C1 Inhibitor Therapy Prevents HAE Long-term in Some Pregnant Women, Study Shows

A Brazilian study shows that C1 inhibitor (C1-INH) therapy is a safe and efficient option for long-term prophylaxis (prevention) of hereditary angioedema (HAE) in pregnant women with who have normal C1-INH levels.

The research, “Use of pdC1-INH concentrate for long-term prophylaxis during pregnancy in hereditary angioedema with normal C1-INH,” was published recently in the The Journal of Allergy and Clinical Immunology: In Practice.

Patients with HAE typically exhibit recurrent angioedema (swelling) attacks that involve multiple organs. The disease is caused by genetic mutations that increase the levels of the inflammatory peptide bradykinin.

The first biochemical change linked with HAE was C1-INH deficiency. C1-INH inhibits the spontaneous activation of the complement system, a part of the immune system, and its deficiency leads to increased bradykinin production.

HAE patients also may have normal C1-INH levels and function, which leads to later disease onset, longer disease-free intervals, and less frequent abdominal pain. These patients may present mutations in the gene coding for the clotting protein factor XII (FXII), which also results in excessive bradykinin concentration.

HAE patients, especially those with normal C1-INH, usually present worsening of symptoms when estrogen levels are high — during pregnancy or after estrogen intake, such as with contraceptives or hormone replacement therapy. Alterations in FXII gene expression, modulation of bradykinin’s B2 receptor expression, and lowering of C1-INH levels are among the proposed mechanisms linking estrogen to deteriorated symptoms.

The discontinuation of long-term HAE prophylaxis during pregnancy, as well as the elevation of blood estrogen levels, contribute to worsened symptoms during pregnancy, which are most evident in the first trimester.

Plasma (blood)-derived C1-INH (pdC1-INH) is one of the three treatment modalities for long-term prophylaxis in HAE, and the only one approved during pregnancy.

So, the research team addressed the use of pdC1-INH for long-term prophylaxis of HAE during pregnancy. “As far as we know this is the first study regarding the use of pdC1-INH for long-term prophylaxis of HAE with normal C1-INH in pregnancy,” the team wrote.

pdC1-INH therapy is effective in the treatment of acute attacks and short-term prophylaxis in HAE patients with normal C1-INH concentration and function. This HAE type mostly affects women, particularly those who are pregnant or take estrogen. However, “the experience with long-term prophylaxis in HAE with normal C1-INH is restricted to case reports only,” the researchers noted.

A number of treatment strategies have been proposed for HAE patients with normal C1-INH, including progestins and anti-fibrinolytic agents, which promote blood clotting. However, no appropriate study on long-term prophylaxis with pdC1-INH in pregnant HAE patients with normal C1-INH had been done, the investigators said.

The scientists hypothesized that elevating blood C1-INH above the physiological levels would increase the inhibition of bradykinin production in these patients.

The study included three HAE patients with normal C1-INH, family history for HAE, frequent attacks, and worsened symptoms during pregnancy.

The first patient started having recurrent angioedema at age 15, but was not diagnosed with HAE with normal C1-INH until she was 28. She began long-term prophylaxis with pdC1-INH at week 20 of pregnancy, which led to milder and less-frequent attacks.

A second patient had recurrent angioedema since age 17 and was diagnosed when she was 30. She began taking progestins, which stopped her attacks until pregnancy. She started long-term prophylaxis with pdC1-INH at 32 weeks of pregnancy. The patient has been asymptomatic since.

The third patient had recurrent angioedema once a year and was diagnosed at age 27. Long-term prophylaxis with pdC1-INH was started at week 27 of pregnancy. Similar to the second patient, this patient has been asymptomatic and has not required medications since. She had no attacks during delivery.

In all three patients, the clinicians administered pdC1-INH at least once a week, but aimed at a twice-weekly dosage.

“We observed that after long-term prophylaxis with pdC1-INH, there was a remarkable improvement in disease in all patients, who had no adverse reactions, no peripartum HAE severe attacks, and who gave birth to healthy babies,” the researchers wrote.

“pdC1-INH may be the first choice for long-term therapy of pregnant women with HAE with normal C1-INH who have been presenting with frequent attacks,” they concluded.