1. Herbal Medicines in Pregnancy
June-Seek Choi, M.D., PhD
Korean Motherisk Program
Div. of Maternal-Fetal Medicine,
Dept. of OB & GYN,
Cheil General Hospital & Women’s Healthcare Center,
School of Medicine, Kwan-dong University, Seoul, Korea
2. Contents
• Definition
• Introduction
• Herbal medicines relate to uterine contraction (in
animal study vs human)
• Herbal medicines relate to spontaneous abortion
(in animal study vs human)
• Data of pregnancy outcomes of herbal medicine
exposure in Korean Motherisk Program
• Summary
3. Definition (1)
• Herbal medicines: include herbs, herbal
materials, herbal preparations and
finished herbal products, that contain as
active ingredients part of plants, or other
plant materials, or combinations.
WHO
4. Definition (2)
• Herbs: crude plant materials such as leaves,
flowers, fruit, seed, stems, wood, bark, roots,
rhizomes or other plant parts, which may be
entire, fragmented or powdered.
• Herbal materials: in addition to herbs, fresh
juices, gums, fixed oils, essential oils, resins and
dry powders of herbs.
WHO
5. Definition (3)
• Herbal preparations: may include
comminuted or powdered herbal materials, or
extracts, tinctures and fatty oils of herbal
materials. They are produced by extraction,
fractionation, purification, concentration, or
other physical or biological processes.
• Finished herbal products: herbal
preparations made from one or more herbs.
WHO
6. Introduction (1)
• It is estimated that about 25% of all modern
medicines are directly or indirectly derived from
higher plants. Farnsworth NR 1976, Shu YZ 1998
• Anticancer and antimicrobial drugs, about 60%
of the medicines currently available on the
Illicii Fructus
market and most of those in the late stages of
clinical trials are derived from natural products,
mainly from higher plants. Gragg GM et al 1997
7. Introduction (2)
• Representing an annual global market of US $60
billion every year, herbal medicines account for
around 20% of the overall drug market.
• Africa- 80% of population
China- 30-50% of total medical consumption
Europe, North America- over 50% of population
have used complementary or alternative medicine at
least once. WHO news 2004
• Fee for herbal medical treatment was increased 57
times in Korea [ US $ 19 million (1990) US $ 1.1 billion (2006)]
A study on the current status and prospect of CAM world market 2007
8. Important factors to growth of this worldwide
Introduction (3) complementary/alternative medicine(CAM)
• Preference of consumers for natural therapies
• Concern regarding undesirable side effects of
modern medicines and the belief that herbal
drugs are free from side effects
• Great interest in alternative medicines
• Herbal medicines might be of effective benefit in
the treatment of certain diseases where
conventional therapies and medicines have
proven to be inadequate
• High cost of synthetic medicines
Grünwald J 1995
9. Compared with well-defined synthetic drugs,
Introduction (4) herbal medicines exhibit some marked difference
• Active principles are frequently unknown.
• Standardization, stability and quality control are
feasible but not easy
• Availability and quality of raw materials are
frequently problematic.
• Well-controlled double-blind clinical and
toxicological studies to prove their efficacy and
safety are rare.
• Wide range of therapeutic use and are suitable for
chronic treatments.
• Usually cost less than synthetic drugs
Calixto J.B. 2000
10. Side effects by Korean herbal medicines-drug interactions
Western Medicine Drug interaction and results
Angelicae Gigantis Radix(Dang gui), Warfarin, Aspirin Decreased International Normalized
Ginseng Radix, Extract of Ginkgonis Ratio and anticoagulant effects
Germen
Glycyrrhizae Radix (Gam cho) Digoxin, Furosemide, Licorice and digoxin may result in
Hydrochlorothiazide increased risk of digoxin toxicity. Licorice
and diuretics may result in increased risk
of hypokalemia and/or reduced
effectiveness of the diuretic.
