OCTREOTIDE

Fetal Risk Summary

This cyclic octapeptide (Octreotide; SMS-201-995), an analogue of the natural hormone, somatostatin, is used to reduce blood levels of growth hormone and somatomedin C in patients with acromegaly and for the symptomatic treatment of patients with profuse watery diarrhea as a result of metastatic carcinoid tumors or vasoactive intestinal peptide–secreting tumors. It has also been used to reduce insulin requirements for patients with diabetes mellitus; to reduce output from gastrointestinal, enteric, and pancreatic fistulas; in the treatment of variceal bleeding; and for various other indications.

No evidence of impaired fertility, teratogenicity, or fetal harm was observed in pregnant rats and rabbits given up to 16 times the highest human dose based on body surface area (1).

Octreotide crosses the human placenta to the fetus (2,3). A 31-year-old infertile woman was treated with octreotide 300 µg/day for hyperthyroidism induced by a thyroid stimulating hormone (TSH)–secreting macroadenoma (2,3). The patient became euthyroid, with return of normal menstruation, after 3 months of therapy. She was found to be pregnant 1 month later and octreotide treatment was stopped. Because her symptoms recurred, therapy was reinstated at 6 months' gestation and continued until an elective cesarean section at 8 months' gestation delivered a normal infant (weight 3300 g, length 51 cm, sex not specified). The concentration of octreotide in umbilical cord serum at delivery was 359 pg/mL compared with the mean maternal level (measured on two different occasions 1 month earlier) of 890 pg/mL (range 764–1191 pg/mL) (2). Although the amount of drug in the newborn was only about 40% that in the mother, the authors concluded that octreotide crossed the placenta by passive diffusion for two reasons (3). First, only the unbound fraction of octreotide is available for placental transfer and, second, the drug is 60%–65% bound to maternal lipoprotein. Thus, assuming that the mother's concentration had not changed significantly, the unbound maternal fraction and the infant's serum level were close to unity. Subsequently, the concentration of octreotide in the infant's serum decreased to 251 pg/mL at 3 hours of age and was undetectable (<20 pg/mL) when next measured (at 40 days).

The cord serum concentrations of TSH, thyroid hormones, prolactin, and growth hormone were normal at birth, at 3 hours, and at 40 and 104 days of age (3). Because the infant's pituitary-thyroid function was not affected by exposure to octreotide at these concentrations, the authors speculated that the somatostatin receptors on thyrotroph cells, as suggested by studies in animals, are not completely functional at birth (3).

The pregnancy of a previously infertile 37-year-old woman who was treated with octreotide for acromegaly during the first 8 weeks of gestation was described in a 1989 Reference (4). Treatment, 100 µg SC 3 times daily, was started within approximately 4 days of conception and discontinued when pregnancy was diagnosed at 8 weeks. A healthy male infant (weight 2530 g, length 46.0 cm) was delivered by cesarean section 2 weeks before term because of the mother's age and imminent fetal asphyxia. No malformations were apparent, and his subsequent development at the time of report (age not specified but estimated to be about 9 months) was normal.

A 37-year-old woman with primary amenorrhea was discovered to have acromegaly as a result of pituitary macroadenoma (5). She was treated with octreotide and bromocriptine with re-appearance of her menses occurring 7 months later. Treatment with octreotide (300 µg 3 times daily) and bromocriptine (20 mg/day) was continued until a 1-month pregnancy was diagnosed approximately 7 months later. She eventually delivered, by emergency cesarean section for fetal distress, a term 3540-g, 50-cm male infant with no evidence of congenital defects. Except for requiring mechanical ventilation for 3 days because of neonatal asphyxia, his subsequent development was satisfactory.

A 1999 case report described the pregnancy of a 36-year-old woman who was treated with octreotide (240 µg/day) for a pituitary adenoma (6). The woman had clinical and laboratory signs of acromegaly. Treatment was started at 13 weeks' gestation and continued until delivery at 40 weeks' of a 3288-g, normal female infant with Apgar scores of 8 and 9 at 1 and 5 minutes, respectively, who was developing normally. Cord concentrations of growth hormone, thyrotropin, and prolactin were within normal limits.

In summary, octreotide is not teratogenic or toxic in two animal species, but published reports have described only four women who were treated during portions of their pregnancies. Although all of the outcomes were normal, the data are too limited to assess the risk that octreotide presents to the embryo or fetus. Moreover, the drug crosses to the fetus and has been measured in the newborn.

Breast Feeding Summary

It is not known whether octreotide is transferred to breast milk, but this should be expected because of the documented placental passage. No reports have been located that described the use of this agent during lactation. However, because of probable digestion following oral therapy, the risk to the nursing infant appears to be nonexistent.

References

1. Product information. Sandostatin. Novartis Pharmaceuticals, 2000.
2. Caron P, Gerbeau C, Pradayrol L. Maternal-fetal transfer of octreotide. N Engl J Med 1995;333:601–2.
3. Caron P, Gerbeau C, Pradayrol L, Cimonetta C, Bayard F. Successful pregnancy in an infertile woman with a thyrotropin-secreting macroadenoma treated with somatostatin analog (octreotide). J Clin Endocrinol Metab 1996;81:1164–8.
4. Landolt AM, Schmid J, Karlsson ERC, Boerlin V. Successful pregnancy in a previously infertile woman treated with SMS-201-995 for acromegaly. N Engl J Med 1989;320:621–2.
5. Montini M, Pagani G, Gianola D, Pagani MD, Piolini R, Camboni MG. Acromegaly and primary amenorrhea: ovulation and pregnancy induced by SMS 201-995 and bromocriptine. J Endocrinol Invest 1990;13:193.
6. Takeuchi K, Funakoshi T, Oomori S, Maruo T. Successful pregnancy in an acromegalic woman treated with octreotide. Obstet Gynecol 1999;93:848.