CARBIDOPA

Fetal Risk Summary

This antiparkinsonian agent has no pharmacologic effect when given alone and is almost always used in conjunction with levodopa (see also Levodopa). Carbidopa (a-methyldopa hydrazine; MK-486) inhibits decarboxylation of extracerebral levodopa. When used in combination with this latter agent, lower doses of levodopa can be administered, resulting in fewer adverse effects, and more levodopa is available for passage to the brain and eventual conversion in that organ to the active metabolite, dopamine.

Combinations of carbidopa and levodopa, as well as levodopa alone, have caused visceral and skeletal malformations in rabbits (1). However, carbidopa, 10 or 100 mg/kg/day given orally to rats from day 1 through day 21 of gestation, did not have a teratogenic effect but did cause a significant dose-related increase in brown fat (interscapular brown adipose tissue) hemorrhage and vasodilation in the newborn pups (2). The hemorrhage, 4.6% and 12.1%, respectively, for the two doses, was thought to be related to dopamine. Combining carbidopa and levodopa resulted in a lower incidence of hemorrhage.

A study published in 1978 examined the effect of carbidopa (20 mg/kg SC every 12 hours for 7 days) and levodopa plus carbidopa (200/20 mg/kg SC every 12 hours for 7 days) on the length of gestation in pregnant rats (3). Only the combination had a statistically significant effect on pregnancy duration, causing a delay in parturition of 12 hours. The results were thought to be consistent with dopamine inhibition of oxytocin release.

In pregnant rats, small amounts of carbidopa cross the placenta and can be detected in amniotic fluid and fetal tissue (4). Carbidopa concentrations were measured at 1, 2, and 4 hours after a 20-mg/kg IV dose administered near the end of gestation (19th day). The highest levels in the maternal plasma, placenta, amniotic fluid, and fetus (time of maximum concentration shown in parentheses) were 9.9 mg/mL (1 hour), 2.35 mg/g (1 hour), 0.32 mg/mL (2 and 4 hours), and 0.65 mg/g (2 hours), respectively.

Human placental transfer of carbidopa, although the amounts were very small, was documented in a study published in 1995 (5). A 34-year-old woman with juvenile Parkinson's disease was treated with carbidopa/levodopa (200/800 mg/day) during two pregnancies (see also Levodopa). Both pregnancies were electively terminated, one at 8 weeks' gestation and the other at 10 weeks. Mean concentrations of carbidopa (expressed as ng/mg protein from 2 fetuses) in the maternal serum, placental tissue (including umbilical cord), fetal peripheral organs (heart, kidney, muscle), and fetal neural tissue (brain and spinal cord) were 2.05, 8.0, 0.14, and <0.15, respectively. The low concentrations of carbidopa in the fetus, compared with those in the mother and placenta, were interpreted as evidence for an effective placental barrier to the transport of carbidopa (5).

Because Parkinson's disease is relatively uncommon in women of childbearing age, only four reports have been located that describe the use of carbidopa, always in combination with levodopa, in human pregnancy (6,7,8 and 9). A woman with at least a 7-year history of parkinsonism conceived while being treated with carbidopa/levodopa (five 25/250-mg tablets/day) and amantadine (100 mg twice/day) (6). She had delivered a normal male infant approximately 6 years earlier, but no medical treatment had been given during that pregnancy. Amantadine was immediately discontinued when the current pregnancy was diagnosed. Other than slight vaginal bleeding in the 1st trimester, there were no maternal or fetal complications. She gave birth to a normal term infant (sex and weight not specified) who was doing well at 1.5 years of age.

A 1987 retrospective report described the use of carbidopa/levodopa, starting before conception in five women during seven pregnancies, one of which was electively terminated during the 1st trimester (7). All of the other pregnancies went to term (newborn weights and sexes not specified). Maternal complications in three pregnancies included slight 1st-trimester vaginal bleeding, nausea and vomiting during the 8th and 9th months (the only patient who reported nausea and vomiting after the 1st trimester) and depression that resolved postpartum, and preeclampsia. One infant, whose mother took amantadine and carbidopa/levodopa and whose pregnancy was complicated by preeclampsia, had an inguinal hernia. No adverse effects or congenital anomalies were noted in the other five newborns, and all remained healthy at follow-up (approximately 1–5 years of age).

