Endocrine/Metabolic Agent (Miscellaneous)
PREGNANCY RECOMMENDATION: Human Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
Cabergoline does not exhibit direct embryo or fetal toxicity or teratogenicity in animals. Because it inhibits prolactin release, the agent can prevent or abort pregnancies in mice and rats, but this has no human relevance because human egg nidation is not regulated by prolactin. A 2002 review stated that cabergoline was the current treatment of choice for most patients with hyperprolactinemia (1). In addition, the review recommended that once ovulatory cycles were established, women should stop treatment 1 month before they intended to conceive. Hyperprolactinemia is a frequent cause of infertility (2). In many of these women, the partial or complete resolution of this condition will result in conception (2). When pregnancy is diagnosed, cabergoline should be discontinued. However, no evidence indicates that exposure to cabergoline in pregnancy is harmful.
FETAL RISK SUMMARY
Cabergoline is a synthetic ergot derivative that is a long-acting dopamine receptor (D2) agonist with low affinity for other dopamine (D1), adrenergic (α1 and α2), and serotonin (5-HT1 and 5-HT2) receptors. The drug has a direct inhibitory effect on prolactin secretion from the anterior pituitary gland. Cabergoline is indicated for the treatment of hyperprolactinemic disorders, either idiopathic or due to pituitary adenomas (3).
Animal reproduction studies have been conducted in mice, rats, and rabbits with daily oral doses (comparisons to human doses are made with the total weekly animal dose and the maximum recommended weekly human dose for a 50-kg human [MRHD], both based on BSA). In mice, doses up to about 55 times the MRHD caused maternal toxicity but no teratogenic effects in the offspring. In rats, a dose about 1/7th the MRHD caused an increase in postimplantation embryo and fetal losses, an effect that was thought to be due to the prolactin inhibitory effects of cabergoline. Conception in female rats was inhibited at a dose 1/28th the MRHD given 2 weeks before mating and throughout the mating period. A similar dose given to pregnant rats from 6 days before delivery throughout the lactation period caused growth restriction and death in offspring because of decreased milk secretion. In rabbits, a dose approximately 19 times the MRHD during organogenesis caused maternal toxicity (decreased food consumption and weight loss). An increased occurrence of various malformations was observed in one rabbit study using a dose 150 times the MRHD, but no increase in defects was observed in a second study at 300 times the MRHD (3).
A 1996 reproduction study in mice, rats, and rabbits concluded that cabergoline did not impair male rat fertility, was not teratogenic in mice and rabbits, had no effects on the latter phase of gestation or parturition in rats, and caused no toxicity in neonatal rats (4). The study also found that cabergoline could inhibit egg nidation in mice and rats and prevent conception. However, this effect has no relevance to humans because egg nidation in these species, but not in humans, is regulated by prolactin through a luteotrophic effect. A 1997 study in rats demonstrated that cabergoline-inhibited prolactin release resulted in the inhibition of ovarian progesterone biosynthesis, thereby preventing implantation and terminating pregnancy (5).
No reports describing the placental crossing of cabergoline in humans have been located. The molecular weight (about 452) is low enough; however, that exposure of the embryo and/or fetus should be expected.
In a group of 56 women with amenorrhea secondary to hyperprolactinemia (serum prolactin levels >20 mcg/L), 17 (81% of pregnancy-seeking women) became pregnant while under treatment with cabergoline (6). Women were instructed to discontinue cabergoline immediately after a positive pregnancy test. Of the 17 pregnancies, there was 1 spontaneous abortion, 10 normal-term outcomes, and 6 outcomes pending. All 10 children have had normal physical and mental development (6).
A 1994 case report described the outcome of a pregnancy exposed to cabergoline (7). A 38-year-old woman with a microadenoma of the pituitary gland was treated for hyperprolactinemia with a stable cabergoline dose of 0.5 mg twice weekly. She had a 17-year history of infertility and was intolerant to bromocriptine therapy. The prolactin level 2 days after a dose was 1133 mU/L (normal range 60–550 mU/L). After return of her menstrual cycles, she became pregnant but had a spontaneous abortion at 17 weeks’ gestation (not mentioned if cabergoline was stopped when pregnancy was diagnosed). Approximately 5 months later (2 months after restarting cabergoline), she again became pregnant and cabergoline was stopped (gestational age not specified). Labor was induced at 38 weeks’ gestation for intrauterine growth restriction. A 2.26-kg male infant without malformations was delivered with Apgar scores of 3 and 8 at 1 and 5 minutes, respectively. The placenta weight was 370 g. He was discharged home with his mother at 6 days of age (7).
