Management of pregnancy with prolactinoma Recommendation 1: Dopamine agonists should be discontinued as soon as possible after the discovery of pregnancy in female patients with prolactinoma (1|○○). In some patients with macroadenomas who are being treated with dopamine agonists and have not had prior surgery or radiation therapy, dopamine agonists may be used with caution for the rest of the pregnancy if pregnancy is detected. Unless the patient’s pituitary tumor is infiltrative or located close to the optic cross (1|○○○). Basis: Bromocriptine can pass through the placenta and the first 4 weeks after conception is a critical period of fetal organogenesis will be exposed to the effects of the drug. In the reported 6
000 women who took bromocriptine for hyperprolactinemia during pregnancy, there was no increased incidence of congenital malformations or miscarriage. Some long-term follow-ups up to the age of 9 years in children also did not reveal any harm from the drug. The drug has also been suggested to be safe in studies of hyperprolactinemic infertile women treated with cabergoline, but the number of clinically reported cases is still small. In a prospective study of 85 cases, 80 of which were conceived while still on treatment with capsaicin, the drug was withdrawn at 5 weeks of gestation and all newborns were healthy and the maternal pituitary tumors did not progress. This evidence suggests that fetal exposure to bromocriptine or cabergoline during early pregnancy does not adversely affect the fetus. Quinagolide has a poorer safety profile, and its use in pregnancy has been reported less frequently; therefore, it is not recommended for female patients preparing for childbirth. Trade-off between pros and cons: The recommendation to discontinue bromocriptine or capsaicin in pregnancy is mainly based on the possible unintended effects of exogenous drugs on fetal development. Recommendation 2: For pregnant patients with prolactinoma, measurement of prolactin (1|) during pregnancy is not recommended. Basis: Serum prolactin can increase up to 10-fold during pregnancy and up to 150-300 μg/L during delivery, and the pituitary gland can increase more than 1-fold in size as estrogen stimulates prolactin cell proliferation. When dopamine agonists are discontinued at the beginning of pregnancy, serum prolactin increases, but the subsequent increase in prolactin does not reflect the size of the pituitary tumor or the viability of the tumor growth. In addition, not all patients with prolactinoma have elevated serum prolactin during pregnancy. The pregnancy process itself may also ameliorate hyperprolactinemia, as it has been observed that postpartum serum prolactin levels may be lower than prior to conception. In some patients, hyperprolactinemia may resolve spontaneously after delivery. The pros and cons are weighed: the pregnancy process itself can elevate prolactin and the measurement is of little significance. Recommendation 3: Routine pituitary MRI during pregnancy is not recommended in pregnant patients with microadenomas or macroadenomas in the pituitary gland, unless symptoms of a growing pituitary tumor, such as visual field defects, are present (1|○○). Rationale: There is concern that prolactin macroadenomas will increase in size during pregnancy, while microadenomas are less likely to increase. Patients may be told to discontinue dopamine agonists after pregnancy is diagnosed, and pituitary tumors that have shrunk with prior treatment may grow. High levels of estrogen during pregnancy stimulate prolactin cell proliferation in the normal pituitary gland, and this physiologic pituitary growth can cause pituitary tumors to develop outside the saddle area. At the same time, the high estrogen environment can directly promote prolactinoma growth. In fact, in general, prolactin microadenomas and macroadenomas within the saddle area do not show signs of enlargement. A review including 457 pregnant patients with microadenomas noted that only 2.6% of patients showed symptoms of pituitary tumor enlargement. The risk of developing symptoms due to pituitary tumor enlargement is low, and patients with microadenomas only require a physical examination every 3 months during pregnancy; the risk of developing symptoms due to macroadenoma growth is much greater. Patients who underwent pituitary decompression surgery or pituitary radiation therapy before pregnancy had only 2.8% of symptoms of pituitary tumor growth during pregnancy, which was not different from the risk in patients with microadenoma. Patients with macroadenomas who did not have surgery or radiation therapy prior to pregnancy had a 31% risk of developing symptoms due to pituitary tumor growth. If headache or worsening headache symptoms and visual field changes occur, a formal visual field examination and pituitary MRI (avoiding gadolinium isotopes) should be performed immediately. Recommendation 4: Patients with prolactin macroadenoma who have been treated with dopamine agonists without pituitary tumor reduction, or who cannot tolerate bromocriptine and capsaicin, may be considered for surgical treatment before preparation for pregnancy (1|○○). Rationale: Although some endocrinologists recommend surgery before pregnancy for all patients with prolactinoma, surgery may result in hypopituitarism, making conception more difficult and requiring treatment such as gonadotropin ovulation, or lifelong hormone replacement therapy. Recommendation 5: Patients with gestational prolactinomas who present with severe headaches and/or visual field changes should have a formal visual field examination and MRI (avoid gadolinium isotopes, 1|○○). Rationale: Most pregnant patients with prolactinoma who do not have symptoms of headache or visual field changes do not need MRI and visual field examinations. Increased physical examinations and formal visual field examinations during pregnancy are recommended for patients with macroadenomas who have not had previous surgery. Trade-offs: This recommendation recommends physical examinations rather than MRI for pregnant patients with prolactinoma to avoid the possible effects of imaging on the fetus and, secondarily, to consider the examination of morphologic changes in pituitary tumors. In contrast, when severe headaches or visual field defects are present, priority is given to avoid permanent optic nerve damage. Recommendation 6: Treatment with bromocriptine (1|○○) is recommended in pregnant patients with prolactinoma presenting as a growing symptom. Basis: If a pituitary tumor grows during pregnancy with symptoms of occupancy, treatment includes dopamine agonists and pituitary tumor surgery. No controlled studies have been reported on this issue, and there is a lack of research on the potential risks of these options. Continued use of bromocriptine during pregnancy has been reported in only about 100 cases, with no definite adverse drug reactions reported and only one case of cryptorchidism and one case of horseshoe inversion malformation seen. Split doses of bromocriptine are recommended because only this drug has been reported relatively frequently, and for patients who cannot tolerate bromocriptine then carte blanche can be used. If the symptoms of pituitary tumor growth are not controlled by reintroduction of dopamine agonists, surgical treatment is indicated. There are no studies comparing the risks of dopamine agonists and surgical treatment during pregnancy, so some endocrinologists prefer to use dopamine agonists. If the fetus is approaching full term, induction of labor should be considered prior to surgical treatment. Trade-off: This recommendation recommends dopamine agonist therapy because the risks of surgery during pregnancy may outweigh the effects of the drug on the fetus.