Case report: Hereditary angioedema in pregnancy

Abstract

Hereditary angioedema (HAE) is a rare genetic condition associated with episodic swelling due to dysfunction of bradykinin regulation pathways. This is most frequently caused by low level and/or function of the C1-esterase inhibitor protein (C1INH) which is known as hereditary angioedema with C1 inhibitor deficiency (C1INH-HAE). Pregnancy and labour can precipitate an attack, but the majority of women have an uncomplicated, spontaneous vaginal delivery. Intravenous C1INH is the first-line therapy in pregnancy and breastfeeding. It should be given if any obstetric intervention is planned. Routine prophylactic administration for uncomplicated vaginal birth is not mandatory but may be appropriate if symptoms recur frequently during the third trimester. Pregnant women with C1INH-HAE should deliver in a hospital with C1INH replacement, fiberoptic intubation and front-of-neck access equipment readily available. A documented treatment plan should be developed within a multi-disciplinary team to pre-empt complications. We describe a case of C1INH-HAE diagnosed in pregnancy.

Introduction

Hereditary angioedema (HAE) is a rare, genetic condition associated with episodic dermal and submucosal swelling due to dysfunction of the bradykinin regulation pathways. The most common cause is a deficient or dysfunctional C1-esterase inhibitor protein (C1INH), a plasma protease which regulates and inhibits several inflammatory pathways. The prevalence is uncertain but is estimated to be approximately 1 case per 50,000 persons. ¹ , ² Precipitants include trauma and surgery, infection, oestrogen-containing medications, ACE inhibitors, pregnancy, labour (thought to be related to tissue damage) and lactation, but many episodes have no identifiable trigger. ² , ³

HAE may be classified into HAE with C1 inhibitor deficiency (C1INH-HAE) and HAE with normal C1INH. C1INH-HAE includes type 1 HAE (low level and function of C1INH) and type 2 HAE (normal level, but low function of C1INH). HAE with normal C1-esterase inhibitor (previously known as Type III HAE) includes forms of HAE caused by mutations in genes encoding coagulation factor XII, angiopoetin-1 and plasminogen.

A low C4 complement component with a normal concentration of C3 is typical of C1INH-HAE, although the C4 level may be normal. Diagnosis of C1INH-HAE involves measuring C1-esterase inhibitor levels and function and can be confirmed with genetic testing, ² although the mutation responsible is only identified in approximately 90% of women with C1INH-HAE. ⁴

We describe a case of type 1 HAE diagnosed in pregnancy and its subsequent management.

Case

A 26-year-old Nigerian primiparous woman had repeated hospital admissions for gastritis during the antenatal period of her first pregnancy, which were treated with proton pump inhibitors. There was no history of facial swelling, but she had suffered from intermittent swelling of her hands and feet since the age of 15 years old. This was occurring three to four times per month and lasted about three days (with no correlation to her menstrual cycle). She was a non-smoker, did not drink alcohol and had no known allergies. Her body mass index was 29 kg/m². She had an uneventful spontaneous vaginal delivery at 40 weeks’ gestation but developed severe hand and feet oedema 48 h postpartum which settled spontaneously (Figure 1). She was an only child, but her mother and mother’s twin sister both have type I HAE and have previously required admission to intensive care with angioedema requiring intubation and ventilation. This information was not known at the time. She was referred postnatally for a specialist allergy opinion for her swelling symptoms but did not attend her appointment.

Figure 1.

Hand swelling experienced 48-h post-vaginal delivery.

In her second pregnancy, she was re-referred to the Immunology team and was reviewed at 22 weeks’ gestation. The C1INH-esterase inhibitor level and function were low (10%) which, with the family history was consistent with a diagnosis of type 1 HAE. Anti-nuclear antibody testing by immunofluorescence was negative and no paraprotein was detected on serum electrophoresis. Although functional C1-INH testing is usually repeated to confirm an accurate result, in this case given the family history and need for urgent diagnosis, a provisional diagnosis was made on the basis of a single result. During pregnancy, C1-INH levels can decrease, and so should also be repeated three months postpartum. ² Genetic testing was performed to provide a definitive diagnosis.

