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research-article2015
JHLXXX10.1177/0890334415580580Journal of Human LactationAmer et al
Review
Safety of Popular Herbal Supplements in Lactating Women
Journal of Human Lactation 1–6 © The Author(s) 2015 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/0890334415580580 jhl.sagepub.com
Marwa R. Amer, BScPharm1, Gabriela C. Cipriano, PharmD1, Jineane V. Venci, PharmD, BCACP2, and Mona A. Gandhi, PharmD1
Abstract The increasing popularity and use of dietary supplements has required health care professionals to become more knowledgeable of their properties, interactions, and adverse effects. The objectives of this review were to evaluate the safety of popular dietary supplements in breastfeeding mothers and the effects on the infants. Nine of the most popular herbal dietary supplements were identified based on the 2011 US market report of the top 10 selling botanicals and the most frequently received inquiries by the Ruth A. Lawrence Lactation Study Center at the University of Rochester Medical Center. Relevant publications were identified through June 2014 using PubMed and EMBASE; tertiary references, including the Drugs and Lactation Database and Natural Medicine Comprehensive Database, were also reviewed. These herbals include black cohosh, cranberry, echinacea, evening primrose, garlic, ginseng, melatonin, milk thistle, and St John’s wort. Studies varied greatly with regard to study design, herbal intervention, and outcome measures. Findings suggested that dietary/herbal supplements have not been evaluated in high-quality clinical trials, and there is limited evidence supporting safety of use, particularly among lactating women. Therefore, it is essential for physicians to provide counseling for nursing mothers seeking information on dietary supplements, highlighting reliable safety profiles, inquiring about the potential benefits the patient is seeking, and assessing the patient’s perception of this supplement during breastfeeding. More research and clinical trials are required in this area to guide the recommendations and expand our current knowledge of these products. Keywords breastfeeding, dietary supplements, galactagogues, herbals, lactation, lactogogues, nursing
Background Over the past 2 decades, use of herbal and dietary supplements has become extremely popular in the United States.1 This popularity is likely due to the presumed safety relative to prescription medications and the fact that they are often viewed as culturally acceptable, easy to access, and more affordable.2,3 A 2007 survey conducted by the Centers for Disease Control and Prevention found nearly 18% of adults reported recent use of “natural products.”4 Popularity was highest among adult women 18 years and older. In 2008, the American Botanical Council reported $4.8 billion in total sales of herbal and dietary products; a 10.6% increase from 2004.5 In addition, the National Health Interview Survey of 2012 estimated that overall, 17.9% of adults in the United States used nonvitamin, nonmineral dietary supplements over the past 12 months.6 Throughout history, women have used certain herbs or food to enhance their milk supply.7,8 Most of these substances have not been scientifically evaluated, but traditional use suggests safety and some efficacy.9 It is estimated that 15% of breastfeeding women in the United States and 43%
internationally use herbal galactagogues.10,11 Rationale for use among breastfeeding women includes increasing milk supply, engorgement, mastitis, and indications unrelated to lactation (eg, constipation, common colds, depression).4,7,8 Although herbals are often promoted as natural and thereby harmless, they are not free from adverse effects. No regulatory guidelines exist that would set a standardized risk assessment to determine the safety and efficacy of these products in lactating women. Unlike prescription and overthe-counter medications, manufacturers of herbal supplements in the United States are not required to show clinical 1
Wegmans School of Pharmacy at St John Fisher College, Rochester, NY, USA 2 University of Rochester Medical Center, Rochester, NY, USA Date submitted: July 28, 2014; Date accepted: March 15, 2015. Corresponding Author: Marwa R. Amer, BScPharm, St John Fisher College, 584 Gleason Circle, Rochester, NY 14445, USA. Email: [email protected]
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Table 1. Nine Most Popular Herbal Dietary Supplements and Common Rationale for Use in Lactating Women. Product Name
Common Uses
Cranberry
•• •• •• ••
Echinacea
••
Evening primrose Garlic
•• •• •• •• ••
Black cohosh
Ginseng
Melatonin Milk thistle
St John’s wort
•• •• •• •• •• •• •• •• •• •• •• •• •• ••
Premenstrual and menopausal symptoms Labor induction Galactagogue15 Treatment and prevention of urinary tract infections20,21 Treatment and prevention of upper respiratory tract infections24,27 Treatment of menstrual disorders18 Hyperlipidemia Hypertension Coronary artery disease Prevention of colorectal and gastric cancers Galactagogue33 Diabetes Digestive aid Enhancing physical and mental performance Preventing aging Sexual dysfunction34 Circadian rhythm disorders38 Hepatic disease Galactagogue Diabetes Anorexia Dyspepsia Allergic rhinitis43 Depression and other psychiatric disorders44-46
data supporting claims for use, product safety, or potential for drug or disease state interactions.12 This lack of information is particularly problematic when products are being used by lactating women. Accordingly, health care providers must take initiative in creating opportunities to discuss herbal medicines with nursing mothers. An awareness of evidence surrounding agent properties, interactions, and adverse effects is essential to adequately discuss risks and benefits with patients. The objective of this review was to evaluate available literature of the 9 most popular herbal dietary supplements used among breastfeeding women.
