Considerations in the management of hereditary angioedema due to C1-INH deficiency in women of childbearing age

HAE-C1-INH management options include on-demand therapy to address acute attacks, short-term prophylaxis (STP) administered prior to medical or dental procedures, and LTP to prevent attacks [8]. Numerous treatment options are available in a variety of formulations. As with any treatment plan, health care providers should engage patients in a risk–benefit discussion about treatment options, patient status and preferences, and contraindications.

On-demand therapies for HAE-C1-INH include intravenous (IV) human plasma–derived (pd)C1-INH, IV recombinant human (rh)C1-INH, subcutaneous (SQ) icatibant, and SQ ecallantide (Table 1). Any of these therapies may be used as on-demand treatment in women of childbearing age who are not pregnant and do not have contraindications [9, 10]. Ecallantide must be administered by a health professional with access to appropriate medical support to manage potential anaphylactic reactions. Icatibant and the C1-INH therapies can be self-administered.

Table 1 On-demand and prophylaxis medications approved for HAE-C1-INH in the United States [9]

Prophylactic options include IV or SQ C1-INH, SQ lanadelumab, and the recently approved oral agent berotralstat. Attenuated androgens such as danazol are recommended only as second-line HAE-C1-INH prophylactic agents due to potential for numerous significant adverse effects, and are contraindicated in pregnancy. C1-INH is the HAEA and WAO/EAACI guideline-preferred therapy for both on-demand and prophylactic treatment for pregnant and lactating women [9, 10].

When pregnancy is confirmed, the health care provider should initiate a discussion of the risks and benefits of LTP, including the potential for fetal exposure, especially in the first trimester, and the importance of effective HAE-C1-INH control during pregnancy [8, 24]. Re-evaluating the female patient’s current regimens, including their impact on continuity of care, may be necessary [24].

Many women with HAE-C1-INH – especially those with frequent or severe attacks – who become pregnant and are not on LTP may benefit from initiation of LTP during pregnancy [24]. Since pregnancy can have a variable impact on the clinical manifestations of HAE-C1-INH, the frequency of attacks during one pregnancy does not predict attack frequency during subsequent pregnancies [8]. The abdomen is the most commonly reported site for HAE-C1-INH attacks during pregnancy, possibly due to stretching of the uterus and fetal movement [9]. As abdominal attacks may be confused with other complications of pregnancy, their presence may be a consideration for starting prophylactic therapy during pregnancy in appropriate patients [8].

One additional consideration when discussing HAE-C1-INH management is the impact of LTP on quality of life. The HAEA and WAO/EAACI guidelines cite restoration of normal quality of life as a treatment goal [9, 10]. LTP is intended to reduce the burden of disease and the frequency and severity of HAE-C1-INH attacks. As HAE-C1-INH symptoms worsen in some women during pregnancy, these patients may derive particular benefit from prophylaxis [10].

Because HAE-C1-INH can affect many aspects of gynecologic care and vice versa, the woman’s HAE-C1-INH specialist should collaborate with her gynecologist or women’s health provider to ensure she receives the best possible care. When prescribing prophylactic treatment for women of childbearing age, consider the safety of a specific medication in early pregnancy and the potential effects of HAE-C1-INH therapies on fertility, pregnancy, and fetal development.

Data on the safety and effects of on-demand and prophylactic therapies during pregnancy, labor, delivery, and lactation generally are limited. With the exception of pdC1-INH, which has a long history of clinical use and safety, the available information comes primarily from case reports and anecdotal evidence.

On-demand optionsEcallantide

Ecallantide, a kallikrein inhibitor, has not been studied in pregnant women. No published data are available for ecallantide use in pregnancy, labor, or delivery, and it is not known whether ecallantide is excreted in human milk [10, 25].

