Drugs in Pregnancy and Lactation Name: ST. JOHN'S WORT
Class: Herb
Risk Factor:    C

Fetal Risk Summary

Hypericum perforatum (St. John's wort) is an aromatic, aggressive perennial weed that is native to Europe but also grows throughout the United States and parts of Canada (1). The plant is harvested for medicinal purposes during July and August (1). A large number of chemical constituents have been isolated from the plant, including hypericin, pseudohypericin, flavonoids, glycosides, phenols, tannins, volatile oils, and other compounds (1,2,3,4,5,6,7 and 8). Hypericin and pseudohypericin are considered to be the primary orally active ingredients (1,5,6,7 and 8).

Preparations made from H. perforatum have been used for medicinal purposes for thousands of years. These uses have included the management of anxiety, depression, insomnia, inflammation, and gastritis. They have also been used as a diuretic and, topically, for the treatment of hemorrhoids and to enhance wound healing (1,2,3,4 and 5). More recently, hypericin has been investigated for activity against the human immunodeficiency virus (HIV) and other viruses (1,5,8). In addition, extracts and tinctures of hypericum have shown activity against gram-negative and gram-positive bacteria (1).

No data are available on the animal or human placental transfer of hypericin, pseudohypericin, or other constituents of St. John's wort.

The mechanism of antidepressant action is thought to be related to selected serotonin-reuptake inhibition, monoamine oxidase inhibitors, a combination of both, or other mechanisms (1,2,3 and 4,6,7,8 and 9). Adverse effects induced by hypericum preparations, relatively infrequent in nonpregnant humans but not studied in pregnant women, include gastrointestinal upset and constipation, allergic reactions, fatigue, dry mouth, dizziness, and confusion (1,2,3 and 4,5,6,7,8,9 and 10). Rare photosensitivity in fair-skinned individuals has also been observed.

Surprisingly, for a product that has been in use since ancient Greek and Roman times, only one report has been located that described its consumption during human pregnancy (see below). Moreover, there are few animal reproductive studies available for evaluation of its embryo and fetal safety. Aqueous extractions of H. perforatum demonstrated weak uterine tonus–enhancing activity in experiments using isolated rabbit and guinea pig uterine horns (11). Uterotonic activity or abortions, however, have apparently not been reported after consumption of the herb by animals or humans.

In a randomized, placebo-controlled reproductive study, adult female mice were fed either hypericum (180 mg/kg/day) or placebo for 2 weeks before mating and then throughout gestation (12). The dose, which has antidepressant efficacy in adult mice, was equivalent to the human dose on a kg/m2 basis (12,13). The birth weights of all exposed pups were smaller than controls, but only the reduced birth weights of male pups reached statistical significance in comparison to controls (1.68 g vs. 1.75 g, p<0.01) (13). Moreover, successful performance on the negative geotaxis task, a measure of behavior during early development, was significantly lower in exposed male pups (but not female pups) on postnatal day 3 (13). Both the body weight and negative geotaxis task performance were comparable to controls by postnatal day 5 (13). No differences, regardless of gender, were observed between exposed and nonexposed pups in body length, head circumference, sexual maturation, or the attainment of developmental milestones up to adulthood (12). Similarly, no differences were observed between the groups in pup-dam interactions, performance of locomotor, depression, and anxiety tasks during juvenile and adult periods, or in male sexual behavior and aggression. An evaluation of second-generation offspring found no differences between the groups in any measurement (12,13).

An aqueous ethanolic extract of hypericum was tested for mutagenic activity in a study published in 1990 (14). Using both in vitro and in vivo test systems (mice, hamsters, etc.), no evidence of mutagenic effects was observed.

In a sperm penetration assay, zona-free hamster oocytes were incubated for 1 hour with two concentrations of H. perforatum, 0.06 mg/mL and 0.6 mg/mL, dissolved in HEPES-buffered synthetic human tubal fluid (modified HTF) (15). Fresh human donor sperm was suspended in the modified HTF and then mixed with the oocytes for 3 hours. Modified HTF served as the control. At the 0.06 mg/mL concentration, all the oocytes were penetrated, whereas at 0.6 mg/mL, zero penetration occurred. The decrease in penetration was not associated with a decrease in sperm motility (15). In the second part of the study, sperm were incubated with the herbal solutions for 7 days (15). Both concentrations caused significant sperm DNA denaturation concomitant with decreases in sperm viability compared with controls. The higher concentration showed point mutation of a selected sperm sentinel gene, the BRCA1 exon 11 gene (15). Extrapolation of these data to the reproductive risk of hypericum in males is difficult, in part because the concentration of hypericum in semen or sperm has not been studied (15). Moreover, although the doses used in this study are small fractions of the actual recommended human dose, usually expressed in grams of hypericin, there is no published evidence that the adverse effects observed have occurred in vivo.