Ginseng Radix, Ephedrae Herba (Ma Glyburide, Insulin, Metformin Severe Hypoglycemia due to increase
hwang) , Zinberis Rhizoma Recens (Saeng insulin
gang)
Glycyrrhizae Radix (Gam cho) Metoprolol, Verapamil, Diltiazem Decrease drug effect and Hypertension
Allii Bulbus (Ma neul) Isoniazid Decrease serum concentration of isoniazid
Zinberis Rhizoma Recens (Saeng gang) Nifedipine, Verapamil, Diltiazem Severe Hypotension
Extract of Ginkgonis Germen Thiazide Hypertension
Extract of Ginkgonis Germen, Ephedrae Anticonvulsant Increase risk of seizure
Herba (Ma hwang)
Ginseng Radix Azathioprine, Cyclosporine, Decrease effect of immunosuppressant
Corticosteroid
Ephedrae Herba (Ma hwang) Pseudoephedrine, MAO inhibitor Hypertension
Ephedrae Herba (Ma hwang) Amiodaron, Procainamide, Quinidine Prolongation of QT interval
Park YC et al 2011
11. Introduction (5)
• Some Chinese medical (CM) natural herbs listed
in the official Chinese Pharmacopoeia (CP), CP
are considered poisonous or toxic due to the
presence of poisonous or toxic chemical
constituents in the herb.
• Of which about 50 of animal, plant and mineral
natural materials are included in the CP.
• In the CP the words “toxic, non-toxic, very-toxic
or slightly toxic” are often used in describing
Chinese Materia Medica.
Chan K 2003
13. Very Toxic Herbal Medicine
Herbal name Common name Korean common Binominal name Toxicity
name
Crotonis Semen Croton seed Pa doo Croton tiglium L. (Euphorbiaceae) Very toxic
Mylabris Mylabris Ban myo 1. Mylabris cichorii Fabricius Very toxic
(Meloidae)
2. Mylabris phalerata Pall.
(Meloidae)
3. Mylabris sidae Fabricius
(Meloidae)
Aconiti Ciliare Tuber Wild aconite (tuber) Cho o Aconitum ciliare DC. Very toxic
(Ranunculaceae)
Aconiti Kusnezoffii Wild aconite (tuber) Cho o Aconitum kusnezoffii Reichb. Very toxic
Radix (Ranunculaceae)
Aconiti Proliferum Wild aconite (tuber) Cho o Aconitum proliferum Nakai Very toxic
Radix (Ranunculaceae)
Aconiti Radix Wild aconite (tuber) Cho o Aconitum triphyllum Nakai Very toxic
(Ranunculaceae)
Aconiti Radix Aconite main tuber Chun o 1. Aconitum carmichaeli Debx. Very toxic
(Ranunculaceae)
2. Aconitum chinense Paxton
(Ranunculaceae)
Strychni Semen seu nux Nuxvomica Ma jun ja Strychnos nux-vomica L. Very toxic
Vomicae Semen (Loganiaceae)
The Pharmacopoeia Commission of PRC, 2000
14. Crotonis Semen (Pa Doo)
• Indications: Scabies ,Eczema, Abscess
Constituents
4-alpha-Deoxy-5-hydroxy-20-acetoxy-12-O-(2-methyl-amino-benzoyl)phorbol
4-alpha-Deoxy-5-hydroxy-12-O-(N-deca-2,4,6-trienoyl)phorbol
4-alpha-Deoxy-12-O-(2-methylbutyryl)-phorbol-13-acetate
4-alpha-Deoxy-12-O-tiglyl-phorbol-13-acetate
• Pretreatment: Croton seed without husk, Croton seed plaster,
4-alpha-Deoxy-12-O-tiglylphorbol-13-isobutyrate
4-alpha-Deoxy-phorbol-13-acetate
4-alpha-Phorbol
Angelic acid
Croton seed frost-like powder
Cocacinogen A1
Cocacinogen A2
Cocacinogen A3
Cocacinogen A4
Cocacinogen B1
• Pharmacological action: increase GI movement (inhalation,
Cocacinogen B2
Cocacinogen B3
Cocacinogen B4
Cocacinogen B6
Cocacinogen B7
human), increase cell differentiation (in vitro)
Crotin I
Crotin tiglium lectin
Crotonoside
4-Deoxyphorbol tiglate acetate
4-Deoxy-5,13,20-triacetoxy-12-O-(n-deca-2,4,6-trienoyl)phorol
4,20-Dideoxy-5-hydroxy-12-O-(n-deca-2,4,6-trienoyl)-phorbol-13-acetate Hanyak yangnihak 2001
12-O-Acetylphorbol-13-acetate
12-O-(alpha-Methyl-butyryl)-phorbol-13-decanoate
Octyl acetate
12-O-[2-Methyl-amino-benzoyl]-4-alpha-deoxy-5-Hydroxy-phorbol
• Toxicity: Croton oil has the ability to promote radiation
12-O-[2-Methyl-amino-benzoyl]-4-alpha-deoxy-phorbol-5,13,20-triacetate
12-O-[2-Methyl-amino-benzoyl]-4-deoxy-5-hydroxy-phorbol-13-acetate
12-O-[2-Methyl-amino-benzoyl]-4,20-dideoxy-5-hydroxy-phorbol
12-O-[2-Methyl-amino-benzoyl]-4,20-dideoxy-5-hydroxy-phorbol-13-acetate
transformation. It is very toxic and carcinogenic (animal study).
