Scholarly article on topic 'Use and safety of Korean herbal medicine during pregnancy: A Korean medicine literature review'

Use and safety of Korean herbal medicine during pregnancy: A Korean medicine literature review Academic research paper on "Clinical medicine"

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Abstract of research paper on Clinical medicine, author of scientific article — Junyoung Jo, Sun Haeng Lee, Jin Moo Lee, Hyangsook Lee, Seung Jun Kwack, et al.

Abstract Introduction Korean herbal medicine (KHM) is widely used as a therapeutic modality during pregnancy in Korea. The purpose of this review is to identify use and adverse events (AEs) associated with KHM during pregnancy in Korean medicine literature. Methods We searched Pubmed, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and five Korean databases to identify relevant studies published before January 2015. Studies were included regardless of their design if they reported original data and involved KHM for any conditions in pregnant women. For safety problems, we also excluded studies if there was no information about maternal and fetal outcomes. Results Fifty-two studies were included in this review. The most frequently reported indication for KHM was hyperemesis gravidarum (26.3%). Anjeonicheon-tang and Atractylodes Rhizome White were the most commonly used in KHM prescriptions and as single herbs during pregnancy. Some studies reported mild or unassessable AEs like diarrhea, pruritis, and preterm birth. Severe AEs were all considered unlikely to have been caused by KHM. Conclusions Hyperemesis gravidarum and maintaining pregnancy accounted for more than two-thirds of clinical indications for KHM during pregnancy in Korean medicine literature. Few studies reported on mild AEs associated with KHM, but due to a lack of large prospective surveys, this finding is not conclusive. Prospective studies with a larger sample size are needed to confirm the safety of KHM during pregnancy.

Academic research paper on topic "Use and safety of Korean herbal medicine during pregnancy: A Korean medicine literature review"

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European Journal of Integrative Medicine xxx (2015) xxx-xxx

Contents lists available at ScienceDirect

|pp ; m European Journal of Integrative Medicine

journal homepage: www.elsevier.com/eujim

Review article

Use and safety of Korean herbal medicine during pregnancy: A Korean medicine literature review

Junyoung Joa,11 Sun Haeng Leeb,1) Jin Moo Leea, Hyangsook Leec, Seung Jun Kwackd, Dong Il Kime'*

a Department of Korean Gynecology, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea

b Department of Clinical Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea

c Acupuncture and Meridian Science Research Center, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea

d Department of Bio Health Science, College of Natural Sciences, Changwon National University, Changwon 51140, Republic of Korea

e Department of Obstetrics and Gynecology, College of Korean Medicine, Dong Guk University, 27, Dongguk-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do 10326,

Republic of Korea

ARTICLE INFO

ABSTRACT

Article history:

Received 16 July 2015

Received in revised form 20 October 2015

Accepted 20 October 2015

Available online xxx

Keywords:

Korean herbal medicine Pregnancy Adverse events Safety

Introduction: Korean herbal medicine (KHM) is widely used as a therapeutic modality during pregnancy in Korea. The purpose of this review is to identify use and adverse events (AEs) associated with KHM during pregnancy in Korean medicine literature.

Methods: We searched Pubmed, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and five Korean databases to identify relevant studies published before January 2015. Studies were included regardless of their design if they reported original data and involved KHM for any conditions in pregnant women. For safety problems, we also excluded studies if there was no information about maternal and fetal outcomes.

Results: Fifty-two studies were included in this review. The most frequently reported indication for KHM was hyperemesis gravidarum (26.3%). Anjeonicheon-tang and Atractylodes Rhizome White were the most commonly used KHM prescription and single herb during pregnancy. Some studies reported mild or unassessable AEs like diarrhea, pruritis, and preterm birth. Severe AEs were all considered unlikely to have been caused by KHM.

Conclusions: Hyperemesis gravidarum and maintaining pregnancy accounted for more than two-thirds of clinical indications for KHM during pregnancy in Korean medicine literature. Few studies reported on mild AEs associated with KHM, but due to a lack of large prospective surveys, this finding is not conclusive. Prospective studies with a larger sample size are needed to confirm the safety of KHM during pregnancy.

