Natasa Teovska Mitrevska, Remedika General Hospital, North Macedonia
This is an open-access article distributed under the terms of the
Hereditary angioedema (HAE) is a rare genetic disorder characterized by recurrent episodes of subcutaneous and/or submucosal angioedema. Pregnancy and breastfeeding may be associated with an increased frequency of attacks. Plasma-derived C1 inhibitor (pdC1INH) is the recommended first-line treatment for long-term prophylaxis (LTP) in these special populations. The pdC1INH currently available in Portugal is one intravenous (IV) formulation not approved for LTP, as are the other IV and subcutaneous (SC) formulations. This report documents the first cases of SC pdC1INH use during pregnancy and breastfeeding in Portugal. It describes two cases of 37-year-old women with HAE type 1 treated with SC pdC1INH as LTP during pregnancy and lactation. Both patients had been previously treated with tranexamic acid. In the first case, the patient was started on IV pdC1INH at 8 weeks' gestation due to clinical deterioration. Due to difficult IV access and inability to space out administrations, SC pdC1INH at a dose of 4,000 U (∼43.5 U/kg) every 72 h was started at 21 weeks' gestation. Administration intervals were progressively increased to 96 and later 120 h. LTP was continued throughout lactation. In the second case, LTP was not administered during pregnancy. However, after delivery, the patient experienced a worsening of angioedema episodes during breastfeeding, which persisted despite tranexamic acid treatment. SC pdC1INH was started six months postpartum at a dose of 2,000 U (∼45 U/kg) twice weekly. The administration interval was later increased to 120 h. Both patients remained free of angioedema episodes and reported no systemic adverse events. The safety of SC pdC1INH was consistent with reports in the literature. Overall, these positive results support the future use of SC pdC1INH in a broader population of pregnant and lactating women in clinical practice.
Hereditary angioedema (HAE) is a rare genetic disorder characterized by recurrent episodes of localized cutaneous and submucosal angioedema (
HAE can be classified into HAE due to C1 inhibitor (C1INH) deficiency (HAE-C1INH) and HAE with normal C1 inhibitor (HAE-nC1INH). Patients with HAE-C1INH may have low plasma levels of C1INH protein (HAE type 1) or normal to elevated plasma levels of dysfunctional C1INH protein (HAE type 2) (
Regarding treatment, the primary goals in HAE are to achieve complete disease control and enable patients to lead normal, unrestricted lives (
Pregnancy may increase, decrease, or have no effect on the frequency and severity of HAE attacks (
During eutocic delivery, the risk of experiencing an angioedema attack is low, and STP is not routinely recommended (
Breastfeeding may be associated with an increased frequency of angioedema attacks in women with HAE, possibly related to elevated serum prolactin levels (
During pregnancy and lactation, therapeutic options for the management of HAE are limited. Attenuated androgens are absolutely contraindicated during pregnancy as they may lead to virilization of the female fetus (
In Portugal, only IV pdC1INH is currently available for on-demand prophylaxis and STP. Subcutaneous (SC) pdC1INH has not been approved for commercialization by INFARMED and can only be used by special authorization.
The aim of this report was to describe the first cases of women with HAE treated with SC pdC1INH for LTP during pregnancy and lactation in Portugal.
This report describes the cases of two women with HAE followed at the Department of Allergy and Clinical Immunology of two Portuguese centers, who were treated with SC pdC1INH during pregnancy and lactation. The first patient started treatment in March 2024 during pregnancy, and the second patient started treatment in June 2024 during lactation.
The first case is a 37-year-old woman with HAE type 1 (
Summary of treatment timeline and outcomes.
| Cases | Age (in years) | SC pdC1INH initiation date | SC pdC1INH initiation dose | SC pdC1INH dose adjustments | Adverse events | Outcomes |
|---|---|---|---|---|---|---|
| Case 1 | 37 | 21st week of gestation | 43.5 U/kg every 72 h | Dosing intervals increased to 96 h at the 23rd week of gestation and to 120 h at the 29th week of gestation. | Mild pain at the injection site | No recurrence of angioedema attacks following treatment initiation |
| Case 2 | 37 | 6 months postpartum | 45 U/kg twice weekly | Dosing intervals increased to 120 h at 8 months postpartum | Mild pain at the injection site | No recurrence of angioedema attacks following treatment initiation |
At the age of 19, shortly after starting an estrogen-containing contraceptive pill, the woman experienced her first angioedema attack, which affected the abdomen and feet. During her first pregnancy at the age of 32, she experienced a moderate worsening of the disease, especially during the first trimester, with weekly abdominal HAE attacks. She was treated with on-demand IV pdC1INH, but declined the proposed option of LTP with the same drug.
At the age of 36, she was on LTP with tranexamic acid (1,000–1,500 mg/day) with only partial HAE control. She experienced angioedema attacks approximately every 2 months, primarily peripheral and typically induced by stress. This treatment was discontinued when she decided to become pregnant. After the first few weeks of pregnancy, there was a marked increase in HAE attacks, which significantly affected the patient's quality of life. In the 8th week of pregnancy, a joint decision was made to start IV pdC1INH at a dose of 1,500 U (∼16 U/kg) twice a week.
At 15 weeks' gestation, as the patient remained attack-free but had difficult IV access, the frequency of IV pdC1INH administration was reduced to once a week. However, due to the recurrence of HAE attacks, a special authorization for the use of SC pdC1INH was requested from INFARMED.
After INFARMED's approval, the patient started LTP with SC pdC1INH at a dose of 4,000 U (∼43.5 U/kg) every 72 h at 21 weeks' gestation. After three hospital administrations and patient and family education, the treatment was successfully transitioned to home administration.
