Objective
The objective of the study was to investigate the rates and characteristics of hereditary angioedema (HAE) attacks associated with pregnancy, delivery, and the postpartum period and their treatment with C1 esterase inhibitor (INH) concentrate.
Study Design
This was an observational study including 22 women with type I HAE, with data collected before, during, and after 35 pregnancies (37 children) based on patient diaries, interviews, and case report forms.
Results
In 83% of pregnancies, attack rates increased during pregnancy; highest mean rates occurred in the second and third trimesters. C1-INH concentrate effectively controlled attacks and was safe for mothers and children. Low-plasma C1-INH activity during pregnancy tended to be associated with an increased chance of giving birth to a child with HAE.
Conclusion
Increased attack rates during pregnancy in women with HAE are well controlled with C1-INH concentrate, indicating the clear benefit of integrating the availability of C1-INH concentrate into the management plan for these women during pregnancy and delivery.
Hereditary angioedema (HAE) is a rare autosomal dominant disease caused by quantitative (type I) or functional (type II) deficiency in C1 esterase inhibitor (C1-INH). It may be caused by new mutations in up to 20% of patients. C1-INH protein is a serine protease inhibitor that is important in controlling vascular permeability by acting on the initial phase of activation in the complement, coagulation, contact, and fibrinolytic systems. A deficiency in functional C1-INH protein permits activation of plasma kallikrein and factor XIIa, with subsequent release of bradykinin, a key mediator of vascular permeability.
Patients with HAE suffer from recurrent, acute attacks of edema that can affect any body location. The main locations affected are the skin and subcutaneous tissues or mucous membranes, often the gastrointestinal tract with colic attacks, and rarely the upper airways, with the latter type of attack being potentially life-threatening (laryngeal edema). The onset of the next attack and its location are unpredictable, but triggering factors can include emotional stress and mechanical trauma, infectious diseases, and intake of estrogens and angiotensin-converting enzyme inhibitors. The edema typically lasts for 1-7 days, followed by a variable attack-free interval.
Where licensed, the recommended treatment for acute type I or II HAE attacks is rapid replacement of the deficient plasma protein via intravenous administration of C1-INH concentrate. This therapy consistently provides safe and rapid relief from the symptoms of the attack. Where C1-INH concentrate is not marketed, acute attacks are treated with fresh frozen plasma or epsilon-amino-caproic acid, which often have variable efficacy and undesirable side effects. In Europe, icatibant, a bradykinin B2 receptor antagonist, is also an option.
Information on the course of HAE during pregnancy is limited to case reports and retrospective studies, generally involving low numbers of pregnancies. Whereas pregnancy often involves traumas known to trigger HAE attacks, reports have varied on whether attack rates increase during pregnancy as a whole or during specific trimesters. Nevertheless, becoming pregnant inherently involves risks for women with HAE because of the chronic and variable nature of the disease and the involvement of unborn children. Furthermore, there is little published information on the treatment of acute attacks occurring during pregnancy.
We investigated the course of HAE during pregnancy and breast-feeding in women cared for by our HAE clinic for a period of more than 12 years, investigating any consequences for the women and their newborn children. Our aim was to characterize the rate and location of acute HAE attacks associated with pregnancy and, as appropriate, assess the efficacy and safety of treating these attacks with C1-INH concentrate. The C1-INH preparation used was Berinert P (CSL Behring GmbH, Marburg, Germany), which is a virus-inactivated C1-INH concentrate derived from human plasma. It has long been approved for the treatment of acute HAE attacks in several European and South American countries as well as Japan, and approval in the United States was obtained in October 2009. The efficacy and safety of Berinert P and predecessor formulations have been demonstrated in more than 30 years of clinical use.
Materials and Methods
This observational study was conducted at the Johann Wolfgang Goethe University Hospital in Frankfurt am Main, Germany. The Clinical Ethics Committee of the Frankfurt University Hospital had previously confirmed that ethical approval was not required for this noninterventional study. We investigated pregnancies in 22 women with HAE type I from March 1995 through August 2007, collecting data associated with 35 pregnancies, including the postpartum period during and after breast-feeding. All patients had first given their written informed consent.
Depending on the medical need and individual course of HAE, acute attacks were treated with C1-INH concentrate with on-demand therapy or individual replacement therapy (IRT). On-demand therapy involved treatment with C1-INH concentrate on presentation of edema or other typical symptoms of an attack either in the clinic or via self-administration at home after consulting the clinic.