The patient was given verbal and written information about her diagnosis together with a prescription of C1INH (Berinert®; CSL-Behring GmbH, Marburg, Germany) and taught how to self-administer this intravenously. A written emergency treatment plan was given to her and supplied to her GP, obstetric team and local emergency medicine department. Written information on the management of HAE in pregnancy was provided to her obstetric team, along with the contact details of her immunology team who provide 24 h a day telephone advice to health professionals.

Her antenatal care was shared across a multidisciplinary team comprising of obstetrics and midwives, obstetric medicine physicians, anaesthetists and immunologists. A delivery plan was made collaboratively between these specialists such that she would receive C1INH during delivery at the following interventions; artificial rupture of membranes, episiotomy, instrumental delivery or caesarean section. It was also recommendation that new significant labial oedema be treated empirically with C1INH.

At 30 weeks’ gestation, she was measuring large for dates. Abdominal circumference and femur length were found to be on the 97th centile (estimated fetal weight was on the 96th centile with normal growth velocity at 32 and 34 weeks’ gestation). Oral glucose tolerance tests were performed at 25 and 32 weeks’ gestation and were both normal.

Due to severe pelvic girdle pain, she elected to have induction of labour at 38 weeks and 3 days’ gestation. Her induction regime involved a dinoprostone 10 mg pessary which remained in situ for 24 hours followed by 2 mg of dinoprostone gel; 1500 units of C1INH were given intravenously prior to artificial rupture of membranes. An epidural was sited, and an oxytocin infusion was used to augment her labour. She delivered vaginally a 3.5 kg female infant 2 h after starting oxytocin and sustained a second-degree tear of the perineum. Estimated blood loss was 200 ml. A further 1500 units of C1INH was given immediately post-delivery as per the multidisciplinary plan, 12 h following the previous dose. She was monitored in an obstetric high-dependency area for 24 h after delivery. There was no evidence of angioedema during the peripartum period.

Genetic testing subsequently showed the patient is heterozygous for the pathogenic c106_107delAG mutation in the SERPING1 gene which is consistent with a diagnosis of C1INH-HAE. The infant will be referred to the Paediatric Immunology team for genetic testing. C1INH-HAE has an autosomal dominant pattern of inheritance.

Discussion

The differential diagnosis for C1INH-HAE includes acquired angioedema, in which antibodies against C1INH may be found. HAE attacks may mimic anaphylaxis but do not respond to adrenaline, antihistamines or corticosteroids. They can also present as acute abdominal pain and may be mistaken for conditions such as appendicitis. Abdominal HAE attacks may be difficult to differentiate from other pregnancy complications, but free peritoneal fluid and oedema within the intestinal wall on ultrasound are suggestive of HAE. ⁵ The most dangerous complication of hereditary angioedema is laryngeal oedema which can lead to airway obstruction – lifetime fatality rates from laryngeal oedema are estimated to be 10–30%. ⁶

Management of acute attacks involve early use of intravenous purified C1INH or icatibant (a bradykinin receptor 2 antagonist). ² Improvement of angioedema is typically seen within 60 min, but full resolution of established swelling may take several hours. If C1INH or icatibant is not available, solvent detergent-treated plasma or fresh frozen plasma can be used but are considered to have lower efficacy and is associated with a risk of transient worsening of symptoms, venous thromboembolism and viral transmission. Tranexamic acid has a role in prophylaxis but little benefit for treatment of acute episodes. ⁷

Plasma levels of C1INH decrease during pregnancy and return to normal after delivery. The effect of pregnancy on C1INH-HAE can be variable, with some women experiencing more frequent attacks and others noticing no change. ² The frequency of attacks prior to pregnancy does not predict frequency attacks in subsequent pregnancies. ⁸ Women carrying a fetus with a HAE mutation may suffer from a higher frequency of third trimester maternal attacks. ⁵