A 27-year-old woman with a history of chemotherapy and radiotherapy for non-Hodgkin's lymphoma occurring approximately 4 years earlier had developed a progressive parkinsonism syndrome that was treated with a proprietary preparation of carbidopa/levodopa (co-careldopa; Sinemet Plus; 375 mg/day) (8). She conceived 5 months after treatment began and eventually delivered a healthy, 3540-g male infant at term. Apgar scores were 9 at both 1 and 10 minutes, respectively. Co-careldopa was continued throughout her pregnancy.

A brief case report, published in 1997, described a normal outcome in the third pregnancy of a woman with levodopa-responsive dystonia (Segawa's type) who was treated throughout gestation with 500 mg/day of levodopa alone (9). The male infant weighed 2350 g at birth and was developing normally at the time of the report. Two previous pregnancies had occurred while the woman was being treated with daily doses of levodopa 100 mg and carbidopa 10 mg. Spontaneous abortions had occurred in both pregnancies; one at 6 weeks and the other at 12 weeks. An investigation failed to find any cause for the miscarriages.

In summary, although the number of reports describing the use of carbidopa (in combination with levodopa) during human pregnancy are few, as expected because of the relatively rarity of this condition in women of childbearing age, exposure to this agent during gestation does not appear to present a major risk to the fetus. Limited studies have not found teratogenicity in animals with carbidopa, except when combined with levodopa, and this outcome may be related to the latter drug. The cause of the two miscarriages described above is unknown, but requires further study. Brown fat hemorrhage observed in newborn rats treated during the 1st week of gestation was dose-related, and the toxicity has not been reported in humans. Moreover, the placental passage of carbidopa in animals and humans is limited. Based on the above data and the fact that lower doses of levodopa can be used if carbidopa is added to the mother's regimen, therapy with carbidopa, if indicated, should not be withheld during gestation.

Breast Feeding Summary

No reports describing the use of carbidopa during lactation or measuring the amount of this drug in human milk have been located. In at least two cases, breast feeding did not occur because of concerns with other drug therapy (levodopa or amantadine) that the mother was taking with carbidopa (6,8). Small amounts of carbidopa, probably from nonionic diffusion, were measured in the milk of five rats (15 days postpartum) 2 hours after a 20-mg/kg IV dose (4). The average milk and plasma concentrations were 0.5 mg/mL and 6.1 mg/mL, respectively, representing a milk:plasma ratio of 0.08. The relationship of these amounts to those that might occur in humans is unknown.

References

1. Product information. Sinemet. DuPont Pharma, 2000.
2. Kitchin KT, DiStefano V. L-Dopa and brown fat hemorrhage in the rat pup. Toxicol Appl Pharmacol 1976;38:251–63.
3. Seybold VS, Miller JW, Lewis PR. Investigation of a dopaminergic mechanism for regulating oxytocin release. J Pharmacol Exp Ther 1978;207:605–10.
4. Vickers S, Stuart EK, Bianchine JR, Hucker HB, Jaffe ME, Rhodes RE, Vandenheuvel WJA. Metabolism of carbidopa [L-(-)-a-hydrazino-3,4-dihydroxy-a-methylhydrocinnamic acid monohydrate], an aromatic amino acid decarboxylase inhibitor, in the rat, dog, rhesus monkey, and man. Drug Metab Dispos 1974;2:9–22.
5. Merchant CA, Cohen G, Mytilineou C, DiRocco A, Moros D, Molinari S, Yahr MD. Human transplacental transfer of carbidopa/levodopa. J Neural Transm Park Dis Dement Sect 1995;9:239–42.
6. Cook DG, Klawans HL. Levodopa during pregnancy. Clin Neuropharmacol 1985;8:93–5.
7. Golbe LI. Parkinson's disease and pregnancy. Neurology 1987;37:1245–9.
8. Ball MC, Sagar HJ. Levodopa in pregnancy. Mov Disord 1995;10:115.
9. Nomoto M, Kaseda S, Iwata S, Osame M, Fukuda T. Levodopa in pregnancy. Mov Disord 1997;12:261.