A brief 1998 case report described the use of St. John's wort by two pregnant women, but only one of the cases has outcome data (16). In the first case, a 38-year-old woman began taking 900 mg/day St. John's wort at 24 weeks' gestation for a major depressive disorder that had recurred during the 1st trimester. She continued the herbal medicine throughout the remainder of her pregnancy, taking her last dose 24 hours before delivery (gestational age not specified). Other than late-onset thrombocytopenia (platelet count 88,000), the pregnancy was unremarkable (16). The woman delivered a healthy, 7-lb, 8-oz (about 3400-g) female infant with Apgar scores of 9 and 9 at both 1 and 5 minutes. The physical examination and laboratory results were normal. Neonatal jaundice developed on day 5 but responded to brief phototherapy. Behavioral assessment at 4 and 33 days of age was normal. The second case involved a 43-year-old woman who had been taking fluoxetine and methylphenidate for a recurrent major depressive disorder (16). After an unexpected conception, she discontinued these medications because of concerns about potential adverse fetal effects and began self-medicating with St. John's wort, 900 mg/day. Apparently, this pregnancy was ongoing, because no outcome data were presented.

In summary, only one report describing the use of St. John's wort (H. perforatum) during human pregnancy has been located, and only one of the two cases contained in the report has outcome data. Two animal studies apparently did not look for structural defects, but neither observed behavioral teratogenic effects. Moreover, no mutagenicity was found with various tests involving mammalian cells. Hypericum has demonstrated human sperm toxicity in vitro, but no reports describing this adverse effect after ingestion of the drug have been located. Similarly, the uterotonic action observed in an in vitro animal experiment has not been reported in animals or humans following consumption. This lack of reported toxicity is reassuring. Moreover, because the use of St. John's wort is widespread and dates back thousands of years, it is doubtful that a major teratogenic action or other reproductive toxicity would have escaped notice. More subtle or low-incidence effects, however, including structural and behavioral teratogenicity, the induction of abortions, and infertility may have escaped detection, and further study is required before human reproductive risk or safety can be assessed.

Because standardization of any herbal product as to its constituents, concentrations, and the presence of contaminants is generally lacking, consumption of these preparations during pregnancy may result in fetal exposure to unintended chemicals and doses. Furthermore, pregnant women should be counseled on the risks to themselves and their pregnancies that may result from self-medication or discontinuing prescribed therapy without first consulting their health care provider.

Breast Feeding Summary

Only one report describing the use of St. John's wort (H. perforatum) during human lactation has been located. A 38-year-old mother had taken 900 mg/day St. John's wort from 24 weeks' gestation until delivery (16). (See case above.) She began breast-feeding her female infant after delivery and then resumed taking the herbal product 20 days after delivery. Neonatal jaundice was noted at 5 days of age but responded to brief phototherapy. Behavioral assessments of the nursing infant at 4 and 33 days of age were normal.

It is not known if any of the constituents and possible contaminants that may be found in preparations of St. John's wort are excreted into human milk or if exposure to them via the milk represents a risk to a nursing infant.

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References

  1. St. John's Wort. The Review of Natural Products. St. Louis, MO: Facts and Comparisons, November 1997.
  2. Chavez ML, Chavez PI. Saint Johns' wort. Hosp Pharm 1997;32:1621–32.
  3. Miller LG. Herbal medicinals. Selected clinical considerations focusing on known or potential drug-herb interactions. Arch Intern Med 1998;158:2200–11.
  4. Klepser TB, Klepser ME. Unsafe and potentially safe herbal therapies. Am J Health-Syst Pharm 1999;56:125–38.
  5. Pepping J. St. Alternative therapies. St. John's wort: Hypericum perforatum. Am J Health-Syst Pharm 1999;56:329.
  6. Wong AHC, Smith M, Boon HS. Herbal remedies in psychiatric practice. Arch Gen Psychiatry 1998;55:1033–44.
  7. Bennett DA Jr, Phun L, Polk JF, Voglino SA, Zlotnik V, Raffa RB. Neuropharmacology of St.John's wort (Hypericum). Ann Pharmacother 1998;32:1201–8.
  8. Cupp MJ. Herbal remedies: adverse effects and drug interactions. Am Fam Physician 1999;59:1239–44.
  9. Zink T, Chaffin J. Herbal `health' products: what family physicians need to know. Am Fam Physician 1998;58:1133–40.
  10. Linde K, Ramirez G, Mulrow CD, Pauls A, Weidenhammer W, Melchart D. St. John's wort for depression—an overview and meta-analysis of randomised clinical trials. Br Med J 1996;313:253–8.
  11. Shipochliev T. Uterotonic action of extracts from a group of medicinal plants. Vet Med Nauki. 1981;18:94–8.
  12. Christensen HD, Rayburn WF, Coleman FH, Gonzalez CL. Effect of antenatal hypericum (St. John's wort) on growth and physical development of mice offspring (abstract). Teratology 1999;59:411.
  13. Rayburn WF, Christensen HD, Gonzalez CL. Effect of antenatal exposure to Saint John's wort (Hypericum) on neurobehavior of developing mice. Am J Obstet Gynecol 2000;183:1225–31.
  14. Okpanyi SN, Lidsba H, Scholl BC, Miltenburger HG. Genotoxicity of a standardized hypericum extract. Arzneimittel-Forschung 1990;40:851–5.
  15. Ondrizek RR, Chan PJ, Patton WC, King A. An alternative medicine study of herbal effects on the penetration of zona-free hamster oocytes and the integrity of sperm deoxyribonucleic acid. Fertil Steril 1999;71:517–22.
  16. Grush LR, Nierenberg A, Keefe B, Cohen LS. St. John's wort during pregnancy. JAMA 1998;280:1566.

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