© 2015 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND

license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Contents

1. Introduction ....................................................................................................... 00

2. Materials and methods .............................................................................................. 00

2.1. Search strategy ............................................................................................... 00

2.2. Study selection ............................................................................................... 00

2.3. Data extraction and analysis .................................................................................... 00

Abbreviations: KHM, Korean herbal medicine; CM, Chinese medicine; AEs, adverse events. * Corresponding author. Fax: +82 0 31 961 9009. E-mail addresses: studd@naver.com (J. Jo), civil011@empas.com (S.H. Lee), hanbang9597@hanmail.net (J.M. Lee), erc633@khu.ac.kr (H. Lee), sjnkwack@changwon.ac.kr (S.J. Kwack), obgykdi@hanmail.net (D.I. Kim). 1 These authors contributed equally to this work.

http://dx.doi.org/10.1016/j.eujim.2015.10.008

1876-3820/© 2015 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/

4.0/).

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3. Results ...........................................................................................................00

3.1. Identification of articles ........................................................................................00

3.2. Commonly used KHM prescriptions and single medicines ............................................................00

3.2.1. Clinical applications of KHM commonly used during pregnancy in Korean medicine literature ........................00

3.2.2. Number of cases of commonly used prescriptions in Korean medicine literature ...................................00

3.2.3. Single KHMs used in pregnancy with at least 100 documented cases in Korean medicine literature....................00

3.3. KHM prescription and single medicines reporting maternal or neonatal outcomes ......................................... 00

3.3.1. Number of cases for which prescriptions were used and reported maternal or neonatal outcomes ....................00

3.3.2. Single KHM with at least 100 documented cases which reported maternal or neonatal outcomes .....................00

3.4. Adverse events ...............................................................................................00

3.4.1. Adverse maternal outcomes .............................................................................00

3.4.2. Adverse neonatal outcomes .............................................................................. 00

4. Discussion.........................................................................................................00

5. Limitation .........................................................................................................00

6. Conclusion ........................................................................................................00

Conflict of interests .................................................................................................00

Acknowledgments ..................................................................................................00

References ........................................................................................................ 00

1. Introduction

An increasing number of women worldwide use complementary and alternative medicine, usually regarded as being natural and safe, to treat illness during pregnancy [1]. Korean herbal medicines (KHM) are used for pregnancy-related indications such as threatened miscarriage, hyperemesis gravidarum, or recurrent miscarriages in Korea [2].

Both traditional medicines and western medicines have the potential to cause adverse pregnancy outcomes and affect embryonic and fetal development in pregnant women [3]. However, it is not ethical to test the adverse effects and toxicity of medicines in human subjects. Therefore, animal studies can provide important data on the potential toxicity of medicines. Two recent experimental studies about the safety of those commonly used Chinese medicine (CM) during pregnancy showed that adverse pregnancy outcomes were common, suggesting CM could do harm during pregnancy [4,5]. But, those studies were criticized because of inconsistencies, implausi-bilities and several severe biometrical flaws [6].

A recent systematic review on adverse outcomes of CM for threatened miscarriage pooled data from clinically very heterogeneous studies, and found adverse events (AEs) like dry mouth, constipation, insomnia, diabetic complications, preterm delivery and neurodevelopmental morbidity [7]. Meta-analysis demonstrated no significant differences between combined CM group and western medicines group for AEs and toxicity or for adverse maternal and fetal outcomes [7].

KHM shares its origins with CM and has been historically utilized as safe during pregnancy. However, there are not sufficient data regarding the use and safety of using KHM during pregnancy. The aim of this study was (i) to identify the commonly used KHM prescription and single medicines during pregnancy; (ii) to analyze the adverse outcomes of KHM during pregnancy.

2. Materials and methods

2.1. Search strategy

We searched electronic databases for relevant studies published before January 2015, including Pubmed, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and five Korean databases: the Korean Studies Information Service System (http://kiss.kstudy.com/), KoreaMed (http://www.kore-amed.org), Oriental Medicine Advanced Searching Integrated System (http://oasis.kiom.re.kr), The Journal of Korean Obstetrics and Gynecology (http://oobgy.or.kr/) and The Journal of Korean

Medicine (http://www.jkom.org/). The following search terms were used: "Korean herbal medicine", "traditional Korean medicine", "miscarriage", "adverse events", and "pregnancy".

2.2. Study selection

To identify use, we included all types of studies if they involved pregnant women treated for any conditions by KHM prescribed by a Korean Medicine physician. For safety questions, the only studies included were those with documented pregnancy outcomes. We excluded studies if there was no information provided about the medicines used or the number of patients treated with KHM. There was no restriction to the type of studies.

2.3. Data extraction and analysis

We analyzed the prescriptions in each study and counted medicines in the prescriptions. We summed the prescriptions and single medicines from all relevant studies. For the safety question, the sum was the number of documented cases for which data about a pregnancy outcome were available. At least 100 documented cases demonstrating pregnancy outcomes was rated as preliminary evidence of safety [6].