The majority of women with C1INH-HAE have a spontaneous vaginal delivery with the number of caesarean sections similar to the general population. ⁹ Labour is a known precipitant for C1INH-HAE, but angioedema is rare even in women who do not receive C1INH prophylaxis. ¹⁰ Intravenous C1INH is the first-line therapy in pregnancy and breastfeeding and is thought to be safe and effective. It should be given if any obstetric intervention is planned such as instrumental delivery (forceps or ventouse) or a caesarean section. Spinal or epidural analgesia should be used where possible due to the risk of laryngeal oedema with endotracheal intubation. The international consensus and practical guidelines on the gynaecologic and obstetric management of women with C1INH-HAE state that routine prophylactic administration of C1INH for uncomplicated vaginal birth is not mandatory, but may be appropriate if symptoms have been recurring frequently during the third trimester. ² If unavailable, solvent detergent-treated plasma or fresh frozen plasma can be used. Table 1 summaries the data available for prophylaxis and treatment of an acute attack in pregnancy. Close monitoring of the mother in the postnatal period is recommended for at least 72 h after giving birth. ² Lactation may be associated with an increased frequency of maternal attacks though breastfeeding is still recommended given the benefits for the infant. ²

Table 1.

Summary of data available for prophylaxis and treatment of an acute attack in pregnancy.

Medication	FDA comments	Role in the management of C1INH-HAE
C1-esterase inhibitor protein	No reported complications during delivery and no harmful effects on the neonate	1st line for prophylaxis and treatment of an acute attack
Solvent detergent-treated plasma	No human or animal data.	If C1-esterase inhibitor protein is unavailable.
Fresh frozen plasma	No human or animal data.	If C1-esterase inhibitor protein and solvent detergent-treated plasma is unavailable.
Tranexamic acid (Antifibrinolytic)	No evidence of adverse effects on the fetus in animal studies.	May be considered for treatment of an acute attack if C1INH concentrate is unavailable.
Icatibant (Bradykinin receptor 2 antagonist)	Animal studies demonstrated delayed parturition and associated fetal death in rats and premature birth and termination of pregnancy in rabbits. 11	Not recommended in pregnancy or lactation. Limited case reports with no maternal or fetal adverse effects reported. 12
Ecallantide (Subcutaneous plasma kallikrein inhibitor)	Animal studies demonstrated developmental toxicity in rats, but not rabbits.	Not recommended in pregnancy or lactation.
Lanadelumab (Monoclonal antibody against plasma kallikrein)	Animal studies demonstrated no evidence of harm to the developing fetus in monkeys.	Not recommended in pregnancy or lactation.

FDA: U.S. Food & Drug Administration.

Future considerations include avoiding oestrogen-containing contraceptives which can increase the frequency and severity of attacks. ¹³ , ¹⁴ Approximately 70% of women with C1INH-HAE who use oral contraceptives containing oestrogen have an increase in severity and frequency of attacks. ¹³ Progestogens are often beneficial, reducing the frequency of attacks by 60–82%. ¹⁰ , ¹⁵ and therefore should be used first line for contraception. ¹³ Anti-gonadotropic agents are more effective than low-dose progestin-only pills. The progesterone-eluting intrauterine system may be beneficial for women with C1INH-HAE and can usually be inserted without requiring C1INH prophylaxis, though this should be available. The contraceptive implant is well tolerated by some women with C1NH-HAE. ¹³ ACE inhibitors worsen symptoms and should be avoided.

Conclusion

Pregnant women with HAE should be delivered in a hospital that provides immediate access to consultants in obstetrics, anaesthesiology and perinatology. A treatment plan should be developed within a multi-disciplinary team to enable forward planning and pre-empting complications. C1INH replacement, fiberoptic intubation and front of neck access equipment should be readily available. Plasma-derived human C1INH inhibitor concentrate is the preferred prophylactic and treatment intervention in pregnancy. Vaginal delivery for the majority of women is the safest method of delivery, with prophylactic C1INH for any obstetric intervention.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Guarantor

Anita Banerjee.

Contributorship

AJ and IT proposed the article and researched the literature. All authors reviewed and edited the manuscript and approved the final version of the manuscript.

Patient consent

Written consent has been provided by the patient. She has reviewed and approved the submitted article.

Ethical approval

Not applicable.

Trial registration

Not applicable.

ORCID iDs

Adam D Jakes https://orcid.org/0000-0003-0943-8618

Anita Banerjee https://orcid.org/0000-0002-9442-9662