HAE in women, pregnancy, and children

Professor Henriette Farkas was invited to give a talk on HAE in women, pregnancy, and children, which are always eagerly awaited topics.

She started by thanking the audience and HAEi for the opportunity to speak, before dedicating her presentation to the memory of some of the inspirational physicians who had devoted their lives to understanding HAE and improving its care.

Women and HAE

Across all types of HAE, more women than men are affected, Prof Farkas told the audience. Additionally, females tend to have more frequent and severe attacks, most likely as a result of the impact the hormone estrogen has on the kinin-kallikrein system, which leads to bradykinin production. The use of estrogen-containing oral contraceptives increases the frequency and severity of HAE attacks. For this reason, Prof Farkas suggested that these contraceptives should be avoided in women with HAE. Other options, such as barrier methods or the progestin-containing oral contraceptive, should be used instead.

All targeted treatments for HAE can be safely administered in females and males, Prof Farkas told the audience. However, androgens should be used only with caution in female patients as these can lead to side effects, including weight gain, hair growth, and changes to the menstrual cycle.

A key trigger for HAE attacks is menstruation, with 68% of cases being linked to a woman’s period. Additionally, Prof Farkas presented a slide that showed that sex hormones change over time, which can mean that HAE symptoms worsen during puberty, but may decrease during the menopause. This is not clear-cut, however, and some patients experience more frequent attacks during menopause. Hormone replacement therapy (HRT) may cause worsening of HAE symptoms, Prof Farkas counselled.

Pregnancy

Overall, there is no consistent change in HAE among all women during pregnancy; some report experiencing fewer attacks, some report a greater number, and some report no change at all. According to Prof Farkas, all three trimesters of a pregnancy may feature attacks, and abdominal attacks may occur more frequently. Perhaps surprisingly, Prof Farkas indicated that giving birth is rarely the cause of an HAE attack. However, breastfeeding has been associated with increased HAE attacks.

The only treatment recommended during pregnancy, post-partum, and during breastfeeding is plasma-derived C1-inhibitor. Fresh-frozen plasma and solvent-detergent plasma represent second-line options for acute treatment and short-term prophylaxis. Androgens are not recommended during pregnancy as they can affect the developing fetus.

For a natural delivery, short-term prophylaxis with intravenous plasma-derived C1-inhibitor is only a consideration (not a recommendation). However, for complicated deliveries, the same short-term prophylaxis treatment is recommended.

Children with HAE

Prof Farkas opened the final part of her talk by asking: What makes pediatric HAE patients unique? Her answer suggested that as children grow, their bodies undergo lots of changes, which can make it challenging to diagnose and treat HAE. She said it was uncommon for clinical symptoms to occur in a fetus or in infants. Only one case has been published on angioedema in the womb, she said. However, half of patients experience their first attack before the age of 18, and the early onset of symptoms may predict more severe HAE attacks.

In terms of symptoms themselves, the most common and often the earliest symptom is swelling in the extremities, with a prodrome of itching, which can lead to a misdiagnosis of urticaria. Additionally, as abdominal pain is a common symptom in children, it can lead to abdominal attacks being misdiagnosed.

Importantly, because of the smaller airway, a laryngeal or throat attack may develop quickly in children.

To diagnose HAE in children, Prof Farkas outlined that C1 and C4 levels can be measured, as in adults. However, in children under 1 year of age, the complement system is underdeveloped, which may result in lower-than-normal readings.

Prof Farkas advised that families with children with HAE need to ensure that everyone involved in the care of the child, such as teachers, are given written information about the disease and can recognize an attack. As soon as they are old enough, patients should be trained to self-administer HAE treatment and be aware of an emergency care plan.

As children reach adulthood, this can be a complicated and challenging time for their HAE care. Prof Farkas suggests that any transition should be planned for. Ideally, the whole family will be cared for in a single center.

In general, the treatment approach to HAE in children is the same as in adults. The use of therapies to prevent attacks, but to have medication on hand to treat and resolve attacks if they occur.

Prof Farkas highlighted that the WAO/EACCI guidelines recommend:

• As prophylaxis, plasma-derived C1-inhibitor and lanadelumab for children
• To treat attacks, plasma-derived and recombinant C1-inhibitor, and icatibant for children and adolescents
• For adolescents, the same long-term prophylaxis medication is recommended as for adults: plasma-derived C1-Inhibitor, lanadelumab, and berotralstat. In the US, ecallantide is available for adolescents.

Prof Farkas concluded by sharing that new guidelines on the management of HAE in children have been developed and submitted for publication this year. She ended the talk by telling the audience that by working together a great deal more can be achieved.

Currently, oral deucrictibant is being trialed to treat attacks in adolescents with HAE in the RAPIDe-3 trial. Sebetralstat is being tested to treat attacks in children (2-11 years old) with HAE. Berotralstat and garadacimab are also being trialed in children (2-<12 years old) to prevent HAE attacks. Navenibart is being tested in adolescents with HAE as prophylaxis.

Prof Farkas concluded by sharing that new guidelines on the management of HAE in children have been developed and submitted for publication this year. She ended the talk by telling the audience that by working together a great deal more can be achieved.