A multinational French study published in 1996 described the outcomes of 226 pregnancies (all singletons) in 205 women who had been receiving cabergoline treatment (0.125–4.0 mg/week) before gestation (2). The women were from a group of 1650 premenopausal hyperprolactinemic women who had been treated with the drug. In seven cases, pregnancy occurred during the first cycle after discontinuation of cabergoline. The time of exposure could not be determined in 18 other cases. In the remaining 201 pregnancies, embryo–fetal exposure to cabergoline was thought to have ranged between 1 and 144 days. The 226 outcomes included early pregnancy loss (N = 56), live births (N = 148), ongoing pregnancies (N = 16), and lost to follow-up (N = 6). Among the 56 early pregnancy losses, there were 28 elective abortions (EABs), 23 spontaneous abortions (SABs), 1 intrauterine death (a cord accident at 25 weeks), 1 tubal pregnancy, and 3 EABs for major anomalies (dose and time of exposure shown in parentheses): Down’s syndrome, maternal age 42 years, woman later conceived on another cycle and gave birth to a normal infant (0.5 mg/week; exposure for 2 weeks after conception); limb-body wall defect—large abdominal wall defect, deformed left leg, and proximal phocomelia of right lower limb (0.5 mg/week; exposure for 2 weeks after conception); and hydrocephalus, cerebral atrophy, and facial dysmorphic (0.5 mg/week; exposure for 7 weeks after conception) (2).
Among the 148 live births, 17 were preterm, and 2 cases had an unknown length of gestation (2). Birth weights ranged from 1600 to 4350 g, with 10 infants below 2500 g (6.8%, 95% confidence intervals [CI] 3%–12%). In addition to the three cases above, seven infants had birth defects, but only two of them were major defects. The major defects were (dose and exposure times not specified) left megaureter as well as craniosynostosis and scaphocephaly. Thus, there were 5 infants with major malformations among 151 outcomes (3.3%, 95% CI 1.0%–7.6%). The postnatal development of 148 infants was known for various periods after birth, of which 107 were followed up for 1 to 72 months. All the infants showed normal physical and mental development (2).
In a 1997 report, 9 women became pregnant (from a group of 47) against medical advice after a mean of 12.4 months (range 1–37 months) of cabergoline therapy for hyperprolactinemia (8). The doses ranged from 0.25 to 3.5 mg/week. Cabergoline was discontinued as soon as pregnancy was diagnosed. One pregnancy aborted spontaneously, and one woman underwent elective abortion at 8 weeks’ gestation. In the remaining cases, all the pregnancies were brought to term without complication. The infants were healthy at birth and all had normal development during long-term follow-up (8 years) that was still ongoing (8).
A 2002 study reported the outcomes of 61 pregnancies in 50 women who had been treated with cabergoline for hyperprolactinemia (9). Pregnancy began during treatment in 60 cases and immediately after stopping treatment in 1 case. The median duration of treatment before pregnancy was 42.5 weeks (range 1–236 weeks) and the mean dose was 1.1 mg/week (range 0.25–7.0 mg/week). The pregnancy outcomes were 5 EABs (1 for a suspected malformation; specific details not available), 6 SABs, 1 hydatidiform mole, and 49 livebirths. Among the livebirths, there was one minor defect and one major defect (trisomy 18) (9).
In a 2005 report, a woman with Parkinson’s disease took levodopa/carbidopa 330 mg/day and cabergoline 1 mg/day throughout an uncomplicated pregnancy and gave birth at term to a healthy baby girl (10). A few years later, now at age 34 and receiving levodopa/carbidopa 625 mg/day and cabergoline 4 mg/day, she became pregnant again. At 32 weeks, she underwent a cesarean section because of placenta abruption. The baby girl was doing well (10).
A 2010 review cited evidence from nearly 600 pregnancies that cabergoline exposure during gestation does not cause teratogenic effects (11). The review included three reports published in 2008–2010 that found no increased risk for SABs, stillbirths, low birth weight, or congenital malformations (12–14).
A 2013 case report described a 29-year-old woman with Cushing disease and noncurative transsphenoidal pituitary surgery who was treated with cabergoline throughout pregnancy (15). The woman had received the drug for about 1 year before she conceived. The cumulative dose during pregnancy was 300 mg. Spontaneous labor occurred at 38 weeks and she gave birth to a healthy, 3350-g female infant with Apgar scores of 7 and 9 at 1 and 5 minutes, respectively. The infant had no signs of congenital defects or hypoglycemia and was doing well at 6 weeks of age. Breastfeeding was unsuccessful because the drug (4.5 mg twice weekly) caused poor milk production (15).
BREASTFEEDING SUMMARY
Although it is not an approved indication, cabergoline suppresses lactation because of its inhibition of prolactin release from the anterior pituitary gland. This action is similar to that of bromocriptine, another prolactin-inhibiting agent. A number of studies have examined this effect (16–21). The oral doses ranged from 0.4 mg to 1 mg, usually given as a single dose within 24 hours of delivery, but sometimes given as a divided dose over 2 days. The 1-mg dose appeared to be the most effective for long-term suppression of lactation.
The manufacturer states that cabergoline should not be used to suppress physiologic lactation because of the known toxicities associated with bromocriptine, when used for this purpose (3). These toxicities include hypertension, stroke, and seizures.
References
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3.Product information. Dostinex. Pharmacia & Upjohn, 2001.
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