Blue Cohosh: A Word of Caution
October 1999; Volume 1: 81-83
By Beth Irikura and Edward J. Kennelly, PhD
Blue cohosh (caulophyllum thalictroides [l.] michx., [Berberidaceae family]) has a long history of use, especially for gynecological conditions. The roots and rhizomes of blue cohosh were reportedly used by Native Americans for inducing labor or abortion. Other uses included colic, epilepsy, rheumatism, hiccups, and sore throat.1
In North America, blue cohosh is available in various forms, including herbal mixtures specifically targeted at women. The herb is oxytocic and has a reputation as an abortifacient. Because of the activity and questionable safety of some of its constituents, blue cohosh should be used only with extreme caution. Many herbalists advise against using it in early pregnancy and it may be best avoided even in late pregnancy.
Background
Blue cohosh is often used in conjunction with black cohosh (Cimicifuga racemosa), an unrelated plant with similar applications but different chemical constituents and an undetermined mechanism of action.2 Both herbs received the Algonquin name cohosh, meaning rough, for the appearance of their roots. From 1882 to 1905, blue cohosh was listed (for labor induction) in the U.S. Pharmacopoeia. Although a casual survey of contemporary herbals reveals a variety of uses, the most common application is still for inducing labor.
A recent survey of 172 certified nurse-midwives (CNMs) found that, of the 90 CNMs who prescribed or encouraged use of labor-stimulating herbal preparations, 64% used blue cohosh and 45% used black cohosh.3 Twenty-one percent of the CNMs reported complications when herbs were used. Those associated with use of blue and black cohosh were nausea, meconium-stained fluid, and transient fetal tachycardia. Two glycosides long known to be present in blue cohosh—caulosaponin and caulophyllosaponin—may be responsible for its reported oxytocic effects. Both saponins have vasoconstrictor activity, uterine-stimulating activity, and cardiotoxic effects.4
Suspected Teratogens
A recent study suggests that blue cohosh contains possible teratogenic compounds.5 Several potentially hazardous alkaloids were identified in extracts of blue cohosh: anagyrine, N-methylcytisine, and taspine. Anagyrine is a known teratogen in grazing animals. When pregnant cattle consume lupine (Lupinus species), containing high levels of anagyrine, offspring often manifest crooked calf disease, a syndrome that includes bowed or twisted limbs, permanently rigid joints, spinal curvature and occasionally cleft palate.6 In the 1970s, statistical correlation and controlled feeding experiments established that anagyrine caused the deformations.7
Anagyrine is one of the main alkaloid constituents of blue cohosh. It has been reported in blue cohosh rhizomes at a concentration of 290 ppm.8 Effects on humans have not been proven, but the severity and frequency of teratogenicity in range animals are reasons for caution. Anagyrine may have very different effects in humans and ruminants because of differences in intestinal flora; it is thought that anagyrine may require metabolism by rumen microflora to exhibit teratogenic effects. One reported case suggests a link between maternal consumption of anagyrine-containing goat milk and birth defects in which the infant displayed vascular anomaly, skeletal dysplasia, and malformation of red blood cells.9 FDA researchers have suggested that women may be wise to avoid ingesting anagyrine at any level, until more is known about its activity in humans.8
A recent study using rat embryo cultures (REC) indicated that anagyrine had teratogenic potential only at the highest concentrations tested, when overall morphogenesis was also impaired.5 The REC is an in vitro method to detect changes in development of an embryo over the 45-hour culture period. Teratogenicity is determined by the presence of malformations that cannot be explained by an overall, non-specific inhibition of growth and morphogenesis. The presence or absence of malformations is assessed separately from the determination of developmental status. The REC can identify potential neurotoxic effects. The relative inactivity of anagyrine at lower concentrations may be explained by the fact that the REC cannot detect musculoskeletal deformations.
N-Methylcytisine is a second potentially hazardous compound identified from blue cohosh. In cultured rat embryos, N-methylcytisine from blue cohosh caused major malformations.5 At a concentration of 20 ppm the effects included open anterior neural tube, poor or absent eye development, and twisted tail. Higher concentrations of N-methylcytisine inhibited overall growth and morphogenesis, in addition to producing similar malformations.
In a separate study, N-methylcytisine was also found to stimulate the ganglion cells of the cardiac vagus in frogs, paralyze the ganglia of the cardiac vagus in dogs, and produce hyperglycemia in rabbits.10
Some of the actions of N-methylcytisine are similar to nicotine.10 Exposure to nicotine via smoking in pregnant women has been linked with impaired fetal growth, neural dysmorphology, fetal death, and cognitive deficits in surviving offspring.11 This epidemiological evidence has been supported by in vitro and in vivo studies.
N-Methylcytisine in blue cohosh-containing dietary supplements has been measured at concentrations ranging from 5-850 ppm.8 No research has been conducted on the pharmacokinetics or pharmacodynamics of blue cohosh or its constituents; therefore, the clinical significance of the experiments discussed above remains unknown. However, women anticipating a pregnancy may want to avoid using blue cohosh-containing dietary supplements until the potential in vivo teratogenic effects of this botanical are understood.