Two authors (JJ and SHL) extracted data regarding author(s), publication year, study design, sample size, gestational week, purpose for KHM, duration of KHM and detailed information on AEs. AEs were classified into maternal and neonatal outcomes.

The severity of each AE was graded 1 (mild) to 3 (severe) according to modified Spilker's AE classification [8,9]. It was determined as mild if the AE had no impact on ability to perform normal delivery, such as diarrhea, headache, and hyperemesis gravidarum. Moderate was defined if AE could impact on delivery with some problems, such as preterm birth. Severe AE is a death of an embryo or fetus, such as spontaneous abortion. Causality - that is, the strength of the relationship between AEs and KHM - was assessed by two reviewers (SHL, paediatrics of Korean Medicine specialist and JJ, obstetrics/gynaecology of Korean Medicine specialist) in accordance with the causality categories in the World Health Organisation-Uppsala Monitoring Centre (WHO-UMC) system for standardised case causality assessment [10]. The causality categories used were certain, probable/likely, possible, unlikely, conditional/unclassified and unassessable/unclassifiable. The incidence of AEs was presented as the number of cases per number of KHM treated participants (%).

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3. Results

3.1. Identification of articles

Three hundred and eighteen publications about KHM during pregnancy were identified from the database search. After duplicates were removed, 222 records were screened by the titles and abstracts and 168 articles were excluded. The full texts of the remaining 54 studies were assessed for study eligibility. Finally, 52 studies were included for review. There were eight retrospective studies, 24 case reports and 20 case series. Pregnancy outcomes or neonatal outcomes were not reported in 23 studies. Twenty-nine studies (395 women) were reviewed for safety issue. There were no randomized controlled trials (RCTs), 17 case reports and 12 case series (Fig. 1). The detailed information of 52 studies are provided in an online supplementary table.

3.2. Commonly used KHM prescriptions and single medicines

3.2.1. Clinical applications of KHM commonly used during pregnancy in Korean medicine literature

Amongst all literature reporting KHM used during pregnancy, hyperemesis gravidarum (26.3%) was the most common clinical indication for KHM (Fig. 2) [11-30]. Less common, clinical indications included recurrent pregnancy loss (16.5%) [12,23,31,32], threatened miscarriage (12.7%) [12,23,27,28,33,34], preventing miscarriage (11.7%) [12,23,35-39], common cold (6.7%) [12,14,17,21,23,27,40], safe delivery (5.2%) [12,21,23,27,28], facial palsy (3.4%) [41-46], lumbago (2.1%) [12,14,47,48], and other obstetric complications (15.3%) (Fig. 2) [12,22,39,49-62].

3.2.2. Number of cases of commonly used prescriptions in Korean medicine literature

Amongst all the prescriptions studied during pregnancy, "Anjeonicheon-tang" was the most frequently used formula (29.5%) (Table 1). "Anjeonicheon-tang" is prescribed mostly for recurrent miscarriage and relieves clinical signs such as vaginal bleeding [63]. Other popular prescriptions include "Bosaeng-tang",

"Dangkwi-san" and "Gyullyeongbosaeng-tang". These three prescriptions are usually used to relieve hyperemesis gravidarum. The compositions of most commonly studied Korean medicines during pregnancy are documented in Table 1.

3.2.3. Single KHMs used in pregnancy with at least 100 documented cases in Korean medicine literature

The single KHM at least 100 documented cases in Korean medicine literature included Atractylodis Rhizoma White (81.6%), Glycyrrhizae Radix (81.4%), Ginseng Radix (62.1%), Citri Peri-carpium (54.1%), Amomi Fructus (51.0%), Rehmanniae Radix Preparata (47.1%), Scutellariae Radix (43.4%), Cyperi Rhizoma (41.6%), Eucommiae Cortex (39.5%), Perilla Herba (38.3%), Paeoniae Radix Alba (38.3%), Angelicae Gigantis Radix (37.7%), Cnidii Rhizoma (35.4%), Lycii Fructus (35.0%), Dioscoreae Rhizoma (34.0%), Poria (33.8%), Zingiberis Rhizoma Crudus (32.6%), Corni Fructus (28.5%), Dolichoris Semen (26.6%), Amomi Fructus Rotundus (23.2%), and Aurantii Fructus (19.7%) in descending order (Table 2).

