August 24, 2007
Hereditary Angioedema and Pregnancy
By Duvvur, S Khan, F; Powell, K
Abstract Hereditary Angioedema is a rare but potentially life threatening condition. It is important that Obstetricians are aware of this condition as it affects women in the reproductive years and thus its recognition and proper management in pregnancy is crucial.Keywords: Pregnancy, Hereditary Angioedema, C-1 esterase inhibitor
NB, a 34-year-old woman was diagnosed with hereditary angioedema (HAE) at the age of 10 years because of recurrent attacks of peripheral edema and a family history of HAE in her father. Her symptoms included peripheral edema and edema of the face and lips, which gradually grew worse from 18 years of age; she was treated with various medications such as hydrocortisone, fresh frozen plasma (FFP), danazol and tranexamic acid with good improvement. She started receiving Cl inhibitor (Cl-INH) concentrates for acute episodes a few years later with good response. There were no systemic complications including respiratory compromise.
Her first pregnancy in 2002 was complicated by recurrent episodes of abdominal angioedema and peripheral edema for which she received Cl-INH concentrates. She was under multidisciplinary care, including a senior obstetrician, anesthetist and general practitioner (GP), with close input from the regional immunology department at Birmingham, UK. Her pregnancy was uneventful apart from occasional attack episodes. She had a normal delivery after peripartum infusion of 1500 units of Cl-INH concentrate.
Her second pregnancy in 2006 was also complicated by recurrent episodes of abdominal pain. Her obstetric outcome was unremarkable and she had a spontaneous vaginal delivery of a healthy baby. Her condition was well controlled with regular peripartum Cl-INH concentrate infusions whenever indicated. Obstetricians should be aware of the condition as it affects women in the reproductive years and is potentially life threatening.
The incidence of HAE is between 1 in 10 000 and 1 in 150 000 in the general population [I]. Defects in the genomic sequence of the Cl esterase inhibitor gene, located on chromosome 11, are responsible for HAE. Some 10-25% of cases are spontaneous mutants who do not have a positive family history  . In hereditary angioedema, there is a deficiency of Cl esterase inhibitor protein. This deficiency may be quantitative (type 1), as in the case of our patient, or qualitative (type 2).
First attacks usually occur in childhood or in early adolescence. It is characterized by recurrent episodes of subcutaneous or submucosal edema resulting in swelling of tissues involving the face, limbs, larynx or the gastrointestinal tract. The skin lesions are non-erythematous, usually non-pruritic, and not painful . The non-pitting edema usually lasts 2-5 days and then regresses over a similar period. In the respiratory tract, laryngeal edema is an ominous symptom and it is the major cause of death due to asphyxiation in these patients. The presentation may mimic an acute abdomen if gastrointestinal tract is involved and this may lead to an unnecessary laparotomy . Swelling of the intestine may cause severe abdominal cramps and vomiting secondary to obstruction. If the colon is involved, patients may have profuse watery diarrhea and can develop hypotension and shock secondary to loss of fluid into the swollen intestine.
The Cl esterase inhibitor is mainly synthesized in the liver. Cl- INH regulates the control of components of the complement, kinin and clotting cascades. In the appropriate setting, complement is activated by Hageman factor and plasmin. In this condition, the individual is unable to block the propagation of the complement cascade, resulting in production of complement fragments, such as C2 kinin and bradykinin, which increases the capillary permeability. The unopposed Cl esterase activity leads to catabolism of the complement fragment C4. To confirm a diagnosis of this disorder, a measurable decrease in C4 must be present both during attacks as well as during remission along with either a decrease in Cl esterase inhibitor protein quantity or activity  . Our patient's persistendy low C4 levels were consistent with the diagnosis of hereditary angioedema.
In pregnancy, attacks usually lessen in the second and third trimester. Abdominal pain in pregnancy and Puerperium may be due to HAE, but obstetric and gastrointestinal causes must be excluded . The recurrence of abdominal pain can cause long-term problems with pain management and such patients need support when approaching labor. Angioedema attacks are rare during delivery despite the associated injury to the birth canal. However, the trauma of normal labor can precipitate airway difficulties, presumably as a result of straining and mucosal swelling in the genital tract, for example vulval edema. Surgery itself can precipitate an attack and ideally operative delivery should be avoided. Symptoms may sometimes worsen in the postpartum period .
Three forms of therapy are available: long-term treatment, short- term prophylaxis, and treatment of acute attacks. Long-term prophylaxis is usually given if patients have frequent abdominal attacks or laryngeal attacks. This has been achieved with either antifibrinolytic agents or androgens. The antifibrinolytic agent epsilon-aminocaproic acid decreases the frequency of attacks . It direcdy inhibits Cl activation and affects the binding of antibody to Cl. Its use is limited due to serious side effects such as muscle necrosis, weakness and thrombotic potential. Androgens such as stanozolol and danazol have been shown to decrease the frequency of attacks and elevate the serum level of both Cl esterase inhibitor protein and C4. Long-term androgen therapy results in hypo- estrogenic and androgenic side effects such as menstrual irregularities, hirsutism, altered libido, and potential masculinization of a female fetus [8,9] . Patients on androgen prophylaxis ovulate and if pregnancy is not desired, contraceptive measures should be taken.
Short-term prophylaxis is given for oropharyngeal and dental procedures as well as for other minor elective surgical procedures. The use of FFP and increased dose of androgens has been quite successful in decreasing attacks [10,11]. FFP contains sufficient Cl esterase inhibitor protein to prevent the unopposed activation of the complement cascade.
Treatment of acute attacks is usually with Cl-INH concentrates. It is also administered before tracheal intubation or before major surgery. It is obtained from pooled human plasma and is not licensed for use in the UK. It is an expensive injection and a vial contains 500 units; this has been steam-treated to prevent viral transmission. The usual dose is 1000-1500 units and its effect lasts for 4-5 days. The long-term prophylaxis is limited by high cost, potential risk of viral transmission, and antibody formation. After vaginal delivery, patients should be carefully monitored and checked for the evidence of abnormal perineal swelling. Replacement of intravascular volume is critical.
In pregnancy HAE runs a variable course and prophylaxis is not indicated unless the attacks are very frequent and severe. Severe attacks should be treated with purified Cl-INH concentrate. Abdominal pain must be carefully evaluated and hasty surgical intervention will possibly trigger a systemic attack. A thorough history and complete physical examination are necessary to differentiate surgical or obstetric causes of severe abdominal pain in these patients. Regional analgesia is preferable for operative deliveries. No specific precaution is required for vaginal delivery but sites of local trauma (intravenous infusion, perineum) need careful inspection. Accessibility of Cl-INH concentrate and an effective liaison and communication between the patient, GP, obstetrician, physician and anesthetist are of paramount importance.
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Department of Obstetrics and Gynaecology, Mid Staffordshire General Hospital, Weston Road, Stafford, UK
(Received 6 February 2007; revised 21 February 2007; accepted 21 February 2007)
Correspondence: Dr Satya Arathi Duwur, 3 Panama Road, Burton-on- Trent, Staffordshire, DE13 OSQ, UK. Tel: +44 (0)7812639511. E-mail: [email protected]
Copyright Taylor & Francis Ltd. Jul 2007
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