Methods The 9 herbal products included in this review were selected based on the 2011 US market report of the top 10 selling botanicals13 and the most frequently received herbal inquiries (> 50%) by the Ruth A. Lawrence Lactation Study Center at the University of Rochester Medical Center. Although saw palmetto, soy, and ginko were included in the top 10 selling botanicals, they were excluded in this review because these accounted for less than 5% of the phone calls received by the Lactation Study Center. On the other hand, evening promise and
melatonin were not listed in the top 10 selling botanicals but were frequent inquiries at the Lactation Study Center. A comprehensive review of PubMed and EMBASE was conducted in June 2014 for publications written in English to evaluate the safety of the herbal product during lactation by using the following keywords: lactation, breastfeeding, nursing, herbals, dietary supplements, galactagogues, lactogogues, black cohosh, cranberry, echinacea, evening primrose, melatonin, milk thistle, garlic, ginseng, and St John’s wort. The criterion for inclusion was any publication that contains an oral herbal product indicated in the search terms above. Each trial was evaluated independently by 2 reviewers. Reference lists of identified publications were manually reviewed to identify additional relevant literature. The Drugs and Lactation Database and Natural Medicine Comprehensive Database were also reviewed to identify additional and/or unpublished works.
Results A total of 135 publications were identified, of which 55 were considered eligible for evaluation. Eighty articles were excluded for the following reasons: prescription medications used as galactagogue, pregnant women, studies without abstracts, and nonherbal dietary supplements. The remaining identified publications have been summarized below in alphabetical order based on the herbal supplement. Common rationale for use is summarized in Table 1.
Black Cohosh (Actaea racemosa, Cimicifuga racemosa) It has been suggested that black cohosh possesses estrogenic activity, which may reduce milk supply in lactating women,14-16 but the validity of this hypothesis is controversial.17 Common adverse effects such as gastrointestinal distress, headache, and dizziness may prove troublesome in nursing women. In addition, in 2008, the United States Pharmacopeia issued a precautionary statement regarding the potential for black cohosh–associated hepatotoxicity; similar warnings have also been issued by Canadian, European, and Australian agencies.18 Limited literature directly evaluating safety of use in lactating women was identified. A single review assessed the efficacy of black cohosh in nursing mothers and the safety of it in mothers and infants during lactation. The investigators concluded that black cohosh should be used with caution as in vitro evidence suggests estrogenic/antiestrogenic properties.19 Given the limited evidence and potential for harm, use should be cautioned in lactating women.
Cranberry (Vaccinium macrocarpon) Cranberry supplements are well tolerated and generally produce adverse effects only at high doses (namely gastrointestinal intolerance).20 In 2008, Mathers et al21 conducted
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Garlic (Allium sativum)
a systematic review to evaluate the safety and pharmacology of cranberry, focusing on issues pertaining to pregnancy and lactation. Overall, cranberry may appear to be a useful therapeutic agent for the prevention of urinary tract infections (UTIs) in women who are either pregnant or breastfeeding. However, a more recent meta-analysis conducted by Jepson et al22 showed that cranberry products (ie, cranberry juice, tablets) did not significantly reduce the occurrence of symptomatic UTI overall (relative risk [RR], 0.86; 95% confidence interval [CI], 0.71-1.04) and in pregnant women specifically (RR, 1.04; 95% CI, 0.971.17) compared with placebo or no treatment. There was no significant difference between gastrointestinal adverse effects from cranberry products compared with those in the placebo/no treatment group (RR, 0.83; 95% CI, 0.31-2.27). Many studies reported a low compliance and high withdrawal/dropout rate, which was attributed to the palatability/acceptability of the cranberry products. Given the large number of dropouts/withdrawals from studies and the limited evidence proving its efficacy, cranberry cannot currently be recommended for the prevention of UTIs.22 Lactating women with a predisposition to nephrolithiasis should be cautious to limit consumption, as continuous use (≥7 days) has been shown to significantly increase urinary oxalate concentration.23
A randomized, placebo-controlled trial conducted by Mennella and Beauchamp31 showed that administration of 1.5 g garlic extract increases the attachment time of infants to the mother’s breast and increases sucking time. Anecdotally, it has been suggested that maternal ingestion of garlic may increase the potential for infant colic18; however, several publications have disputed this claim. In a survey conducted by Lust et al,32 153 mothers were no more likely to report colic in their infants in the previous week if they had ingested garlic. The study by Mennella et al31 found that mothers who were given 1.5 g of garlic extract or placebo capsules once daily in a blinded fashion for 3 days were asked if their infants had exhibited any signs of colic after capsule ingestion (were fussier, cried more, or had more gas). Four of 20 (20%) women who ingested garlic extract thought their infants had colic; however, 4 of 10 (40%) who received placebo thought they had received garlic and reported colic in their infants. Although limited data suggest no detrimental effects on nursing infants, garlic extract may alter the effects of several medications and should be used cautiously. It has been reported that garlic extract may decrease platelet aggregation and should be avoided in persons receiving antiplatelet and anticoagulant therapy to avoid the risk of bleeding.33
Echinacea (Echinacea angustifolia, Echinacea purpurea)
Ginseng (Panax quinquefolius [American Ginseng], Panax ginseng [Asian Ginseng])
A single case report noted breast milk concentrations to be similar to serum concentrations 1 to 4 hours following administration of 4 tablets (containing 675 mg Echinacea purpurea root and 600 mg Echinacea angustifolia); however, the clinical relevance of this was not discussed in detail.24,25 Furthermore, variability in compound molecular weight within in the Echinacea species may further complicate predictability in lactating women.26 Perri et al27 assessed the safety of echinacea and concluded that although an expert panel28 on botanical medicine reported that oral consumption of echinacea in recommended doses is safe for use during lactation, it should be used with caution until there is stronger evidence to support its safety.