Icatibant

Icatibant, a B2 bradykinin receptor antagonist, has not been studied in pregnant women, and there are no data on the agent’s presence in human milk [26]. Anecdotal reports of icatibant use during pregnancy have been published. Hakl et al. reported that 6 women treated with icatibant during pregnancy delivered healthy babies (1 by caesarean section, 5 by spontaneous vaginal delivery) [27]. All pregnancies went to full term, and there were no complications during delivery. No congenital abnormalities were detected in the neonates [27]. Farkas et al. and Zanichelli et al. each reported a single case of a woman treated acutely with icatibant. One patient had Type 1 HAE-C1-INH, self-treated throughout her pregnancy, and delivered a healthy baby with no labor or delivery complications [22]. The other patient had Type 2 HAE-C1-INH, used icatibant to treat a laryngeal attack during her third pregnancy, and delivered a healthy baby [28].

C1-esterase inhibitor

In pregnant women, C1-INH is the preferred first-line therapy for on-demand treatment of HAE-C1-INH attacks and STP. The HAEA and the WAO/EAACI guidelines recommend C1-INH treatment for women who are pregnant [9, 10]. The recommendation for pdC1-INH is based on a long history of clinical experience, a well-established safety profile, and safety during pregnancy as documented by several case reports and observational studies in more than 120 women and more than 150 pregnancies [1, 7, 9, 17, 29, 30].

Use of rhC1-INH also may be considered for on-demand treatment of attacks in pregnancy. Though data for rhC1-INH are limited, the fact that rhC1-INH works by a similar mechanism as pdC1-INH is reassuring. Hakl et al. reported that pregnant women treated on demand with rhC1-INH (50 attacks) all delivered healthy, full-term babies; no complications during labor or delivery were reported [27]. Moldovan et al. also reported good efficacy and safety outcomes among pregnant women treated with rhC1-INH for acute attacks (N = 14) [31]. Patients for whom delivery methods were reported (n = 10, 8 vaginal, 2 cesarean) delivered full-term, healthy babies with no labor or delivery complications [31].

Long-term prophylaxis optionsAttenuated androgens

Attenuated androgens (AAs) such as danazol, stanozolol, oxandrolone, and methyltestosterone are highly effective as LTP. However, they can cause adverse effects that may be particularly problematic for women [32]. In addition to weight gain, dose-dependent side effects in women include hyperandrogenemia with possible virilization (clitoromegaly); hirsutism; hoarseness or deepening of the voice; menstrual irregularities; pseudomenopause; acne; burning, dryness, or itching of the vagina; and mood changes [33,34,35,36,37,38]. Androgens also may be associated with long-term adverse effects, including hypercholesterolemia, hypertension, and hepatotoxicity.

AAs are associated with fetal abnormalities and are contraindicated in pregnancy [39]. Women taking AAs as LTP should use additional contraception, regardless of whether they plan to conceive. Aside from their teratogenicity, AAs can impact a woman’s ability to conceive. Amenorrhea is a common adverse effect with AA use that can impact fertility. In a study of patients with HAE-C1-INH (N = 118) that included 58 women treated with danazol for 2 months to 30 years, amenorrhea was reported in 16 of 38 premenopausal women [32].

A negative pregnancy test result should be obtained before commencing AA therapy [39]. If a patient becomes pregnant while taking AAs, the drug should be discontinued and the patient and family informed about the risk of abnormalities of sexual differentiation in the fetus [24]. AAs are also contraindicated in lactating women [9].

Androgen use for managing HAE-C1-INH has declined with the availability of effective on-demand treatments and highly effective, more tolerable, long-term prophylactic therapies. [40].

Lanadelumab

Lanadelumab, a plasma kallikrein inhibitor, has not been studied in pregnant women and little is known about its effects on fertility, pregnancy, fetal development, or presence in human milk [41]. Monoclonal antibodies such as lanadelumab are transported across the placenta during the third trimester of pregnancy, so potential effects on a fetus are likely to be greater during this period [41].

Berotralstat

Berotralstat, the most recently approved option for HAE-C1-INH prophylaxis, is an oral plasma kallikrein inhibitor [42]. Berotralstat has not been studied in pregnant women, and there are no data on the presence of berotralstat in human milk [42].

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