3.3. KHM prescription and single medicines reporting maternal or neonatal outcomes

3.3.1. Number of cases for which prescriptions were used and reported maternal or neonatal outcomes

"Anjeonicheon-tang" was also the most frequently used formula (33.4%) (Table 1). Bosaeng-tang, Dangkwi-san, Antae-eum, Gungso-san, Gyoaesamul-tang, Dalsaeng-san, and Antae-geumchul-tang were also in the frequent remedies of KHM prescribed to pregnant women (Table 1).

3.3.2. Single KHM with at least 100 documented cases which reported maternal or neonatal outcomes

Single KHM with at least 100 documented cases in Korean medicine literature included Atractylodis Rhizoma White (86.6%), Glycyrrhizae Radix (86.1%), Ginseng Radix (68.1%), Rehmanniae Radix Preparata (55.3%), Citri Pericarpium (50.9%), Amomi Fructus (48.6%), Eucommiae Cortex (46.0%), Scutellariae Radix (43.7%),

Fig. 1. Flow diagram of study selection.

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Fig. 2. Clinical applications of KHM commonly used during pregnancy in Korean medicine literature.

Dioscoreae Rhizoma (43.2%), Lycii Fructus (42.9%), Paeoniae Radix Alba (39.3%), Angelicae Gigantis Radix (39.1%), Cyperi Rhizoma (39.1%), Perilla Herba (38.6%), Corni Fructus (36.0%), Cnidii Rhizoma (35.7%), Dolichoris Semen (34.2%), Poria (28.3%), and Zingiberis Rhizoma Crudus (27.5%) in descending order (Table 3). Rehmanniae Radix Preparata was used by the largest mean doses (19.55 g/day) and maximum dose (30.0g/day).

3.4. Adverse events

We identified a total of 65 AEs from 52 cases in the 10 reports (Tables 4 and 5). When AEs were graded according to modified Spilker's AE classification and WHO-UMC causality assessment, mild AEs (n = 3) occurred in 2 cases with 2 certain and 1 unassessable causality. Moderate AEs (n = 24) occurred in 12 cases with 19 unlikely and 5 unassessable causality. Severe AEs (n = 38) were all considered unlikely to have been caused by KHM

prescriptions. Detailed AEs associated with KHM prescriptions are summarised in Tables 4 and 5. The AE incidence of KHM with certain or unassessable causality was 1.5%, and limiting the calculation to AEs evaluated as certain in the causality assessment resulted in an incidence of 0.3%.

3.4.1. Adverse maternal outcomes

Five hundred and twelve women took KHM during pregnancy, but the pregnancy outcome was only available in 395 women. Among 395 women, 343 women had normal deliveries (86.8%), 11 women had preterm deliveries (2.8%), 3 women had preterm or postmature delivery (0.8%), and 38 women had miscarriages (9.6%). Most miscarriages were from threatened miscarriage and recurrent pregnancy loss patients [12,14,21,23,36]. Mild or unassessable AEs such as diarrhea, pruritus, or preterm birth were reported in one case report [50] and 4 retrospective studies [11,12,17,23].

Table 1

Compositions of most commonly used Korean herbal medicines during pregnancy.

Korean medicine Usea formulae

Use reported pregnancy outcomea

Compositions and daily dose (g)

Anjeonicheon-tang 151 (29.5%)

Bosaeng-tang 68 (13.3%)

Dangkwi-san 47 (9.2%)

Antae-eum 41 (8.0%)

Gyullyeongbosaeng- 40 (7.8%) tang

Gungso-san 36 (7.0%)

Gyoaesamul-tang 25 (4.9%)

Dalsaeng-san

Antaegeumchul-tang

Ondam-tang

Samul-tang Palmul-tang

19 (3.7%)

16 (3.1%)

13 (2.5%)

132 (33.4%) Atractylodis Rhizoma White, Ginseng Radix, Rehmanniae Radix Preparata 26.67, Corni Fructus,

Dioscoreae Rhizoma 13.33, Eucommiae Cortex 8, Dolichoris Semen, Lycii Fructus 5.33, Glycyrrhizae Radix 2.67

44 (11.1%) Atractylodis Rhizoma White, Citri Pericarpium, Cyperi Rhizoma, Linderae Radix 15, Ginseng Radix,

Glycyrrhizae Radix 7.5

37 (9.4%) Angelicae Gigantis Radix, Cnidii Rhizoma, Paeoniae Radix Alba, Scutellariae Radix 3.33, Atractylodis

Rhizoma White 1.67

23 (5.8%) Angelicae Gigantis Radix, Atractylodis Rhizoma White, Paeoniae Radix, Rehmanniae Radix 7.5, Citri

