Abstract
Several genetic diseases have had advances in treatment, including some new drugs. This column will focus on a few of these drug therapies and their implications for breastfeeding. More detailed information and references on specific drugs can be found in the corresponding drug records in LactMed.
Phenylketonuria
Phenylketonuria (PKU) is an autosomal recessive disorder that results from a deficiency of the hepatic enzyme phenylalanine hydroxylase, causing an accumulation of phenylalanine in the blood. Mothers with PKU have higher than normal phenylalanine levels in their milk, but this is not a concern if their infant does not have PKU. If an infant is known to have PKU, breastfeeding should be recommended only in consultation with a pediatrician who has expertise caring for children with PKU, according to new guidelines from the American College of Obstetricians and Gynecologists. 1
More than 600 variants of PKU have been described and about half of these are responsive to tetrahydrobiopterin (BH4). BH4 is a cofactor in the enzymatic conversion of phenylalanine to tyrosine by phenylalanine hydroxylase. BH4 is a normal component of human milk. In a study of 10 women without PKU, colostrum was obtained from 9 women and mature milk was obtained from 6 women. Colostrum levels of BH4 averaged about 100 nmol/L (241 μg/L), and mature milk levels averaged about 500 nmol/L (1206 μg/L). Sapropterin is a synthetic version of BH4 that is used in conjunction with dietary restriction of protein and phenylalanine by patients who are responsive to exogenous administration of BH4. Three mothers who were taking sapropterin for PKU had breast milk samples taken. Their milk BH4 levels were greater than those reported in normal human milk, but specific values for sampling time and milk levels were not reported in the meeting abstract.
Some experience with use of sapropterin by nursing mothers has been reported. A Japanese woman with PKU took sapropterin dihydrochloride 500 mg (10 mg/kg) daily during pregnancy and postpartum. She breastfed her infant until 25 months of age, although the extent of breastfeeding was not specified. The infant had normal developmental milestones and normal growth at 31 months of age. In two postmarketing pregnancy registries of women taking sapropterin, a total of 16 women were identified who breastfed for a mean of 3.5 months. No lactation-related safety concerns were reported in breastfed infants of these mothers. In addition, sapropterin is FDA approved for use in infants with PKU who are 1 month of age or older, so concern is low with older infants. United States and European guidelines state that sapropterin dihydrochloride supplementation is not contraindicated as an adjunct to dietary therapy in breastfeeding women who are responsive to BH4.
Pegvaliase is a PEGylated form of phenylalanine ammonia lyase given subcutaneously that converts phenylalanine to ammonia and trans-cinnamic acid. It substitutes for the deficient phenylalanine hydroxylase activity in patients with PKU and reduces blood phenylalanine concentrations. It is used in PKU patients with high phenylalanine concentrations on existing therapy. One woman with PKU stopped her pegvaliase during pregnancy and for 7 months postpartum while breastfeeding her infant. After weaning, she restarted pegvaliase and pumped breast milk samples for analysis while taking a dose of 20 mg daily. The activity of phenylalanine ammonia lyase in milk was equal to background levels found in blank breast milk.
Sickle Cell Disease
Sickle cell disease is caused by abnormal hemoglobin (hemoglobin-S) that causes abnormally shaped red cells that are prone to causing veno-occlusion. Several drug therapies are available to treat sickle cell disease and its manifestations. The traditional drug therapy, hydroxyurea, increases the production of fetal hemoglobin. Because it is a cancer chemotherapeutic agent, hydroxyurea has traditionally not been thought to be safe during breastfeeding. In one recent study, 16 lactating women, 2 with sickle cell disease, were given 1 g of hydroxyurea orally. Milk samples were collected before the dose and at 10 time points over the next 12 hours. A milk sample obtained at 24 hours after the dose contained no detectable drug. A pharmacokinetic model created using these data predicted that the daily hydroxyurea dosage that an exclusively breastfed infant would receive would be 0.46 mg/kg. By avoiding breastfeeding for 3 hours after the dose, the amount of drug transferred to the infant would be cut in half. These amounts were estimated to be 3.1% and 1.6%, respectively, of the maternal weight-adjusted dosage or relative infant dosage. Although no infant outcome data have been reported, this study indicates that hydroxyurea may be acceptable in nursing mothers in the dosages used in sickle cell disease, which are lower than those used to treat leukemias.