No human studies regarding the safety of ginseng in lactating women were identified.34 A study by Hu et al35 found cows with subclinical mastitis caused by Staphylococcus aureus were given subcutaneous injections of an extract of the Panax ginseng root to activate the innate immunity and contribute to recovery. However, due to the lack of data in breastfeeding women and potential estrogenic activity, expert consensus recommends against use in lactating women. Moreover, ginseng decreases the blood levels of some drugs such as warfarin and enhances the effect of sedating drugs.36 Ginseng can be poorly tolerated, and long-term use should be avoided since it may result in an abuse syndrome characterized by nervousness, diarrhea, confusion, depression or depersonalization, gynecomastia, and breast pain.37
Evening Primrose (Trigonella foenugraecum) Evening primrose seed oil contains γ-linolenic acid. A single study evaluated the impact of daily administration of evening primrose 2000 mg (2800 mg linoleic acid and 320 mg γ-linolenic acid) in a small population of nursing women (n = 36) compared with placebo.29,30 After 8 months, women who received evening primrose had significantly higher linoleic acid, γ-linolenic acid, and metabolite breast milk concentrations compared with placebo. The authors reported no maternal or infantile adverse effects.
Melatonin (N-Acetyl-5-Methoxytryptamine) Endogenous melatonin contained in breast milk has been shown to transfer to nursing infants and may potentially increase infantile sleep duration and improve irritability and colic.38,39 Cohen Engler et al40 demonstrated breast milk melatonin levels to fluctuate with circadian rhythm; average nocturnal concentrations were 0.23 mcg/L, while afternoon levels were less than 10 ng/L. The authors suggested that mothers should nurse in the dark at night to avoid reductions
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in the melatonin content of breast milk, which could disturb infant sleep patterns. Of note, normal serum melatonin levels in normal humans are very low during most of the day but increase significantly to a mean of 80 ng/L (range, 0-200) between 0200 and 0400 h (1 ng/L) and remain elevated during the normal hours of sleep, falling sharply to daytime values around 0900 h.41 It is estimated that breast milk concentrations would increase by 0.4 to 1 mcg/L for every 1 mg of exogenous maternal melatonin consumed. Such an increase is expected to be lower than dose, which has been safely used in shortterm clinical trials. Given the known transfer into breast milk, it is possible that long-term use may alter the natural development of infantile circadian rhythm and sleep cycle.42
Milk Thistle (Silybum marianum) A single study evaluated the safety of milk thistle (micronized) 420 mg/d in lactating women.43 Women who received milk thistle had no difference in milk composition compared with other study groups. No adverse effects were observed in mothers or infants throughout the 2-month study duration. Of note, this study lacked blinded randomization and did not evaluate infantile effects beyond the 63-day study period.
St John’s Wort (Hypericum perforatum) St John’s wort is believed to contain 2 primary active components: hypericin and hyperforin. Following maternal doses of 900 mg/d, hyperforin was shown to be detectable in breast milk, whereas hypericin concentrations were undetectable.44,45 Infantile levels of both hyperforin and hypericin were undetectable. It should be noted that these observations were made in older (10- to 28-week-old) infants. While conflicting evidence exists regarding the potential effects on prolactin levels, a single study reported doses of 900 mg/d did not affect milk supply.46,47 A matched cohort study of 33 women who took St John’s wort (average dose: 705 mg/d) during breastfeeding reported more frequent infant colic (n = 2), drowsiness (n = 2), and lethargy (n = 1) than mothers in 2 control groups who were either disease matched (primarily depression) or age and parity matched, in which only 1 case of infant colic was reported in each group.48 The difference was statistically significant between the treatment and disease-matched control groups. None of the affected infants required specific medical treatment, and there was no difference in infant weight between the groups. St John’s wort is a potent inducer of the cytochrome P450 enzyme system and P-glycoprotein efflux pump. It is known to alter levels of many prescription items, including oral contraceptives, digoxin, phenobarbital, and warfarin.49,50 Given the conflicting evidence and potential for severe drug interactions, use of another antidepressant may be preferred in lactating women.