Pericarpium, Cnidii Rhizoma, Ginseng Radix 3.75, Amomi Fructus, Glycyrrhizae Radix, Perilla Herba, Scutellariae Radix 2.25

- Citri Pericarpium 18.75, Amomi Fructus, Atractylodis Rhizoma White, Cyperi Rhizoma, Poria 7.5 Alpiniae Katsumadai Semen, Pogostemonis Herba, Scutellariae Radix 5.25 Glycyrrhizae Radix 3.75, Zingiberis Rhizoma Crudus 10 pieces, Mume Fructus 2 pieces

31 (7.8%) Liriopis Tuber, Peucedani Radix, Scutellariae Radix 7.5, Atractylodis Rhizoma White, Citri Pericarpium,

Cnidii Rhizoma, Paeoniae Radix Alba 6, Perilla Herba 4.5, Pueraiae Radix 3.75, Glycyrrhizae Radix 2.25

24 (6.1%) Amomi Fructus, Angelicae Gigantis Radix, Artemisiae Argi Folium, Asini Gelatinum, Atractylodis Rhizoma

White, Cnidii Rhizoma, Cyperi Rhizoma, Paeoniae Radix Alba, Rehmanniae Radix Preparata, Scutellariae Radix 7.5

19 (4.8%) Arecae Pericarpium 15, Glycyrrhizae Radix 11.25, Angelicae Gigantis Radix, Atractylodis Rhizoma White,

Paeoniae Radix Alba 7.5, Amomi Fructus, Aurantii Fructus, Citri Pericarpium, Ginseng Radix, Perilla Herba 3.75

15 (3.8%) Terba Flava Usta 24, Atractylodis Rhizoma White 16, Pinelliae Rhizoma, Zingiberis Rhizoma Crudus 12,

Citri Pericarpium, Cyperi Rhizoma, Poria, Scutellariae Radix 8, Amomi Fructus, Amomi Rotundus Fructus, Perilla Herba 6, Aucklandiae Radix, Aurantii Fructus, Citri Reticulatae Viride Pericarpium, Glycyrrhizae Radix 4

- Aurantii Immaturus Fructus, Citri Pericarpium, Pinelliae Rhizoma 7.5, Poria 4.13, Glycyrrhizae Radix 3, Zingiberis Rhizoma Crudus 14 pieces, Jujubae Fructus 2 pieces, Bambusae Caulus in Taeniam 2 pieces

10 (2.5%) Angelicae Gigantis Radix, Cnidii Rhizoma, Paeoniae Radix Alba, Rehmanniae Radix Preparata 9.38

8 (2.0%) Angelicae Gigantis Radix, Atractylodis Rhizoma White, Cnidii Rhizoma, Ginseng Radix, Glycyrrhizae

Radix, Paeoniae Radix Alba, Poria, Rehmanniae Radix Preparata 9

% is the number of cases of each prescription/total amount of cases x 100.

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Table 2

Number of cases on which single medicinal herb was used in Korean medicine literature during pregnancy.

Scientific names (Biological names) Totala (%)

Atractylodis Rhizoma White (Atractylodes japonica) 418 (81.6%)

Glycyrrhizae Radix (Glycyrrhiza glabra) 417 (81.4%)

Ginseng Radix (Panax ginseng) 318 (62.1%)

Citri Pericarpium (Citrus unshiu) 277 (54.1%)

Amomi Fructus (Amomum villosum) 261 (51.0%)

Rehmanniae Radix Preparata (Rehmannia glutinosa) 241 (47.1%)

Scutellariae Radix (Scutellaria baicalensis) 222 (43.4%)

Cyperi Rhizoma (Cyperus rotundus) 213 (41.6%)

Perilla Herba (Perilla frutescens) 202 (39.5%)

Eucommiae Cortex (Eucommia ulmoides) 196 (38.3%)

Paeoniae Radix Alba (Paeonia lactiflora) 196 (38.3%)

Angelicae Gigantis Radix (Angelica gigas) 193 (37.7%)

Cnidii Rhizona (Cnidium officinale) 181 (35.4%)

Lycii Fructus (Lycium chinense) 179 (35.0%)

Dioscoreae Rhizoma (Dioscorea batatas) 174 (34.0%)

Poria (Poria cocos) 173 (33.8%)

Zingiberis Rhizoma Crudus (Zingiber officinale) 167 (32.6%)

Corni fructus (Cornus officinalis) 146 (28.5%)

Dolichoris Semen (Dolichos lablab) 136 (26.6%)

Amomi Fructus Rotundus (Amomum krabanh) 119 (23.2%)

Aurantii Fructus (Citrus aurantium) 101 (19.7%)

a 512 cases.

