56]. They recommend SC or IV use of pdC1-INH as first-line therapy for pregnant and lactating patients, as they have the least reported side effects as well as a 40-year history of safe usage in Europe during pregnancy and lactation. The data regarding the use of rhC1-INH during pregnancy and lactation are limited; however, the guidelines include its use as appropriate and safe [57]. In contrast, the use of androgens, such as danazol, is contraindicated in pregnancy and lactation. Androgens can cross the placenta and affect the fetus during pregnancy and can be secreted in the milk of a breastfeeding HAE patient. Maternal androgen use can ultimately cause virilization in the neonate. Anti-fibrinolytics, such as tranexamic acid, can be used, but their efficiency and risk are not clear. For this reason, the current guidelines suggest avoidance during pregnancy [5,56]. Tranexamic acid, however, can safely be used during lactation and has an indication during pregnancy for hemorrhage. The efficacy of tranexamic acid for HAE has not been demonstrated by clinical trials, but it appears to be safe to use if alternatives do not exist and if it is effective at reducing attacks [58]. Due to a lack of safety data during pregnancy for berotralstat and lanadelumab, recommendations regarding their use have not been made at this time. In addition, due to gastrointestinal adverse events with berotralstat and the ability of lanadelumab to cross the placenta, both should generally be avoided in these populations [5,56,59,60].

The International/Canadian guidelines also stress the importance of LTP in pregnant and/or lactating females with HAE. They recommend pdC1-INH as a first-line treatment in these patients, with a recommended dosage of 1000 IU of IV pdC1-INH every 3–4 days or 60 IU/kg body weight of SC C1-INH twice a week. They also recommend against using androgens due to the risk of virilization in the fetus [34].

The German-speaking consensus recommends LTP in pregnant females with recurrent attacks during the third trimester or a history of genital edema due to mechanical trauma during labor, such as a vacuum-assisted vaginal delivery [61].

Lastly, the Hereditary Angioedema International Working Group (HAWK), which is a group consisting of HAE physician experts around the world, released consensus guidelines recommending LTP in patients who experience more than 24 days of symptoms each year or more than 12 moderate/severe attacks each year. The decision to initiate LTP should involve a discussion regarding the risks and benefits. Although specific management for pregnant and lactating patients was not discussed, they reaffirmed that androgens should not be used [62].

4. Short-Term Prophylaxis

Numerous guidelines note pdC1-INH as being the safest form of treatment for rescue therapy, LTP, and STP during pregnancy and lactation, as noted above, due to minimal side effects on the mother and child [14]. Its long history of use in Europe without reports of adverse outcomes further supports this recommendation. Different guidelines, however, report various dosages for STP. The USA Hereditary Angioedema Medical Advisory Board 2020 recommends 20 IU/kg, while the WAO HAE Consensus Guideline recommends 1000 IU [5]. Given the data extrapolated from STP use, dosing is performed according to the weight, and, thus, 20 IU/kg is more reliable and recommended over a set dose of 1000 IU [63].

The importance of STP cannot be overemphasized [63]. Proper planning is key to success. At the time of delivery, at least two doses of pdC1-INH should be available: one dose for a procedure, if needed, and one dose for rescue therapy, if necessary, for an attack. During preparation for a procedure, surgery, or dental work, STP with pdC1-INH should be administered intravenously over 10 or so minutes shortly before the procedure. We recommend use of 20 IU/kg, and with the average person weighing 80 kg in the USA, this would result in a 1500 IU infusion. Since each vial has 500 IU, rounding to the nearest 500 prevents waste of this expensive medication. Even with STP, there is a minimal risk of having an attack of HAE, and the second dose can be administered as needed for an attack.

Vaginal delivery with local anesthesia may result in vulvar angioedema over the next three days, but the guidelines suggest that as long as vulvar manipulation, vaginal and uterine procedures, and trauma are not excessive, STP with pdC1-INH is not essential [63,64,65]. For this reason, vaginal delivery is the preferred choice for delivery [64]. If emergency cesarean delivery is indicated, pdC1-INH should be administered to prevent HAE attack secondary to the procedure. If cesarean delivery has already been planned to be the choice of delivery, STP with C1-INH at 20 IU/kg is recommended 30–60 min prior to the procedure [63,64]. In addition, STP should also be given prior to any upper airway manipulation to avoid irritation that may cause upper airway swelling. For this reason, local anesthesia is preferred over general anesthesia to avoid intubation [65]. These recommendations are summarized in

Table 1. Best practices for managing pregnant HAE patients.

Pre-Operative Period:	Peri-Operative Period:	Post-Operative Period:
Ensure availability of at least 2 doses of appropriate rescue medication *	Use local anesthetic and/or nerve blocking to avoid need for intubation	Ensure availability of appropriate rescue medication throughout recovery and discharge periods
Assess for history of prior HAE attacks during surgical procedures	Perform vaginal delivery when possible to avoid surgical trauma	Prior to discharge, provide patient with education on rescue medication self-administration, if needed
Pretreat patient with appropriate STP medication *	Maintain ability to protect airway at all times during procedure

See Table 2 for recommended medications and dosing *.

.