At 24 weeks' gestation, the administration interval was increased to 96 h, and at 29 weeks' gestation, it was further increased to every 120 h (i.e., every five days). The patient remained attack free throughout this period and reported no side effects other than mild pain at the injection site.
A healthy baby boy was delivered at 38 weeks gestation. STP with IV pdC1INH 1,500 U was administered prior to cesarean section and the delivery was uneventful. After delivery and throughout lactation, LTP was continued with SC pdC1INH 4,000 U (∼43.5 U/kg) every five days. The patient remained free of angioedema attacks and with good disease control, as evidenced by an Angioedema Control Test (AECT) score of 15, an Angioedema Quality of Life Questionnaire (AE-QoL) score of 20, and an Angioedema Activity Score (AAS) of zero at five weeks postpartum, all collected in paper forms during medical appointments, as part of the routine clinical assessment.
The second case is another 37-year-old woman with HAE type 1 (
During her first pregnancy at the age of 32, the disease remained under control without the need for LTP and delivery was uneventful. However, during breastfeeding, the frequency of angioedema attacks increased and LTP with tranexamic acid was initiated with a good clinical response.
During her second pregnancy, at the age of 36, the disease was managed exclusively with on-demand treatment. In the second trimester, the patient experienced an increase in the frequency of episodes, with abdominal angioedema occurring once or twice a week. These episodes resolved with medical leave and rest. Delivery occurred at 38 weeks' gestation under STP with IV pdC1INH and was uneventful.
During breastfeeding, the patient experienced an increase in the frequency of abdominal and peripheral angioedema attacks, prompting the initiation of LTP with tranexamic acid at a dose of 2,000 mg daily. Despite prophylaxis, she continued to experience weekly angioedema episodes lasting an average of two days each, with a significant impact on her quality of life. Special authorization for the use of SC pdC1-INH was requested and granted.
At six months postpartum, treatment with SC pdC1INH was initiated at a dose of 2,000 U (∼45 U/kg) administered twice weekly. After five in-hospital administrations and training, the patient transitioned to home administration. The only adverse event reported was tolerable pain in the injection site.
Following the introduction of SC pdC1INH LTP, the patient remained free of angioedema attacks. Two months later, based on the good clinical response as evidenced by an AECT score of 16, an AE-QoL score of zero, and an AAS of zero, combined with a reduction in breastfeeding frequency, the SC pdC1INH administration interval was increased to every 120 h (i.e., every five days).
Currently, both women continue to breastfeed, with treatment duration adjusted according to clinical progression.
The efficacy and safety of SC pdC1INH as LTP at the doses of 40 and 60 U/kg administered twice weekly was previously demonstrated in the COMPACT (Clinical Study for Optimal Management of Preventing Angioedema with Low-Volume Subcutaneous C1-Inhibitor Replacement Therapy) open-label extension study (
In this report, the first patient experienced an increase in angioedema attacks during the first pregnancy trimester. Prophylaxis with IV pdC1INH successfully achieved complete disease control. However, the need for twice-weekly hospital visits and the difficulty in IV access hampered treatment adherence. It should be noted that several IV pdC1INH preparations are available, but Berinert© is not approved for LTP (
The second patient experienced an increase in the frequency of angioedema attacks during the second pregnancy trimester, but the symptoms were controlled with rest. However, during breastfeeding, she experienced weekly angioedema attacks before the introduction of SC pdC1INH.
The administered doses, 43.5 UI/kg in the first case and 45 UI/KG in the second, did not exactly match the recommended dosage of 60 UI/kg due to limitations related to the fixed-dose format of the syringes used for subcutaneous administration (
In both cases, stopping breastfeeding itself may have reduced the number of angioedema episodes in the postpartum period (
Since the initiation of SC pdC1INH, both patients have remained completely asymptomatic, consistent with findings from a similar case report (
Although SC pdC1INH has been shown to be effective and safe during pregnancy and lactation, its use in Portugal is limited by the requirement to obtain it from abroad through a special authorization, resulting in delays in access to this life-changing treatment.
To the authors' knowledge, these are the first two cases of SC pdC1INH use in Portugal. The authors emphasize the importance of individualized treatment and highlight the potential of SC pdC1INH as a therapeutic option for other pregnant and lactating women in the country.
Case 1: “When I started using subcutaneous Berinert®, the changes in my life were significant: I gained more independence (no need to go to the hospital for intravenous medication) and more security (my disease is under control with effective medication and no side effects). I feel that my life has returned to normal, which has had a very positive impact on both my physical and mental well-being.”
Case 2: “Berinert® has brought me a great improvement in my quality of life. Today, I feel more confident, more active, and freer.”
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Ethical approval was not required for the study involving humans in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
ALP: Investigation, Writing – original draft, Writing – review & editing. NS: Conceptualization, Writing – review & editing. EDdC: Conceptualization, Supervision, Writing – review & editing.
The author(s) declare that financial support was received for the research and/or publication of this article. The authors declare that financial support was received from CSL Behring Portugal for the language editing and publication of this article.
The authors acknowledge the editorial support provided by Joana Cavaco-Silva, Ph.D. (
NS has received advisory board and/or speaker fees from Abbvie, Novartis, CSL Behring, Leo Pharma and Sanofi and congress support from Medinfar, Biocryst, Bial, Roxall and Mylan. EDdC has received advisory board and/or lecture fees from Takeda, Kalvista, CSL Behring and Biocryst and congress support from Takeda and CSL Behring. ALP has received congress support from Biocryst, Takeda and CSL Behring.
The author(s) declare that no Generative AI was used in the creation of this manuscript.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.