3.4.2. Adverse neonatal outcomes

One neonatal jaundice [39], three very low birth weight infants [11,12] and five low birth weight infants [12,17] were reported due to preterm delivery. One fetal macrosomia was reported due to gestational diabetes [12]. Also, one hypoxia and hypoglycemia [17] and one patent ductus arteriosus [12] infants were reported among low birth weight infants due to preterm delivery. The status of the remaining two infants out of the 11 preterm deliveries was not documented [23,62].

4. Discussion

In this review, we found that hyperemesis gravidarum was the most common clinical indication of KHM and Anjeonicheon-tang was the most frequently used formula. We also analyzed the prescriptions and tabulated use of single herb medicines that documented at least 100 cases in Korean medicine literature. Atractylodis Rhizoma White was the most common single herb during pregnancy. We identified the adverse maternal and

neonatal outcomes associated with KHM during pregnancy were rarely reported in most studies, and reported AEs were evaluated as mild in severity or had unassessable or unlikely causalities. Therefore, there was limited evidence for us to find a direct relation between the adverse maternal outcomes with KHM.

Anjeonicheon-tang has been applied for threatened miscarriages or supporting implantation by tonifying "innate qi" and "acquired qi" [36,64]. Amongst all the formulae studied for threatened miscarriage in CM, "Anjeonicheon-tang" was the fifth frequently used formula [63]. Antae-eum which was fourth frequently used decoction in this review was third frequently used decoction amongst all the formulae studied for threatened miscarriage in CM [63]. Other decoctions were not overlapped between two reviews. These discrepancies might come from the differences of indication of herbal medicine used for threatened miscarriage in CM and for all indications during pregnancy in KHM. Also, the reports on KHM during pregnancy mostly came from one hospital.

There is a lack of appropriate information regarding AEs in specific CM as well as specific KHM. Therefore, it may be difficult to make any meaningful comparisons of AEs between these two countries. Antae-eum was related with diarrhea in patient with preterm labor [50] and preterm birth in patient with preeclampsia [62], but other eight studies reported no AEs [13,26,31,34,43,45,47,53]. Such results are in line with CM review on threatened miscarriage [7] which reported 0.7% of preterm delivery, 0.7% of neonatal death due to prematurity, and 0.3% of epilepsy. Comparisons of AEs of other decoctions were not feasible due to lack of data.

Atractylodis Rhizoma White is one herb of Antae-eum which is highly recommended to benefit and help the fetus survive by improving the function of "kidney" and regulating "Qi" and "blood" [63]. Atractylodis Rhizoma White is also the most commonly used CM for threatened miscarriage [5]. Recent animal studies reported that Atractylodis Rhizoma White affects limb development by suppressing the expression of limb developmental genes and disturbing programmed cell death during limb formation in mice [5]. Potential reproductive toxicity of Atractylodis Rhizoma White in pregnant animals was identified within the clinical dose range [65]. However, there was no toxicity identified in our review including more than 300 cases of Atractylodis Rhizoma White.

Reproductive toxicities of CM commonly used during pregnancy such as Atractylodis Rhizoma White, Scutellariae Radix,

Table 3

Doses and number of cases of single KHM used in studies reporting maternal or perinatal outcome.

Scientific names (Biological names) Dosea (g) Cases (%)b

Atractylodis Rhizoma White (Atractylodes japonica) 19.07 ± 7.15 (5.63-26.67) 348 (88.1)

Glycyrrhizae Radix (Glycyrrhiza glabra) 5.29 ±2.85 (2.25-12.00) 346 (87.6)

Ginseng Radix (Panax ginseng) 17.29 ±10.20 (3.75-26.67) 273 (69.1)

Rehmanniae Radix Preparata (Rehmannia glutinosa) 19.54±9.42 (5.71-30.00) 217 (54.9)

Citri Pericarpium (Citrus unshiu) 9.26±4.35 (3.75-18.75) 209 (52.9)

Amomi Fructus (Amomum villosum) 6.65 ±1.67 (2.25-12.00) 200 (50.6)

Eucommiae Cortex (Eucommia ulmoides) 7.66 ±1.11 (5.71-12.00) 179 (45.3)

Scutellariae Radix (Scutellaria baicalensis) 6.83 ±2.71 (1.43-16.00) 175 (44.3)

