Hereditary Angioedema and Wilson's Disease During Breastfeeding

C1 esterase inhibitor

The most typical treatment of HAE consists of replacement of C1 esterase inhibitor. This product is derived from human plasma and is usually injected intravenously twice weekly by self-administration for prophylaxis, although subcutaneous injection is sometimes used. It can also be used on demand for acute HAE attacks, and a recombinant human C1 esterase inhibitor is also approved for treating acute attacks. U.S. guidelines consider either of the products suitable for prophylactic or on-demand use in nursing mothers. ³

More than 25 published case reports exist of mothers with HAE who used C1 esterase inhibitor for on-demand treatment or prophylaxis while they were breastfeeding their infants. None of the breastfed infants experienced any adverse reactions. In addition, a patient with Factor XII HAE was also successfully treated with subcutaneous C1 esterase inhibitor during pregnancy and lactation.

Icatibant

Icatibant is used to treat acute attacks of HAE. It is a decapeptide bradykinin antagonist that is rapidly and almost completely absorbed after subcutaneous injection. The maximum serum concentration is reached at about 45 minutes after injection. Icatibant is extensively metabolized by proteolytic enzymes to inactive metabolites. Its average plasma half-life is 1.4 hours, and it is not detected in the serum after 6 hours. Because of these characteristics, timing of the doses around breastfeeding might be possible to largely avoid exposure of the breastfed infant.

This strategy was used in one woman with HAE who began using icatibant 30 mg subcutaneously as needed for HAE attacks when her breastfed infant was 4 months of age. She continued breastfeeding for 1 year while taking icatibant. Doses were injected at night before the infant's longest sleep period and breastfeeding was not resumed until at least 6 hours after a dose. In cases of swelling of the face and neck and abdominal pain, icatibant was immediately self-administered, and formula was given instead of breast milk. In her second pregnancy 2 years later, she used C1 esterase inhibitor until the infant was 1 month of age, when she resumed icatibant therapy. There was no apparent harm to the infant.

Ecallantide

Ecallantide is a recombinant protein produced in yeast cells. It is a human plasma kallikrein inhibitor that is given by subcutaneous injection for on-demand use. Kallikrein inhibition reduces bradykinin production. Because it can cause anaphylaxis, it should only be given in a health care setting. No information is available on the use of ecallantide during breastfeeding. Because ecallantide is a large protein molecule with a molecular weight of about 7,000 Da, the amount in milk is likely to be very low and absorption is unlikely because it is probably destroyed in the infant's gastrointestinal tract. Until more data become available, ecallantide should be used with caution during breastfeeding, especially while nursing a newborn or preterm infant.

Lanadelumab

Lanadelumab is a fully human monoclonal antibody that binds plasma kallikrein and inhibits its proteolytic activity, thereby reducing production of bradykinin. It is given subcutaneously every 2 or 4 weeks for HAE prophylaxis. No information is available on the clinical use of lanadelumab during breastfeeding. Lanadelumab is a large protein molecule with a molecular weight of about 146,000 Da, so the amount in milk is likely to be very low and absorption is unlikely because it is probably destroyed in the infant's gastrointestinal tract. Until more data become available, lanadelumab should be used with caution during breastfeeding, especially while nursing a newborn or preterm infant. Waiting for at least 2 weeks postpartum to resume therapy may minimize transfer to the infant.

Berotralstat

Berotralstat is a small-molecule oral plasma kallikrein inhibitor used to prevent attacks of HAE. No information is available on the excretion of berotralstat into breast milk. Berotralstat is about 99% bound to plasma proteins, so the amounts in milk are likely to be very low. If berotralstat is required by the mother, it is not a reason to discontinue breastfeeding. Until more data become available, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.

STAR-0215

STAR-0215 is a monoclonal antibody that is a plasma kallikrein inhibitor and has been given fast-track status by the US Food and Drug Administration. It appears that subcutaneous injections will provide suppression of HAE attacks for at least 3 months. STAR-0215 is a potential first-line treatment for the disease, but clinical trials are ongoing. Like other monoclonal antibodies, it is unlikely to reach the breastfed infant in clinically important amounts, but no data are available.

Second-line therapies

These include the anabolic androgens, such as danazol or stanozolol, and antifibrinolytics, such as tranexamic acid or aminocaproic acid. Anabolic androgens are considered to be contraindicated during breastfeeding because of a lack of data and the possibility of masculinization and hirsutism of the infant. Aminocaproic acid is also contraindicated because of a lack of information during breastfeeding. Although some older guidelines recommend against using tranexamic acid, newer information indicates that it is probably acceptable to use during breastfeeding. A controlled study found no adverse outcomes among breastfed infants whose mothers took tranexamic acid in dosages up to 4 g daily during breastfeeding. One center in Canada reports routine use of tranexamic acid 3 g daily in nursing mothers with bleeding disorders until bleeding stops. Tranexamic acid is used for HAE in low-income countries where first-line treatments are not available, but should not be used if C1-INH is available.

Penicillamine

Information from 11 nursing mothers indicates that penicillamine is not detectable in breast milk. Case reports of nursing mothers taking penicillamine for Wilson's disease date back to the 1990s. No adverse effects have been reported among >30 breastfed infants whose mothers were taking penicillamine.

In some early case reports and studies, milk concentrations of copper and zinc were reduced during therapy of Wilson's disease with penicillamine. A more recent study compared copper concentrations in the milk of 7 mothers taking penicillamine with those of 25 control mothers without Wilson's disease. The copper concentration in the colostrum (0–4 days postpartum) of penicillamine-treated women was slightly higher than normal. Copper and zinc concentrations were normal in mature breast milk (>14 days postpartum) from all mothers treated with penicillamine, despite lower copper concentrations in maternal serum.

Trientine

Information from 10 patients taking trientine in dosages up to 1,750 mg/day indicates that trientine is not detectable in breast milk. Reports exist on about 60 infants who were breastfed during maternal trientine therapy and no adverse effects have been reported. The effect of trientine on copper and zinc concentrations in milk is somewhat conflicting, but breastfed infants appear to have normal serum copper and zinc plasma levels.

Zinc

Zinc is a normal component in human milk. Typical daily doses of 15 mg or less of oral zinc from prenatal vitamins or other multimineral supplements do not alter milk zinc levels in lactating women. Daily oral doses of 15–25 mg have negligible effects on milk zinc levels. One nursing mother in Japan with Wilson's disease was taking 75 mg/day of zinc acetate. Zinc concentrations in her colostrum at 4 days postpartum and mature milk at 32 days postpartum were within the normal range of zinc in breast milk in Japanese women. Another small study found that average zinc concentrations in the mature milk of six women receiving oral zinc for Wilson's disease were somewhat elevated, but within the range of control mothers not receiving zinc.