Two new drugs have recently become available for sickle cell disease. Crizanlizumab is a monoclonal antibody that binds to P-selectin, a protein on the surface of the endothelium that initiates adhesion of platelets. Crizanlizumab thereby inhibits platelet adhesion, reduces vaso-occlusion, and increases microvascular blood flow. No information is available about crizanlizumab during breastfeeding. However, it is a humanized IgG2 kappa monoclonal antibody with a molecular weight of about 146,000 Da that is given intravenously. Its large molecular weight inhibits its passage into milk, but endogenous IgG does appear in milk in small amounts. The drug is probably not absorbed orally by the infant. The effects of local gastrointestinal (GI) exposure and limited systemic exposure in the breastfed child to crizanlizumab are not known, but the drug is not contraindicated in nursing mothers.
Voxelotor is an orally administered small molecule that binds to hemoglobin S, inhibiting polymerization. No information is available on the appearance of volexetor in milk or on the safety of the drug in breastfed infants. Because of the potential for serious adverse reactions in the infant, breastfeeding is currently not recommended during treatment and for at least 2 weeks after the last dose.
Cystic Fibrosis
Cystic fibrosis (CF) is caused by various mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Historically, treatment of CF was aimed at treating disease manifestations such as poor absorption of fats and lung infections when they occur. Several new drugs are available to treat the disease more directly. These pharmacologically related drugs are called CTFR modulators. Elexacaftor, ivacaftor lumacaftor, tezacaftor, and their combinations, increase chloride transit across the cell membrane. With the elxacaftor, tazacaftor, and ivacaftor triple combination, about 90% of CF patients can be treated successfully.
Some information is available on the use of these drugs during breastfeeding. Data from one maternal-infant pair with ivacaftor and lumacaftor indicate that maternal ivacaftor therapy produces low levels in milk. The breastfed infant had transient elevations in bilirubin and liver enzymes during maternal therapy that could not definitively be attributed to the drugs in breast milk; however, lumacaftor is known to cause elevations in hepatic transaminases and bilirubin levels. The other CTFR modulators do not cause these elevations in bilirubin and transaminases. Until more data are available, monitoring of infant bilirubin and liver enzymes might be advisable during breastfeeding with maternal lumacaftor and ivacaftor therapy.
A survey of lead clinicians of adult CF centers in Europe, the United Kingdom, United States, Australia, and Israel requested anonymized data on pregnancy outcomes in women using CFTR modulators during pregnancy and lactation. Responses were received from 31 centers for a total of 64 pregnancies in 61 women, resulting in 60 live births. Thirteen infants were breastfed on ivacaftor alone, 9 infants were breastfed on lumacaftor and ivacaftor, and 5 infants were breastfed on tezacaftor and ivacaftor for a total of 27 infants exposed to ivacaftor in breast milk, all with no reported complications. The extent of breastfeeding was not reported. A task force of respiratory experts from Europe, Australia, and New Zealand considers these drugs to be probably safe during breastfeeding. 2
For CF patients taking pancreatic enzymes, the enzymes appear safe because they are not appreciably absorbed from the mother's GI tract, so they should not reach the infant. Another enzyme is dornase alfa, which is a mucolytic given by inhalation to CF patients. No information is available on the clinical use of dornase alpha during breastfeeding. Because it is a large protein molecule with a molecular weight of about 37,000, the amount in milk is likely to be very low and absorption is unlikely. A task force of respiratory experts found both pancrelipase and dornase alfa to be compatible with breastfeeding. 2
Gaucher Disease
Gaucher disease is caused by a genetic deficiency of the enzyme glucocerebrosidase that leads to accumulation of glucosylceramide in the lysosomes of reticuloendothelial cells, primarily in the liver, spleen, and bone marrow. 3 The most common method of treatment involves intravenous enzyme replacement therapy at about 2-week intervals. Four versions of beta-glucocerebrosidase are marketed in the United States. Alglucerase is the slightly modified placenta-derived form of beta-glucocerebrosidase. The other three drugs are biosynthetic versions of beta-glucocerebrosidase. Velaglucerase alfa is produced in human fibroblasts and has the same amino acid sequence as the naturally occurring human enzyme. Imiglucerase is made in Chinese hamster ovary cell cultures and differs from the endogenous enzyme by one amino acid. Taliglucerase alfa is synthesized in carrot cell culture and differs from the endogenous enzyme by two amino acids at the N-terminal end and up to seven amino acids at the C-terminal end. Enzyme activity in breast milk has been reported with imiglucerase and taliglucerase alfa. Enzyme activity values were lower with taliglucerase alfa than those found in the milk of mothers treated with imiglucerase.