Dioscoreae Rhizoma (Dioscorea batatas) 13.16 ±1.71 (3.75-16.00) 169 (42.8)

Lycii Fructus (Lycium chinense) 5.60 ±2.16 (5.33-24.00) 167 (42.3)

Cyperi Rhizoma (Cyperus rotundus) 9.34 ±3.68 (5.71-16.00) 161 (40.8)

Perilla Herba (Perilla frutescens) 5.95 ±2.67 (2.25-12.00) 161 (40.8)

Angelicae Gigantis Radix (Angelica gigas) 8.19 ± 2.08 (3.75-16.00) 155 (39.2)

Paeoniae Radix Alba (Paeonia lactiflora) 8.23 ±2.39 (5.71-18.75) 155 (39.2)

Cnidii Rhizoma (Cnidium officinale) 7.50 ± 2.29 (3.75-16.00) 141 (35.7)

Corni Fructus (Cornus officinalis) 13.38 ±1.29 (8.00-22.50) 141 (35.7)

Dolichoris Semen (Dolichos lablab) 5.33 133 (33.7)

Poria (Poria cocos) 7.56 ±2.24 (4.00-16.00) 120 (30.4)

Zingiberis Rhizoma Crudus (Zingiber officinale) 13.10 ± 7.50 (6.00-28.57) 110 (27.8)

a Dose are presented as mean ±SD (min-max) per day. b Total cases were 395 cases.

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Table 4

Adverse maternal outcomes associated with KHM prescriptions.

RN Author (year) Agea (years) Maternal herbal prescription Concomitant treatment Herbal medicine use Maternal AEs

Purpose (diagnosis) Duration (day) Occurs Severity Causality

[11] Ahn et al 28-38 (31.37) Multiple NS HA 5-25 1 SA Severe Unlikely

(2014) 1 IA from maternal disease Severe Unlikely

1 Preterm birth Moderate Unassessable

[12] Jung et al (32 ±4.3) Multiple Antihistamine (Pruritis Multiple 2-28 3 SA Severe Unlikely

(2014) gravidarum), Surgery 1 Gestational diabetes Moderate Unlikely

(Cervical incompetency, 1 Pruritus gravidarum Mild Unassessable

Intestinal obstruction, 1 Preterm birth from Moderate Unassessable

Ovarian cancer) premature rupture of

membranes

3 Preterm birth from Moderate Unlikely

surgery

[62] Kim et al 40 ATE Acup Pre-eclampsia 43 Preterm birth from pre- Moderate Unlikely

(2013) eclampsia

[50] Jo et al 33 DKJYS NS Abdominal pain 7 Diarrhea Mild Certain

(2012) ATE Progesterone Preterm labor 10 Diarrhea Mild Certain

[36] Lee et al NS AJICT WM(partially) Preventing 1.73 ±1.26 10 SA Severe Unlikely

(2010) miscarriage months

[14] Jo et al 22-35 Multiple NS Multiple 4-40 1 SA Severe Unlikely

(2008) (29.7 ±3.4)

[17] Choi et al (29.8 ±4.70) Multiple NS Multiple 3-47 3 SA Severe Unlikely

(2005) 1 IA from r/o Down Severe Unlikely

syndrome

1 Gestational diabetes & Moderate Unlikely

Preterm birth from

premature rupture of

membrane

1 Preterm birth from Moderate Unassessable

preterm labor

1 preterm birth from twins Moderate Unlikely

[39] Zhang et al 37 PMT None Preventing 7 Preterm birth from fetal Moderate Unlikely

(2004) miscarriage death in utero

(1 Fetal death in

utero of twins)

[21] Kim et al (30.06 ±3.73) Multiple NS Multiple 2-40 2 SA Severe Unlikely

(2003) 1 IA from severe HA Severe Unlikely

[23] Heo et al NS Multiple NS Multiple NS 1 preterm birth Moderate Unassessable

(2002) Recurrent 10 abortion Severe Unlikely

pregnancy loss

Threatened 5 abortion Severe Unlikely

abortion

Multiple: Details of the "Multiple" are provided in Supplementary data. RN: reference number, AEs: adverse events, NS: Non-specific, ATE: Antae-eum, DKJYS: Dangkwijagyak-san, AJICT: Anjeonicheon-tang, HSPWS: Hyangsapyeongwi-san, PMT: Palmul-tang, BCS: Banchong-san, CJHBH: Chiljehyangbu-hwan, DKS: dangkwi-san, BST: Bosaeng-tang, WM: Western medicine, Acup: Acupuncture, Moxa: Moxibustion, HA: Hyperemesis gravidarum, SA: Spontaneous abortion, 1A: Induced abortion. a (Mean ± standard deviation).