Taspine, another constituent of caulophyllum, is found only in low yield (0.00013% by weight) in blue cohosh rhizomes.5 Taspine is cytotoxic at concentrations of 0.5 ppm.12 In rat embryo cultures, taspine was lethal at concentrations of 5 ppm.5 Taspine is related to other phenanthrene alkaloids such as morphine, heroin, and codeine, which are highly cytotoxic and suspected human teratogens.13
Adverse Fetal Effects in Humans
There are several reported cases of adverse birth outcomes associated with ingestion of blue cohosh. In the best-documented case, the infant suffered profound congestive heart failure associated with acute anterolateral myocardial infarction from maternal ingestion of three times the recommended dose for three to four weeks prior to parturition.14 The infant required mechanical ventilation 20 min after parturition, and displayed poor perfusion, mitral regurgitation murmur, cardiomegaly, and pulmonary edema. Hepatomegaly and abnormal liver function, consistent with cardiogenic shock, subsided gradually. The infant was hospitalized initially for 31 days and remained on the respirator for three weeks. Two years later the child was developing normally, but still required digoxin treatment for persistent cardiomegaly and reduced left ventricular function. The researchers ruled out other possible causes of myocardial infarction, such as coronary artery anomalies.
In another case, the mother was advised by a midwife to take a mixture that included blue cohosh and black cohosh to induce labor.15 The researchers in this case suggest that the myocardial toxicity (known to be associated with caulosaponin and caulophyllosaponin found in blue cohosh) could explain the severe hypoxic-ischemic symptoms observed in the newborn.16 This work has been criticized for not providing specific information on dosage, frequency or timing of usage, and type of herbal preparation ingested by the patient.17
In addition, two cases related to consumption of blue cohosh are listed in the FDA Special Nutritionals Adverse Event Monitoring System database.18 The first involved stroke in an infant, following ingestion of blue cohosh with grain alcohol. In the second case, the infant developed aplastic anemia following maternal exposure to blue cohosh and unspecified product(s).
Conclusion
Several adverse birth outcomes may be explained by fetal exposure to blue cohosh. Additionally, recent work indicates that constituents of blue cohosh cause teratogenic effects in rat embryo cultures. Future studies may be able to correlate additional epidemiological evidence with animal studies. Practitioners are advised that blue cohosh is a powerful pharmacological agent and may be contraindicated during the course of pregnancy. Women of childbearing age are urged to consult knowledgeable health professionals before using this herb.
Dr. Kennelly is an Assistant Professor of Biological Sciences and Ms. Irikura is in the doctoral Plant Sciences program at Lehman College, City University of New York, Bronx, NY.
References
1. Crellin JK, Philpott J. Herbal Medicine Past and Present: A Reference Guide to Medicinal Plants. Vol II. Durham, NC: Duke University Press; 1990:168.
2. Foster S. Black cohosh: A literature review. HerbalGram 1999;45:35-49.
3. McFarlin BL, et al. A national survey of herbal preparation use by nurse-midwives for labor stimulation. Review of the literature and recommendations for practice. J Nurse Midwifery 1999;44:205-216.
4. Ferguson HC, Edwards LD. A pharmacological study of a crystalline glycoside of Caulophyllum thalictroides. J Am Pharm Assoc 1954;43:16-21.
5. Kennelly EJ, et al. Detecting potential teratogenic alkaloids from blue cohosh rhizomes using an in vitro rat embryo culture. J Nat Prod 1999. In press.
6. Keeler RF. Livestock models of human birth defects, reviewed in relation to poisonous plants. J Anim Sci 1988;66:2414-2427.
7. Keeler RF. Naturally occurring teratogens from plants. In: Keeler RF, Tu AT, eds. Handbook of Natural Toxins. New York, NY: Marcel Dekker, Inc.; 1983:161-199.
8. Betz JM, et al. Gas chromatographic determination of toxic quinolizidine alkaloids in blue cohosh Caulophyllum thalictroides (L.) Michx. Phytochem Anal 1998;9:232-236.
9. Ortega JA, Lazerson J. Anagyrine-induced red cell aplasia, vascular anomaly, and skeletal dysplasia. J Pediatr 1987;111:87-89.
10. Scott CC, Chen KK. The pharmacological action of N-methylcytisine. J Pharmacol Exp Ther 1943;79:334-339.
11. Roy TS, et al. Nicotine evokes cell death in embryonic rat brain during neurulation. J Pharmacol Exp Ther 1998;287:1136-1144.
12. Pieters L, et al. Isolation of a dihydrobenzofuran lignan from South American dragon’s blood (Croton spp.) as an inhibitor of cell proliferation. J Nat Prod 1993;56:899-906.
13. Kilgore WW, et al. Toxic plants as possible human teratogens. Calif Agric 1981;35:6-10.
14. Jones TK, Lawson BM. Profound neonatal congestive heart failure caused by maternal consumption of blue cohosh herbal medication. J Pediatr 1998;132:550-552.
15. Gunn TR, Wright IM. The use of black and blue cohosh in labour. NZ Med J 1996;109:410-411.
16. Wright IM. Neonatal effects of maternal consumption of blue cohosh. J Pediatr 1999;134:384.
17. Baillie N, Rasmussen P. Black and blue cohosh in labour [comment]. NZ Med J 1997;110:20-21.
18. FDA/CFSAN resources page. Food and Drug Administration Web site. Available at: http://vm.cfsan.fda.gov/ ~dms/aems.html. Accessed August 27, 1999.
October 1999; Volume 1: 81-83
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