5. Recommendations

As recommended by various international HAE consensus guidelines, therapy should be available during pregnancy and throughout the lactation period to reduce morbidity and possible mortality. PdC1-INH remains the drug of choice for rescue therapy for HAE attacks, STP, and LTP [57]. This recommendation is maintained despite cases of thrombotic events associated with pdC1-INH. Importantly, the thrombotic events are believed to be due to the presence of IV indwelling port catheters rather than the medication itself [66]. As an alternative for pdC1-INH, rhC1-INH is also recommended during pregnancy and lactation for on-demand therapy. Fresh frozen plasma is another alternative, although there may be variable amounts of C1-INH in each unit and higher rates of adverse effects [67]. Tranexamic acid should not be used for on-demand therapy given the risk of thrombotic/embolic events in addition to a lack of studies regarding its use in pregnant and/or lactating HAE patients [58]. Multiple case reports suggest icatibant as a safe choice for rescue therapy during pregnancy without any reportable adverse effects or abnormalities, but we believe the data are far too shallow to make this recommendation [68,69,70,71,72].

For STP, pdC1-INH remains the therapy of choice during pregnancy and lactation. The recommended dosage is 20 IU/kg at least 1 h prior to medical surgeries or dental procedures [5]. The alternatives include rhC1-INH and fresh frozen plasma [68,69,70,71].

The first-line therapy for LTP during pregnancy and lactation is C1-INH, including SC and IV options [5]. SC is preferred due to less invasiveness compared to IV and is dosed at 60 IU/kg twice weekly. The efficacy of this dosage is reported to result in an 85% reduction rate of attacks [69]. The IV route is standardly dosed at 1000 IU twice weekly, but post-approval higher doses of up to 2500 IU can be given twice a week if necessary. The phase 3 data of this dosage every 3–4 days has demonstrated a 50% reduction in attacks [56]. Both SC and IV C1-INH carry similar adverse effect profiles, which have been discussed earlier, with local injection site reactions being the most common [56,69]. Although tranexamic acid should not be used for on-demand therapy, it is frequently used in low- and median-income countries for LTP and appears to be effective and safe. For example, tranexamic acid is considered the first line in countries such as China and India [73,74]. However, it is not considered a first-line agent for LTP in more developed nations, such as the United States, for reasons stated earlier [58]. The cost of C1-INH may make many hesitant to initiate LTP, but we believe the risk and cost favor its use during pregnancy and lactation. During pregnancy, abdominal attacks may be misinterpreted as labor contractions or gastrointestinal problems, which can subsequently lead to inappropriate clinical decision-making, surgery, and unnecessary radiologic procedures. Also, since the growing fetus can potentially trigger an attack via mechanical trauma, it is important to suppress attacks. Pregnancy can also increase stress levels, which may lead to increased HAE attacks during this period. Shared decision-making should be encouraged when making the decision to initiate LTP [5,75]. A summary of medications for pregnant and/or lactating HAE patients is shown below in

Table 2. Recommended medications for pregnant and lactating females with HAE.

Drug Name (Route of Administration)	Rescue Therapy	Short-Term Prophylaxis	Long-Term Prophylaxis	Dosage
pdC1-INH (IV)	1st line	1st line	1st line	Rescue: 20 IU/kg STP: 20 IU/kg 1–12 h before stressor LTP: 1000 IU every 3–4 days (may be increased up to 2500 IU)
pdC1-INH (SC)	-	-	1st line	60 IU/kg twice weekly
Fresh frozen plasma (IV)	2nd line	2nd line	-	2 to 4 units
Recombinant C1-INH (IV)	2nd line	2nd line	-	50 IU/kg up to 4200 IU
Tranexamic acid (oral)	3rd line	3rd line	-	20–40 mg/kg
Berotralstat (oral)	Recently approved for LTP. Insufficient data for use in pregnancy and lactation			150 mg daily
Icatibant (SC)	Approved for rescue therapy. Insufficient data for use in pregnancy and lactation			30 mg
Lanadelumab (SC)	Approved for LTP. Insufficient data for use in pregnancy and lactation			300 mg every 2–4 weeks
Androgens (oral)	Contraindicated during pregnancy and lactation			-
Ecallantide (SC)	Contraindicated during pregnancy and lactation			-

, while

Table 3. Reducing risk of HAE attacks during pregnancy.

Consider long-term prophylaxis for most pregnant women who have active HAE symptoms

Pretreat with 20 IU/kg intravenous pdC1-INH 1 h before procedures, dental work, or surgery. Recombinant C1-INH and fresh frozen plasma may be alternate therapies if pdC1-INH is not available

Have 2 doses of rescue therapy available of C1-INH or recombinant C1-INH at all times

During delivery, use vaginal delivery when possible

Always have capability to protect the airway during procedures and for 72 h after procedures

Consider long-term prophylaxis for most pregnant women who have active HAE symptoms

summarizes ways of reducing the risk of HAE attacks during pregnancy.

6. Conclusions

HAE is an inherited disease that can cause complications in pregnancy, labor, and lactation. Pregnant women with HAE should be educated regarding the symptoms, triggers, and management of the condition. At least two doses of IV pdC1-INH, which is safe to use during pregnancy, should be available as a form of rescue therapy in cases of acute HAE attacks. IV pdC1-INH should also be used for STP prior to medical and dental procedures or any other known triggers to the patient. In cases of emergency cesarean section, providers should be aware of avoiding intubation unless necessary, using local anesthetic if possible, and administering STP prior to the procedure. To improve the quality of life of the mother, C1-INH is recommended as a first-line therapy for LTP with a choice of either IV or SC; however, SC administration at the recommended doses is more effective and, in most cases, has less drug burden for the patient. These suggestions for treatment should be extended throughout the lactation period, as increased prolactin has also been shown to trigger the onset of HAE attacks. Shared decision-making is crucial throughout the care of a pregnant and lactating HAE patient and is highly recommended when discussing the initiation of HAE therapies.