Rehmanniae Radix Preparata, Cnidii Rhizona, Citri Pericarpium, Glycyrrhizae Radix, Dioscoreae Rhizoma, and Amomi Fructus were identified in mice [4], but these animal studies includes many inconsistencies, implausibilities and several severe biometrical flaws [6]. The evidence regarding the use of CM for threatened miscarriage on adverse effects/toxicity, and adverse maternal and fetal outcomes, is limited, but the review suggest that CM for threatened miscarriage may not be associated with increased risk of preterm delivery, neonatal mortality and congenital malformation. Our results are in line with these results. The prevalence of birth defects was 286.9 per 10,000 livebirths in 2005-2006 in Korea [66], but only two birth defects including one patent ductus arteriosus, and one hypoxia and hypoglycemia were identified in 354 babies in our review, as opposed to 10 expected.

Those medicines with higher case numbers (over 100 cases) in our review suggest that a preliminary positive safety statement is warranted. Also, it seems that they had no severe AEs with certain or possible causality. Atractylodis Rhizoma White, Glycyrrhizae Radix, Eucommiae Cortex, Dioscoreae Rhizoma, Paeoniae Radix

Alba, Angelicae Gigantis Radix, Amomi Fructus are considered safe with regard to fetal growth or birth weight [6]. Using these herbs below reported maximum daily dose (Table 3) result in side effects only rarely to pregnant women and fetus.

5. Limitation

We tried to conduct comprehensive electronic database search but, we cannot rule out that we might have missed some relevant articles or unpublished data. Most studies did not evaluate AEs as study outcome assessment. It may be because the occurrence of AEs was indeed too rare or because awareness of the AEs was actually too low, as in the CM review [7]. There were no RCTs, and all studies are case reports and case series without controls that were retrospectively studied. The sample sizes of the studies were very small. To detect teratogenicity, a large epidemiological study is needed [6]. Therefore, we could not draw a firm conclusion of the safety of KHM during pregnancy. More studies with rigorous designs to assess the safety are needed.

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J.Jo et al./European Journal of Integrative Medicine xxx (2015) xxx-xxx 7

Table 5

Adverse neonatal outcomes associated with KHM prescriptions.

RN Author (year) Agea (mean) Maternal herbal prescription Concomitant treatment Herbal medicine use Purpose (Diagnosis) Duration (day) Neonatal AEs Occurs Severity Causality

[11] Ahn et al 28-38 Multiple NS Hyperemesis 5-25 1 Very low birth Moderate Unassessable

(2014) (31.37) gravidarum weight infant

[12] Jung et al (32 ±4.3) Multiple Antihistamine (Pruritis Multiple 2-28 2 Low birth weight Moderate Unlikely

(2014) gravidarum), Surgery infant

(Cervical incompetency, 2 Very low birth Moderate Unlikely

Intestinal obstruction, weight infant

Ovarian cancer) 1 Fetal macrosomia Moderate Unlikely

1 Patent ductus Moderate Unlikely

arteriosus

[17] Choi et al (29.8 ±4.70) Multiple NS Multiple 3-47 3 Low birth weight Moderate Unlikely

(2005) infant

1Hypoxia and Moderate Unlikely

hypoglycemia

[39] Zhang et al 37 PMT None Preventing 7 Neonatal jaundice Moderate Unlikely

(2004) miscarriage (Fetal

death in utero)

a (Mean ± standard deviation). Multiple: Details of the "Multiple" are provided in Supplementary data. RN: reference number, AE: adverse event, NS: Non-specific, WM: Western medicine, Acup: Acupuncture, Moxa: Moxibustion, PMT: Palmul-tang.

6. Conclusion

We found that hyperemesis gravidarum was the most common clinical indication of KHM and Anjeonicheon-tang was the most frequently used formula in Korean medicine literature. Atracty-lodis Rhizoma White was the most common single herb used during pregnancy in Korean medicine literature. Few studies reported on mild AEs associated with KHM, but due to a lack of large prospective surveys, the question is still open. Prospective studies with a larger sample size are needed to confirm the safety of KHM during pregnancy.

Conflict of interests

All authors declare that they have no conflict of interests. Acknowledgments

This study was supported by the Association of Korean Medicine and Korean Academy of Breastfeeding Medicine.

Appendix A. Supplementary data

Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.eujim. 2015.10.008.

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