Discussion Despite the prevalent use of herbal products among lactating women, our research finds inconclusive safety evidence in this population as nursing mothers may turn to supplements without the knowledge that these products may pose a threat to themselves and their infants.7,8 Many reports have been published to describe the use of herbal remedies during breastfeeding. A population-based survey conducted in western Australia found that a majority of participants (70.1%) believed there was a lack of information available regarding the use of herbal medicines during breastfeeding; however, 43.4% perceived herbal agents to be safer than conventional medicines. In addition, only 28.6% reported informing their doctor of herbal use while breastfeeding, and 71.6% reported avoiding conventional medications due to concerns regarding safety of their infant.51 Another 2 recent reviews were published to assess the effect of supplements on breastfeeding mothers.52,53 Mortel and Mehta52 reviewed several herbal galactagogues to increase breast milk production. However, the authors reported several limitations, including small sample size, insufficient randomization methods, poorly defined eligibility criteria, use of poly-herbal interventions, and variable breastfeeding practices among enrolled subjects. The second systematic review from Budzynska et al53 evaluated the safety and efficacy of several herbal agents during lactation. The clinical studies included in this review were divided into 3 categories: survey studies, safety studies, and efficacy studies. Studies were very heterogeneous with regard to study design, herbal intervention, and outcome measures. Overall, poor methodological quality predominated among the studies. As of June 2014, our review identified 55 studies evaluating the safety and efficacy of 9 popular herbal products in the United States. Most of the studies reported heterogeneous interventions, study designs, and outcomes measured. The result of our review aligns with previous systematic reviews addressing the challenge to develop accurate information on the safety of specific herbals used during breastfeeding.52,53 Despite the aforementioned findings, our study has certain limitations, including exclusion of non-English studies and methodological errors included in the publications reviewed. Most of the analyzed studies were cohort or observation designs with poorly designed eligibility criteria and use of multiple interventions, and the majority do not meet Herbal Consort guidelines.54 However, as ethical concerns limit high-quality trial designs in lactating women, data are often limited to lower quality designs or animal models. It is important for nursing mothers and practitioners to acknowledge that supplements have not been evaluated in high-quality clinical trials, and limited evidence supports the safety of use. It is also important to note that many herbal preparations are sold as tinctures and fluid extract, which contain a mixture of alcohol (20%-90%), and caution should be emphasized, particularly for breastfeeding women in
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Amer et al alcohol recovery.55 Caffeine can also exist as an excipient in many herbal products, and excessive maternal consumption may cause irritability in nursing infants. Therefore, it is crucial for practitioners to review any supplement use prior to use in nursing mothers beginning breastfeeding. Thorough patient education may promote increased awareness and minimize potential adverse effects.
Conclusion The use of herbal remedies is a tradition held in many cultures throughout the world and widely used during breastfeeding. Because of the limitations of the current literature, it is difficult to develop accurate information on the safety of specific herbs used during breastfeeding. It is critical that randomized clinical trials are conducted in this area to guide the recommendations and expand our current knowledge of these products. Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The authors received no financial support for the research, authorship, and/or publication of this article.
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aappolicy.aappublications.org.pluma.sjfc.edu/cgi/reprint/pediatrics; 108/3/776.pdf. Accessed June 8, 2014. 27. Perri D, Dugoua JJ, Mills E, Koren G. Safety and efficacy of Echinacea during pregnancy and lactation. Can J Clin Pharmacol. 2006;13(3):e262-e267. 28. Blumenthal M, Busse WR, Goldberg A, et al. The Complete German Commission E Monographs: Therapeutic Guide to Herbal Medicines. Boston, MA: American Botanical Council; 1998. 29. Kitz R, Rose MA, Schönborn H, Zielen S, Böhles HJ. Impact of early dietary gamma-linolenic acid supplementation on atopic eczema in infancy. Pediatr Allergy Immunol. 2006;17(2): 112-117. 30. Cant A, Shay J, Horrobin D. The effect of maternal supplementation with linoleic and gamma- linolenic acids on the fat composition and content of human milk: a placebo-controlled trial. J Nutr Sci Vitaminol. 1991;37(6):573-579. 31. Mennella JA, Beauchamp GK. The effects of repeated exposure to garlic-flavored milk on the nursling’s behavior. Pediatr Res. 1993;34(6):805-808. 32. Lust KD, Brown JE, Thomas W. Maternal intake of cruciferous vegetables and other foods and colic symptoms in exclusively breast-fed infants. J Am Diet Assoc. 1996;96(1):46-48. 33. O’Hara M, Kiefer D, Farrell K, Kemper K. A review of 12 commonly used medicinal herbs. Arch Fam Med. 1998;7(6):523-536. 34. Seely D, Dugoua JJ, Perri D, Mills E, Koren G. Safety and efficacy of Panax ginseng during pregnancy and lactation. Can J Clin Pharmacol. 2008;15(1):e87-e94. 35. Hu S, Concha C, Johannisson A, Meglia G, Waller KP. Effect of subcutaneous injection of ginseng on cows with subclinical Staphylococcus aureus mastitis. J Vet Med B Infect Dis Vet Public Health. 2001;48(7):519-528. 36. Coon JT, Ernst E. Panax ginseng: a systematic review of adverse effects and drug interactions. Drug Saf. 2002;25(5):323-344. 37. Siegel RK. Ginseng abuse syndrome: problems with the panacea. JAMA. 1979;241(15):1614-1615. 38. Sanchez-Barcelo EJ, Mediavilla MD, Reiter RJ. Clinical uses of melatonin in pediatrics. Int J Pediatr. 2011;2011:892624. 39. Gitto E, Aversa S, Reiter RJ, Barberi I, Pellegrino S. Update on the use of melatonin in pediatrics. J Pineal Res. 2011;50(1): 21-28. 40. Cohen Engler A, Hadash A, Shehadeh N, Pillar G. Breastfeeding may improve nocturnal sleep and reduce infantile colic: potential role of breast milk melatonin. Eur J Pediatr. 2012;171(4):729-732.