Alglucerase use has been reported in one nursing mother and imiglucerase has been used in four nursing mothers, with infant follow-up times from 1 to 3 years. None of the five breastfed infants showed any signs of abnormal development. Since beta-glucocerebrosidase is a normal component of breast milk and is likely not absorbed by the breastfed infant, these drugs are considered to be acceptable in nursing mothers.
Two oral drugs are available to treat Gaucher disease in those who cannot receive enzyme replacement therapy. Miglustat and eliglustat are small-molecule inhibitors of the enzyme glucosylceramide synthase, the initial enzyme in the glucosylceramide synthesis pathway. No information is available on either drug in nursing mothers. Miglustat has frequent, severe side effects, including diarrhea, weight loss, peripheral neuropathy, and tremor, so it is contraindicated during breastfeeding. Eliglustat is not contraindicated during breastfeeding, but it is currently avoided because of the lack of information. 3
Mucopolysaccharidosis
Several forms of mucopolysaccharidosis exist. Drug treatment of the various forms generally involves administration of a replacement enzyme intravenously. Mucopolysaccharidosis I is caused by a deficiency of the enzyme alpha-
Other commercially available enzymes in the United States are idursulfase for mucopolysaccharidosis II (Hunter syndrome), elosulfase alfa for mucopolysaccharidosis IVA (Morquio A syndrome), galsulfase for mucopolysaccharidosis VI (Maroteaux-Lamy syndrome), and vestrodinase for mucopolysaccharidosis VII (Sly syndrome). None of these have been studied in nursing mothers, but it is unlikely that any of them are of concern during nursing. In addition to being merely replacements for deficient normal enzymes, they are all large protein molecules whose concentrations in milk are likely to be very low, with GI absorption by the infant unlikely.
Fabry Disease
Fabry disease is caused by deficient activity of the lysosomal enzyme alpha-galactosidase A, leading to impaired catabolism of the glycosphingolipid, globotriaosylceramide. Agalsidase beta is a recombinant human alpha-galactosidase A that is given by intravenous infusion. Although no breastfeeding information is available on agalsidase beta, the similar enzyme agalsidase alfa has been used in Europe in nursing mothers. Six patients with Fabry disease were treated with agalsidase alfa 0.2 mg/kg every 2 weeks during pregnancy and postpartum. One infant who was partially breastfed for 10 months had asthma at age 4 years and another infant who was partially breastfed for 5 months had recurrent urinary tract infections up to 2 years of age, but was normal at the age of 5 years. None of the adverse effects appear to have been caused by agalsidase alfa. Three other infants who were exclusively breastfed for 6 months and partially breastfed until 12 months and one partially breastfed for 12 months all developed normally.
Migalastat is an oral alpha-galactosidase A pharmacological chaperone used in some types of Fabry disease. It is a small molecule, likely to be found in breast milk, but no lactation information is available. Although it is not contraindicated during breastfeeding, the lack of data indicates that caution is required in its use in nursing mothers.
Footnotes
Disclosure Statement
No competing financial interests exist.
Funding Information
No funding was received for this article.