12-O-[2-Methyl-amino-benzoyl]-4,20-dideoxy-phorbol-5,13-diacetate
12-O-(2-Methyl-butyryl)-phorbol-13-acetate
12-O-(2-Methylbutyryl)-phorbol-13-isobutyrate
12-O-[n-Deca-2,4,6-trienoyl]-4-deoxy-5-hydroxy-phorbol-13-acetate
Huang, K.C., The pharmacology of Chinese herbs II, CRC press, 1999.
12-O-[n-Tetradecanoyl]-4,20-dideoxy-5-hydroxy-phorbol-13-acetate
12-O-Tigloylphorbol-13-(2-methyl)-butyrate
12-O-Tiglylphorbol 13-isobutyrate
12-O-Tiglylphorbol-13-acetate
• Caution: Not use in pregnancy
Phorbol
Phorbol 13-butyrate 12-tiglate
Phorbol 13-caprylate 12-acetate
Phorbol 13-caprylate 12-tiglate
Phorbol 13-linoleate 12-acetate
Phorbol 13-myristate 12-acetate
• Formula in Korea: 35/ OTC in Korea:1
Phorbol-13-acetate
Phorbol-12-tiglate
www.tradimed.co.kr
www.tradimed.co.kr/www.kimsonline.co.kr
15. Mylabris (Ban Myo)
• Indications: Rabies, Scabies, Mercury intoxication, Hepatic
Cantharidin
cirrhosis due to Clonorchiasis, Tuberculosis, Tuberculous
lymphadenitis, Eczema, Abscess, Atopic dermatitis, Fever and
• Phytochemical group: Monoterpenoid
chill
• Molecular weight: 196.2
• • Pretreatment: cause symptoms from dermal inflammation to
Cantharidin may parched Mylabris with rice
blisters. If ingested, it may cause irritation and burning of the
• Pharmacological action: intoxication of snake venom,
increase urination, increase abortion GI tract, diarrhea, and
mouth, severe vesication of the upper Dong-Eui-Bo-Gam
kidney and cardiovascular damage.
• Caution: Not use in pregnancy
• Ii is a weak experimental animal carcinogen.
• Formula in Korea: 4 www.tradimed.co.kr
www.thomsonhc.com, www.tradimed.co.kr
16. Aconiti Ciliare Tuber, Aconiti Kusnezoffii Radix, Aconiti
Proliferum Radix, Aconiti Radix (Cho O)
• Indications: Beriberi Aconiti Ciliare Tuber Myalgia, Cold type
Constituents of edema, Cold limbs,
& Aconiti Porliferum Radix
Aconitine Aconitine
dysentery, Epigastric pain, Child epilepsy, Chronic osteomyelitis,
Hypaconitine
Mesaconitine
• Phytochemical group: Alkaloid
Hemiparalysis, Hemiplegia, Migratory arthropathy
• Molecular weight: 645.75
• Pretreatment: processedKusnezoffii Radix tuber
Constituents of Aconiti Wild aconite
• Bioactivity: bind to neurotoxin binding site 2 of α-subunit of
3-Acetylaconitine
Aconitine
• Pharmacological action:Na+ channel ,anti-inflammation,
Acontine
Na+ channel activation of analgesics, increase intracellular
Beiwutine
Bullatine A(structure unknown){formula: C(21)H(31)NO(2)}
vasodilatation, and local anesthetic action in animal study 2010
Ca2+ arrhythmia
Bullatine C Hanbang Yangnihak
Chasmanine; 6-Epimer
Denudatine
• • Toxicity: Toxictoxic if swallowed orbradycardia and irregular
Toxicity: Very symptoms include by skin absorption. Human
Hypaconitine
Lepenine
Mesaconitine
systemic effects by ingestion. LD50 (mus, orl) 1 well LD50 (mus, of
rhythm. Nausea and vomiting may occur, asmg/kg, as spasm ivn)
Neoline
Pendulin
0.175 mg/kg, exp. lethal doses by subcutaneous route reported. LD50 in mice
extremities and cardiac arrhythmias. The intestinal absorption of
Songorine
(mg/kg): 0.166 i.v.; 0.328 i.p.; approx 1 orally (Dybing); also reported as LD50 in
the alkaloids 1.8 relatively s.c.; 0.380 i.p.; 0.12of this, gastric lavage is
mice (mg/kg): is orally, 0.270 fast. Because i.v. (Sato).