41. Lynch HJ, Brzezinski A, Deng MH, Lieberman H, Wurtman RJ. Effect of behavioral and physiological variables on melatonin secretion in humans. Adv Pineal Res. 1987;2:181-189. 42. Illnerova H, Buresova M, Presl J. Melatonin rhythm in human milk. J Clin Endocrinol Metab. 1993;77(3):838-841. 43. Di Pierro F, Callegari A, Carotenuto D, Tapia MM. Clinical efficacy, safety and tolerability of BIO-C (micronized silymarin) as a galactagogue. Acta Biomed. 2008;79(3):205-210. 44. Klier CM, Schäfer MR, Schmid-Siegel B, Lenz G, Mannel M. St. John’s wort (Hypericum perforatum): is it safe during breastfeeding? Pharmacopsychiatry. 2002;35(1):29-30. 45. Klier CM, Schmid-Siegel B, Schafer MR et al. St. John’s wort (Hypericum perforatum) and breastfeeding: plasma and breast milk concentrations of hyperforin for 5 mothers and 2 infants. J Clin Psychiatry. 2006;67(2):305-309. 46. Canning S, Waterman M, Orsi N, Ayres J, Simpson N, Dye L. The efficacy of Hypericum perforatum (St John’s wort) for the treatment of premenstrual syndrome: a randomized, doubleblind, placebo-controlled trial. CNS Drugs. 2010;24(3):207-225. 47. Franklin M, Cowen PJ. Researching the antidepressant actions of Hypericum perforatum (St. John’s wort) in animals and man. Pharmacopsychiatry. 2001;34(suppl 1):S29-S37. 48. Lee A, Minhas R, Matsuda N, Lam M, Ito S. The safety of St. John’s wort (Hypericum perforatum) during breastfeeding. J Clin Psychiatry. 2003;64(8):966-968. 49. Dugoua JJ, Mills E, Perri D, Koren G. Safety and efficacy of St. John’s wort (hypericum) during pregnancy and lactation. Can J Clin Pharmacol. 2006;13(3):e268-e276. 50. Clauson KA, Santamarina ML, Rutledge JC. Clinically relevant safety issues associated with St. John’s wort product labels. BMC Complement Altern Med. 2008;8:1-42. 51. Sim TF, Sherriff J, Hattingh HL, Parsons R, Tee LB. The use of herbal medicines during breastfeeding: a population-based survey in western Australia. BMC Complement Altern Med. 2013;13:317. 52. Mortel M, Mehta SD. Systematic review of the efficacy of herbal galactogogues. J Hum Lact. 2013;29(2):154-162. 53. Budzynska K, Gardner ZE, Dugoua JJ, Low Dog T, Gardiner P. Systematic review of breastfeeding and herbs. Breastfeed Med. 2012;7(6):489-503. 54. Herbal Medicinal Interventions. Herbal consort guideline. http://www.consort-statement.org/extensions/overview/ herbal-medicinal-interventions. Accessed June 2, 2014. 55. Haastrup MB, Pottegard A, Damkier P. Alcohol and breastfeeding. Basic Clin Pharmacol Toxicol. 2014;114(2):168-173.
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research-article2015
JHLXXX10.1177/0890334415580580Journal of Human LactationAmer et al
Review
Safety of Popular Herbal Supplements in Lactating Women
Journal of Human Lactation 1–6 © The Author(s) 2015 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/0890334415580580 jhl.sagepub.com
Marwa R. Amer, BScPharm1, Gabriela C. Cipriano, PharmD1, Jineane V. Venci, PharmD, BCACP2, and Mona A. Gandhi, PharmD1
Abstract The increasing popularity and use of dietary supplements has required health care professionals to become more knowledgeable of their properties, interactions, and adverse effects. The objectives of this review were to evaluate the safety of popular dietary supplements in breastfeeding mothers and the effects on the infants. Nine of the most popular herbal dietary supplements were identified based on the 2011 US market report of the top 10 selling botanicals and the most frequently received inquiries by the Ruth A. Lawrence Lactation Study Center at the University of Rochester Medical Center. Relevant publications were identified through June 2014 using PubMed and EMBASE; tertiary references, including the Drugs and Lactation Database and Natural Medicine Comprehensive Database, were also reviewed. These herbals include black cohosh, cranberry, echinacea, evening primrose, garlic, ginseng, melatonin, milk thistle, and St John’s wort. Studies varied greatly with regard to study design, herbal intervention, and outcome measures. Findings suggested that dietary/herbal supplements have not been evaluated in high-quality clinical trials, and there is limited evidence supporting safety of use, particularly among lactating women. Therefore, it is essential for physicians to provide counseling for nursing mothers seeking information on dietary supplements, highlighting reliable safety profiles, inquiring about the potential benefits the patient is seeking, and assessing the patient’s perception of this supplement during breastfeeding. More research and clinical trials are required in this area to guide the recommendations and expand our current knowledge of these products. Keywords breastfeeding, dietary supplements, galactagogues, herbals, lactation, lactogogues, nursing
Background Over the past 2 decades, use of herbal and dietary supplements has become extremely popular in the United States.1 This popularity is likely due to the presumed safety relative to prescription medications and the fact that they are often viewed as culturally acceptable, easy to access, and more affordable.2,3 A 2007 survey conducted by the Centers for Disease Control and Prevention found nearly 18% of adults reported recent use of “natural products.”4 Popularity was highest among adult women 18 years and older. In 2008, the American Botanical Council reported $4.8 billion in total sales of herbal and dietary products; a 10.6% increase from 2004.5 In addition, the National Health Interview Survey of 2012 estimated that overall, 17.9% of adults in the United States used nonvitamin, nonmineral dietary supplements over the past 12 months.6 Throughout history, women have used certain herbs or food to enhance their milk supply.7,8 Most of these substances have not been scientifically evaluated, but traditional use suggests safety and some efficacy.9 It is estimated that 15% of breastfeeding women in the United States and 43%