IRT involved self-administration of C1-INH concentrate at home following early signs for the onset of an attack. Patients using IRT generally had high rates of severe attacks (≥1 per week), whereas patients using on-demand therapy generally had lower attack rates (maximum of 3 per month). In both cases, 500 or 1000 U of C1-INH concentrate were administered according to the patients’ clinical histories.
Typically, the dose of C1-INH concentrate required no adjustment during long-term treatment, and the doses used before pregnancy were also suitable for treating attacks during pregnancy. In addition, based on the gynecologist’s judgment, C1-INH concentrate (usually 1000 U) was to be given prophylactically to all patients approximately 1 hour before delivery, regardless of whether a vaginal delivery or a cesarean section was planned. No recommendation was made for pain relief during labor but, where given, epidural anesthesia was the method of choice. Danazol was not allowed during pregnancy.
Patient diaries, interviews, and case report forms were used to collect the following:
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Maternal demographic characteristics and background information, including disease status and prior therapy.
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Timing and location of HAE attacks before, during, and after pregnancy, including an assessment of attack rate during pregnancy by trimester.
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Routine evaluations of plasma C1-INH activity and antigen as well as C4 levels before and during pregnancy. Samples for these analyses were taken either once or twice per year at routine visits to the clinic and/or at 1 or more visits at unspecified times during the pregnancy.
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Treatment of HAE attacks with C1-INH concentrate and patient-reported outcome with respect to efficacy.
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Pregnancy outcome, including timing and type of delivery.
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Characteristics of newborn children, including HAE status.
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Safety of C1-INH treatment, assessed according to adverse events, safety laboratory parameters, and plasma viral status.
Data were analyzed descriptively and are presented as tabulations and figures, as appropriate. Statistical analyses were conducted using SAS, version 9.2 (SAS Institute, Inc, Cary, NC).
Results
Maternal characteristics and pregnancy details
A total of 35 pregnancies were analyzed in 22 women: 11 women had a single pregnancy, 9 women had 2 pregnancies, and 2 women had 3 pregnancies. C1-INH concentrate at a dose of 500 or 1000 U was used for treating HAE attacks before 24 of the pregnancies using on-demand therapy and before 2 of the pregnancies using IRT. No C1-INH concentrate was used before the remaining 9 pregnancies. Before 10 pregnancies, prophylactic treatment with danazol at a median dose of 150 mg/day (range, 50–400 mg/day) was documented.
The median age at confirmation of pregnancy was 29.5 years (range, 20–38 years), and the median body mass index before pregnancy was 28.2 kg/m 2 (range, 16.9–37.9 kg/m 2 ). The median gestation period was 39 weeks (range, 34–42 weeks). The premature delivery at 34 weeks involved twins. No abortions occurred. Deliveries in approximately half the pregnancies were vaginal (17 pregnancies), and 8 pregnancies each involved primary or secondary cesarean sections (no details for 2 pregnancies). Breast-feeding was documented for 21 of the 35 births, with a median duration of 4.8 months (range, 1–34 months).
Characteristics of newborn children
A total of 37 children (2 twin births) were delivered (19 female and 18 male). The median birth weight was 3.3 kg (range, 2.0–4.3 kg), and the median crown-heel length was 51 cm (range, 46–57 cm). The weight and length of the newborn children generally fell within the 10th and 90th percentiles for Germany. Eighteen children (8 female and 10 male) were diagnosed with HAE. No malformations were observed. At birth, severe asphyxia occurred in 1 child and dysplasia of 1 hip and dislocation of the first vertebra were diagnosed in a second child. Both cases were unrelated to HAE or its treatment. Further details are available in the following sections.
HAE attacks and treatment with C1-INH concentrate
In 29 of the 35 pregnancies, increases in attack rates occurred, compared with decreases in only 4 pregnancies (no change in 1 pregnancy and no details for 1 pregnancy).
The mean attack rate per 9 month period increased from 9.4 before pregnancy to 44.0 during pregnancy ( Figure 1 , A). The rate then decreased to 25.4 attacks per 9 months during breast-feeding and 18.6 attacks per 9 months after breast-feeding. During pregnancy, the highest rates occurred during the second and third trimesters (16.2 and 18.0 attacks per 3 months, respectively) ( Figure 1 , B).
Throughout the study, the highest mean attack rates were observed in the abdominal region (eg, gastrointestinal colic attacks), followed by the extremities and the facial region ( Figure 2 ). The highest attack rates in the abdominal region were observed during pregnancy and breast-feeding (27.4 and 17.0 attacks per 9 months, respectively). Attacks were less frequent in the urogenital region and laryngeal attacks were rare (associated with only 5 pregnancies).