Aconiti Ciliare Tuber
www.tradimed.co.kr
recommended in case of overdose.
Huang, K.C., The pharmacology of Chinese herbs II, CRC press, 1999.
Aconiti Kusnezoffii Radix
• Formula in Korea: 16 / OTC in Korea: 10
www.tradimed.co.kr/www.kimsonline.co.kr
17. Aconiti Radix (Chun O)
• Indications: Beriberi edema, Myalgia, Cold type dysentery, Paxton
Constituents of Aconitum carmichaeli Debx. Constituents of Aconitum chinense
14-Acetyltalatizamine Violdelphin
Aconine
Paresthesia, Child epilepsy, Epigastric pain, Chronic
Aconitan A
Aconitan B
Aconitan C
Aconitan D
osteomyelitis, Vomiting and Diarrhea, Testiculitis
Aconitine
Aldohypaconitine
Beiwutine
Benzoylaconine
Benzoylhypaconine
• Pretreatment: processed Aconite main tuber
Benzoylmesaconine
Chuanfumine
Chuan-Wu base A (structure unknown)(Tertiary base with 20H, 20Me and one N-Et groups.)
Chuan-Wu base B(structure unknown){formula: C(32)H(35)NO(4)}
Coryeine
Coryneine
• Pharmacological action: analgesics, anti-inflammation,
Fuzitine
Hokbusine A
Hokbusine B
Hypaconitine
vasodilatation, and local anesthetic action in animal study
Ignavine
Isodelphinine
Isotalatisamine
Isotalatizamine
Karakoline
• Caution: not
Lipoaconitine (R = linoleoyl, palmitoyl, oleoyl, stearoyl, linolenoyl)
use in pregnancy
Lipodeoxyaconitine (R = linoleoyl, palmitoyl, oleoyl, stearoyl, linolenoyl)
Lipohypaconitine (R = linoleoyl, palmitoyl, oleoyl, stearoyl, linolenoyl)
Lipomesaconitine (R = linoleoyl, palmitoyl, oleoyl, stearoyl, linolenoyl)
Mesaconitine
• Toxicity: headache, paralysis of tongue, paraplegia, pain on
Neojiangyouaconitine
Neoline
Salsolinol
upper extremity, nausea, vomiting, respiration difficulty, coma
Senbusine A
Senbusine B
Senbusine C
Songarine Hanyak yangnihak 2001
Songorine
Talatizamine
• Formula in Korea: 1/ OTC in Korea:
www.tradimed.co.kr 5
www.tradimed.co.kr/www.kimsonline.co.kr
19. Korean women have a chance to be exposed to herbal
medicine from marriage to lactation
Increase Decrease Increase
Promote Decreased
pregnancy nausea & breast
Health lochia
chance vomiting milk
35. Demographic characteristics of participants(n=321)
Age (years) 32.0 ± 3.6 Comorbidities [n (%)]
Gravidity (n) 2.2 ± 1.3 a) type 2 diabetes mellitus 1 (0.3)
Parity (n) 1.0 (0, 3.0) b) hypertension 2 (0.6)
Body mass index (kg/m2) 20.8 ± 3.2 c) thyroid disease 2 (0.6)
d) cancer 1 (0.3)
Exposure to X-rays
e) renal disease 1 (0.3)
a) n (%) 54 (16.8)
Education level [n (%)]
b) total dose (mSv) 0.005 (0.0005, 28.8)
a) post-secondary education 130 (40.5)
c) gestational age at exposure (weeks) 4.8 ± 3.2
b) high school 20 (6.2)
Exposure to alcohol (%)
c) not answered 171(53.3)
a) n (%) 128 (39.9)
Occupation
b) total dose (oz) 1.6 ± 1.4
a) professional, technical and related occupatio 54 (16.8)
c) gestational age at exposure (weeks) 4.6 ± 2.3 ns
Smoking (%) b) executive, administrative, managerial and sal 136 (42.4)
a) n (%) 23 (7.2) es
occupations
b) cigarettes/day 5.4 ± 4.4
c) construction workers 124 (38.6)
c) gestational age at exposure (weeks) 6.3 ± 4.6
d) unemployed 7 (2.2)
Korean Motherisk Program, unpublished
36. Indications of herbal exposure (n=321)