internationally use herbal galactagogues.10,11 Rationale for use among breastfeeding women includes increasing milk supply, engorgement, mastitis, and indications unrelated to lactation (eg, constipation, common colds, depression).4,7,8 Although herbals are often promoted as natural and thereby harmless, they are not free from adverse effects. No regulatory guidelines exist that would set a standardized risk assessment to determine the safety and efficacy of these products in lactating women. Unlike prescription and overthe-counter medications, manufacturers of herbal supplements in the United States are not required to show clinical 1
Wegmans School of Pharmacy at St John Fisher College, Rochester, NY, USA 2 University of Rochester Medical Center, Rochester, NY, USA Date submitted: July 28, 2014; Date accepted: March 15, 2015. Corresponding Author: Marwa R. Amer, BScPharm, St John Fisher College, 584 Gleason Circle, Rochester, NY 14445, USA. Email: [email protected]
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Table 1. Nine Most Popular Herbal Dietary Supplements and Common Rationale for Use in Lactating Women. Product Name
Common Uses
Cranberry
•• •• •• ••
Echinacea
••
Evening primrose Garlic
•• •• •• •• ••
Black cohosh
Ginseng
Melatonin Milk thistle
St John’s wort
•• •• •• •• •• •• •• •• •• •• •• •• •• ••
Premenstrual and menopausal symptoms Labor induction Galactagogue15 Treatment and prevention of urinary tract infections20,21 Treatment and prevention of upper respiratory tract infections24,27 Treatment of menstrual disorders18 Hyperlipidemia Hypertension Coronary artery disease Prevention of colorectal and gastric cancers Galactagogue33 Diabetes Digestive aid Enhancing physical and mental performance Preventing aging Sexual dysfunction34 Circadian rhythm disorders38 Hepatic disease Galactagogue Diabetes Anorexia Dyspepsia Allergic rhinitis43 Depression and other psychiatric disorders44-46
data supporting claims for use, product safety, or potential for drug or disease state interactions.12 This lack of information is particularly problematic when products are being used by lactating women. Accordingly, health care providers must take initiative in creating opportunities to discuss herbal medicines with nursing mothers. An awareness of evidence surrounding agent properties, interactions, and adverse effects is essential to adequately discuss risks and benefits with patients. The objective of this review was to evaluate available literature of the 9 most popular herbal dietary supplements used among breastfeeding women.
Methods The 9 herbal products included in this review were selected based on the 2011 US market report of the top 10 selling botanicals13 and the most frequently received herbal inquiries (> 50%) by the Ruth A. Lawrence Lactation Study Center at the University of Rochester Medical Center. Although saw palmetto, soy, and ginko were included in the top 10 selling botanicals, they were excluded in this review because these accounted for less than 5% of the phone calls received by the Lactation Study Center. On the other hand, evening promise and
melatonin were not listed in the top 10 selling botanicals but were frequent inquiries at the Lactation Study Center. A comprehensive review of PubMed and EMBASE was conducted in June 2014 for publications written in English to evaluate the safety of the herbal product during lactation by using the following keywords: lactation, breastfeeding, nursing, herbals, dietary supplements, galactagogues, lactogogues, black cohosh, cranberry, echinacea, evening primrose, melatonin, milk thistle, garlic, ginseng, and St John’s wort. The criterion for inclusion was any publication that contains an oral herbal product indicated in the search terms above. Each trial was evaluated independently by 2 reviewers. Reference lists of identified publications were manually reviewed to identify additional relevant literature. The Drugs and Lactation Database and Natural Medicine Comprehensive Database were also reviewed to identify additional and/or unpublished works.
Results A total of 135 publications were identified, of which 55 were considered eligible for evaluation. Eighty articles were excluded for the following reasons: prescription medications used as galactagogue, pregnant women, studies without abstracts, and nonherbal dietary supplements. The remaining identified publications have been summarized below in alphabetical order based on the herbal supplement. Common rationale for use is summarized in Table 1.
Black Cohosh (Actaea racemosa, Cimicifuga racemosa) It has been suggested that black cohosh possesses estrogenic activity, which may reduce milk supply in lactating women,14-16 but the validity of this hypothesis is controversial.17 Common adverse effects such as gastrointestinal distress, headache, and dizziness may prove troublesome in nursing women. In addition, in 2008, the United States Pharmacopeia issued a precautionary statement regarding the potential for black cohosh–associated hepatotoxicity; similar warnings have also been issued by Canadian, European, and Australian agencies.18 Limited literature directly evaluating safety of use in lactating women was identified. A single review assessed the efficacy of black cohosh in nursing mothers and the safety of it in mothers and infants during lactation. The investigators concluded that black cohosh should be used with caution as in vitro evidence suggests estrogenic/antiestrogenic properties.19 Given the limited evidence and potential for harm, use should be cautioned in lactating women.
Cranberry (Vaccinium macrocarpon) Cranberry supplements are well tolerated and generally produce adverse effects only at high doses (namely gastrointestinal intolerance).20 In 2008, Mathers et al21 conducted
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Garlic (Allium sativum)
a systematic review to evaluate the safety and pharmacology of cranberry, focusing on issues pertaining to pregnancy and lactation. Overall, cranberry may appear to be a useful therapeutic agent for the prevention of urinary tract infections (UTIs) in women who are either pregnant or breastfeeding. However, a more recent meta-analysis conducted by Jepson et al22 showed that cranberry products (ie, cranberry juice, tablets) did not significantly reduce the occurrence of symptomatic UTI overall (relative risk [RR], 0.86; 95% confidence interval [CI], 0.71-1.04) and in pregnant women specifically (RR, 1.04; 95% CI, 0.971.17) compared with placebo or no treatment. There was no significant difference between gastrointestinal adverse effects from cranberry products compared with those in the placebo/no treatment group (RR, 0.83; 95% CI, 0.31-2.27). Many studies reported a low compliance and high withdrawal/dropout rate, which was attributed to the palatability/acceptability of the cranberry products. Given the large number of dropouts/withdrawals from studies and the limited evidence proving its efficacy, cranberry cannot currently be recommended for the prevention of UTIs.22 Lactating women with a predisposition to nephrolithiasis should be cautious to limit consumption, as continuous use (≥7 days) has been shown to significantly increase urinary oxalate concentration.23
A randomized, placebo-controlled trial conducted by Mennella and Beauchamp31 showed that administration of 1.5 g garlic extract increases the attachment time of infants to the mother’s breast and increases sucking time. Anecdotally, it has been suggested that maternal ingestion of garlic may increase the potential for infant colic18; however, several publications have disputed this claim. In a survey conducted by Lust et al,32 153 mothers were no more likely to report colic in their infants in the previous week if they had ingested garlic. The study by Mennella et al31 found that mothers who were given 1.5 g of garlic extract or placebo capsules once daily in a blinded fashion for 3 days were asked if their infants had exhibited any signs of colic after capsule ingestion (were fussier, cried more, or had more gas). Four of 20 (20%) women who ingested garlic extract thought their infants had colic; however, 4 of 10 (40%) who received placebo thought they had received garlic and reported colic in their infants. Although limited data suggest no detrimental effects on nursing infants, garlic extract may alter the effects of several medications and should be used cautiously. It has been reported that garlic extract may decrease platelet aggregation and should be avoided in persons receiving antiplatelet and anticoagulant therapy to avoid the risk of bleeding.33
Echinacea (Echinacea angustifolia, Echinacea purpurea)
Ginseng (Panax quinquefolius [American Ginseng], Panax ginseng [Asian Ginseng])
A single case report noted breast milk concentrations to be similar to serum concentrations 1 to 4 hours following administration of 4 tablets (containing 675 mg Echinacea purpurea root and 600 mg Echinacea angustifolia); however, the clinical relevance of this was not discussed in detail.24,25 Furthermore, variability in compound molecular weight within in the Echinacea species may further complicate predictability in lactating women.26 Perri et al27 assessed the safety of echinacea and concluded that although an expert panel28 on botanical medicine reported that oral consumption of echinacea in recommended doses is safe for use during lactation, it should be used with caution until there is stronger evidence to support its safety.
No human studies regarding the safety of ginseng in lactating women were identified.34 A study by Hu et al35 found cows with subclinical mastitis caused by Staphylococcus aureus were given subcutaneous injections of an extract of the Panax ginseng root to activate the innate immunity and contribute to recovery. However, due to the lack of data in breastfeeding women and potential estrogenic activity, expert consensus recommends against use in lactating women. Moreover, ginseng decreases the blood levels of some drugs such as warfarin and enhances the effect of sedating drugs.36 Ginseng can be poorly tolerated, and long-term use should be avoided since it may result in an abuse syndrome characterized by nervousness, diarrhea, confusion, depression or depersonalization, gynecomastia, and breast pain.37
Evening Primrose (Trigonella foenugraecum) Evening primrose seed oil contains γ-linolenic acid. A single study evaluated the impact of daily administration of evening primrose 2000 mg (2800 mg linoleic acid and 320 mg γ-linolenic acid) in a small population of nursing women (n = 36) compared with placebo.29,30 After 8 months, women who received evening primrose had significantly higher linoleic acid, γ-linolenic acid, and metabolite breast milk concentrations compared with placebo. The authors reported no maternal or infantile adverse effects.