INDICATIONS a n (%)
Analgesics 8 (2.5)
Anti-acne preparations 2 (0.6)
Anti-emetics & anti-nauseants 1 (0.3)
Anti-inflammatory enzymes 8 (2.5)
Anti-inflammatory & anti-rheumatic products 7 (2.2)
Anti-obesity preparations 21 (6.5)
Anti-thrombotic agents 2 (0.6)
Cough and cold preparations 129 (40.2)
Dermatological preparations 3 (0.9)
21 cases: Tonic
Drugs for acid related disorder 1 (0.3)
medicine
Functional gastrointestinal disorders 93 (29.0)
Gynecological anti infectives and antiseptics 11 (3.4)
Psycholeptics 2 (0.6)
Sex hormones & modulators the genital system 7 (2.2)
Others 26 (8.1)
aAccording to the pharmacological/therapeutic subgroups of the ATC classification system (World Health Organization Korean Motherisk Program, unpublished
Collaborating Centre for Drug Statistics Methodology 2011)
37. Exposure to herbal medicine in pregnant women (n=321)
Median (range)
Numbers of herbal medicine including 7.0 (1.0 - 40.0)
one prescription
Duration of exposure (days) 3.0 (1.0 – 365.0)
Gestational age at last dose (weeks) 4.7 (0.1 - 25.0)
197 kinds of herbal medicines
Korean Motherisk Program, unpublished
38. Frequencies of Herbal medicine (>10%)
n 188
200
150
100 75 91 81 71 103
50 46 65 71
57 57
48 43 45
0 43 45 41
40 33
Korean Motherisk Program, unpublished
39. Fetal outcomes
Cases (n= 307)
Gestational age at birth (weeks) 38.9 ± 2.4
Birth weight (g) 3,294.2 ± 511.8
Birth length (cm) 49.7 ± 2.2
Head circumference at birth (cm) 34.6 ± 1.4
Apgar score, 1 min 8.3 ± 0.9
Apgar score, 5 min 9.0 ± 0.7
IUFD (%) 6 (2.0)
Malformationsa (%) 7 (2.3)
NICU admission (%) 12 (3.9)
Duration of NICU admission (days) 12.5 ± 9.2
Neonatal jaundice (%) 10 (3.3)
a A baby born with megacisterna magna, second one with dysplastic change of left kidney, left ectopic ureteral
insertion, third one with small pulmonary artery, fourth one with polydactyly of 5th toe of left foot and cleft palate and
patent ductus arteriosus, fifth one with small echogenic foci of anterior papillary muclse of left ventricle heart, sixth
one with borderline left ventriculomegaly of cerebrum, and seventh one with patent ductus arteriosus
Korean Motherisk Program, unpublished
40. Summary (1)
• Although herbal medicines have been used in
clinical practice for thousands of years, basic
research on herbal substances should be focused on
the toxicity and efficacy relationship for those potent
and poisonous herbal substances according to
composite formula.
• Most traditional medical herbs are used in the form
of an aqueous decoction. Therefore research
projects should be centered on development of
analytical and biological procedures for use to give
quality assurance, control, and clinical assessment of
efficacy, and safety of products.
41. Summary (2)
• Herbal medications should be regulated for safety,
quality and for appropriate evidence of efficacy.
• Dosage and indications for treatment should be
standardized. And contraindications should be
clearly identified.
• Language problem is another aspect as herbal
ingredients are supplied with similarly names
substitutes that could be toxic.