Melatonin (N-Acetyl-5-Methoxytryptamine) Endogenous melatonin contained in breast milk has been shown to transfer to nursing infants and may potentially increase infantile sleep duration and improve irritability and colic.38,39 Cohen Engler et al40 demonstrated breast milk melatonin levels to fluctuate with circadian rhythm; average nocturnal concentrations were 0.23 mcg/L, while afternoon levels were less than 10 ng/L. The authors suggested that mothers should nurse in the dark at night to avoid reductions
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in the melatonin content of breast milk, which could disturb infant sleep patterns. Of note, normal serum melatonin levels in normal humans are very low during most of the day but increase significantly to a mean of 80 ng/L (range, 0-200) between 0200 and 0400 h (1 ng/L) and remain elevated during the normal hours of sleep, falling sharply to daytime values around 0900 h.41 It is estimated that breast milk concentrations would increase by 0.4 to 1 mcg/L for every 1 mg of exogenous maternal melatonin consumed. Such an increase is expected to be lower than dose, which has been safely used in shortterm clinical trials. Given the known transfer into breast milk, it is possible that long-term use may alter the natural development of infantile circadian rhythm and sleep cycle.42
Milk Thistle (Silybum marianum) A single study evaluated the safety of milk thistle (micronized) 420 mg/d in lactating women.43 Women who received milk thistle had no difference in milk composition compared with other study groups. No adverse effects were observed in mothers or infants throughout the 2-month study duration. Of note, this study lacked blinded randomization and did not evaluate infantile effects beyond the 63-day study period.
St John’s Wort (Hypericum perforatum) St John’s wort is believed to contain 2 primary active components: hypericin and hyperforin. Following maternal doses of 900 mg/d, hyperforin was shown to be detectable in breast milk, whereas hypericin concentrations were undetectable.44,45 Infantile levels of both hyperforin and hypericin were undetectable. It should be noted that these observations were made in older (10- to 28-week-old) infants. While conflicting evidence exists regarding the potential effects on prolactin levels, a single study reported doses of 900 mg/d did not affect milk supply.46,47 A matched cohort study of 33 women who took St John’s wort (average dose: 705 mg/d) during breastfeeding reported more frequent infant colic (n = 2), drowsiness (n = 2), and lethargy (n = 1) than mothers in 2 control groups who were either disease matched (primarily depression) or age and parity matched, in which only 1 case of infant colic was reported in each group.48 The difference was statistically significant between the treatment and disease-matched control groups. None of the affected infants required specific medical treatment, and there was no difference in infant weight between the groups. St John’s wort is a potent inducer of the cytochrome P450 enzyme system and P-glycoprotein efflux pump. It is known to alter levels of many prescription items, including oral contraceptives, digoxin, phenobarbital, and warfarin.49,50 Given the conflicting evidence and potential for severe drug interactions, use of another antidepressant may be preferred in lactating women.
Discussion Despite the prevalent use of herbal products among lactating women, our research finds inconclusive safety evidence in this population as nursing mothers may turn to supplements without the knowledge that these products may pose a threat to themselves and their infants.7,8 Many reports have been published to describe the use of herbal remedies during breastfeeding. A population-based survey conducted in western Australia found that a majority of participants (70.1%) believed there was a lack of information available regarding the use of herbal medicines during breastfeeding; however, 43.4% perceived herbal agents to be safer than conventional medicines. In addition, only 28.6% reported informing their doctor of herbal use while breastfeeding, and 71.6% reported avoiding conventional medications due to concerns regarding safety of their infant.51 Another 2 recent reviews were published to assess the effect of supplements on breastfeeding mothers.52,53 Mortel and Mehta52 reviewed several herbal galactagogues to increase breast milk production. However, the authors reported several limitations, including small sample size, insufficient randomization methods, poorly defined eligibility criteria, use of poly-herbal interventions, and variable breastfeeding practices among enrolled subjects. The second systematic review from Budzynska et al53 evaluated the safety and efficacy of several herbal agents during lactation. The clinical studies included in this review were divided into 3 categories: survey studies, safety studies, and efficacy studies. Studies were very heterogeneous with regard to study design, herbal intervention, and outcome measures. Overall, poor methodological quality predominated among the studies. As of June 2014, our review identified 55 studies evaluating the safety and efficacy of 9 popular herbal products in the United States. Most of the studies reported heterogeneous interventions, study designs, and outcomes measured. The result of our review aligns with previous systematic reviews addressing the challenge to develop accurate information on the safety of specific herbals used during breastfeeding.52,53 Despite the aforementioned findings, our study has certain limitations, including exclusion of non-English studies and methodological errors included in the publications reviewed. Most of the analyzed studies were cohort or observation designs with poorly designed eligibility criteria and use of multiple interventions, and the majority do not meet Herbal Consort guidelines.54 However, as ethical concerns limit high-quality trial designs in lactating women, data are often limited to lower quality designs or animal models. It is important for nursing mothers and practitioners to acknowledge that supplements have not been evaluated in high-quality clinical trials, and limited evidence supports the safety of use. It is also important to note that many herbal preparations are sold as tinctures and fluid extract, which contain a mixture of alcohol (20%-90%), and caution should be emphasized, particularly for breastfeeding women in
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Amer et al alcohol recovery.55 Caffeine can also exist as an excipient in many herbal products, and excessive maternal consumption may cause irritability in nursing infants. Therefore, it is crucial for practitioners to review any supplement use prior to use in nursing mothers beginning breastfeeding. Thorough patient education may promote increased awareness and minimize potential adverse effects.
Conclusion The use of herbal remedies is a tradition held in many cultures throughout the world and widely used during breastfeeding. Because of the limitations of the current literature, it is difficult to develop accurate information on the safety of specific herbs used during breastfeeding. It is critical that randomized clinical trials are conducted in this area to guide the recommendations and expand our current knowledge of these products. Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The authors received no financial support for the research, authorship, and/or publication of this article.
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