review article systematic review of chinese medicine for...

Review ArticleSystematic Review of Chinese Medicine forMiscarriage during Early Pregnancy

Lu Li,1 Ping Chung Leung,2 Tony Kwok Hung Chung,1 and Chi Chiu Wang1

1 Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong2 Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong

Correspondence should be addressed to Chi Chiu Wang; [email protected]

Received 22 April 2013; Revised 30 November 2013; Accepted 1 December 2013; Published 5 February 2014

Academic Editor: Xiaoke Wu

Copyright © 2014 Lu Li et al. This is an open access article distributed under the Creative Commons Attribution License, whichpermits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background. Miscarriage is a very common complication during early pregnancy. So far, clinical therapies have limitation inpreventing the early pregnancy loss. Chinese Medicine, regarded as gentle, effective, and safe, has become popular and common asa complementary and alternative treatment for miscarriages. However, the evidence to support its therapeutic efficacy and safetyis still very limited. Objectives and Methods. To summarize the clinical application of Chinese Medicine for pregnancy and providescientific evidence on the efficacy and safety of Chinese medicines for miscarriage, we located all the relevant pieces of literatureon the clinical applications of Chinese Medicine for miscarriage and worked out this systematic review. Results. 339,792 pieces ofliterature were identified, but no placebo was included and only few studies were selected for systematic review and conductedfor meta-analysis. A combination of Chinese medicines and Western medicines was more effective than Chinese medicines alone.No specific safety problem was reported, but potential adverse events by certain medicines were identified. Conclusions. Studiesvary considerably in design, interventions, and outcome measures; therefore conclusive results remain elusive. Large scales ofrandomized controlled trials andmore scientific evidences are still necessary to confirm the efficacy and safety of Chinesemedicinesduring early pregnancy.

1. Introduction

Miscarriage is defined as spontaneous abortionwithoutmed-ical ormechanical means to terminate a pregnancy before thefetus is sufficiently developed to survive [1]. It denotes earlypregnancy loss prior to completion of the 20th gestationalweek, or 139 days, counting from the first day of the last nor-mal menses [2]. The incidence of miscarriage is commonlystated as 10%–15% of all pregnancies, and it is the most com-mon complication during pregnancy [3]. However, the inci-dence is difficult to determine precisely, since as many as 30%may go unrecognized, and these can occur very early during apregnancy. The etiology of miscarriage is largely unknownand the underlying cause of most cases cannot be identified.

Miscarriage can be classified as threatened, inevitable, in-complete, missed, or recurrent. Threatened miscarriage pre-sents as vaginal bleeding/spotting with or without cervicaldilatation [1]. It will become inevitable when gross rupture offetal membranes occurs along with severe vaginal bleeding

and cervical dilatation; imminent fetal loss is almost certainin these cases [1]. Incomplete miscarriage refers to the inter-nal cervical os remaining open and allows for passage ofblood, but the products of conception could remain entirelyor partially in utero extrude [1]. Missed miscarriage is usedto describe dead fetus and placenta that remained for days orweeks in the uterus with a closed cervical os and/or withoutany symptoms of abortion [4]. Recurrent miscarriage is gen-erally defined as spontaneous abortions repeated consecu-tively over three or more times [1].

Current treatment formiscarriage is rather empirical. Bedrest does not alter the course and progress of miscarriagesignificantly [5]. Acetaminophen-based analgesia may havesome effects on relieving the pains only [6]. Most commonlyused Western medicines were progesterone and human cho-rionic gonadotropin (HCG).HCGmaintains the luteotrophiceffects after luteinizing hormone secretion decreases in orderto support continued secretion of estrogen and progesterone.Progesterone maintains the endometrial proliferation and

Hindawi Publishing CorporationEvidence-Based Complementary and Alternative MedicineVolume 2014, Article ID 753856, 16 pageshttp://dx.doi.org/10.1155/2014/753856

2 Evidence-Based Complementary and Alternative Medicine

prevents pregnancy loss [7, 8]. However, their beneficial effectstill cannot be verified [7, 9].

The mission of the National Center for Complementaryand AlternativeMedicine (NCCAM) defines complementaryand alternative medicine as a group of diverse medical andhealth care systems, practices, and products, which are notgenerally considered part of the conventional medicine [10].There are different types of CAM [11], including natural prod-ucts (a variety of herbal medicines, vitamins, minerals, etc.),mind and body medicine (deep-breathing exercises, guidedimagery, etc.), and manipulative and body-based practices(spinal manipulation, meditation, and yoga). CAM also en-compassesmovement therapies (a broad range of Eastern andWesternmovement-based approaches used to promote phys-ical, mental, emotional, and spiritual well-being) such asFeldenkrais method, Alexander technique, and Pilates.

Chinese medicine is well accepted as the mainstream ofmedical care throughout East Asia with a history of 5,000years; it has been spread aboard since the sixth century BC[12]. It has been widely used to promote health and treat ill-nesses since then [13] and accepted as a major approach ofcomplementary and alternative medicine in Western worldnow [14]. Chinese medicine includes several different treat-ments which are applied quite differently, but they are allbased on the same understandings of assumptions and in-sights in the nature of the human body [15]. Main therapeuticapproaches [16] include acupuncture (by stimulating certainacu-points with or without acupuncture needles to treat dis-orders or improve the health condition), Chinese medicines(applying traditional medicines, mainly from herbs, animals,andminerals, to cure illness andmaintain good health,), foodtherapy (dietary recommendations on certain foods andherbs to balance inner body), Qi Gong (promoting health byspecial breathing and meditation exercise), Tai Chi (benefit-ing different systems by the movements of muscles and theactivities of related joints), Tui Na (applying massage on thesurface of the body to clear the meridians and improve theblood flow), Cupping (relieving blood stasis and pain by cre-ating vacuum on body), Die Da (commonly applied in theinjuries of limbs by direct stimulation on the body surface),and Gua Sha (scaling the skin to stimulate specific acu-pointsuntilmild tomoderate subcutaneous hemorrhage) [12, 13, 17].

In Chinese Medicine [18, 19], miscarriage is defined as“fetal irritability” or “fetal restlessness,” while recurrent mis-carriage is called “stirring fetus”. Miscarriage shares the sameclinical signs and symptoms as inWesternMedicine.The pre-sentations of miscarriage are similar, mainly with abdominalpains and vaginal bleeding. But unlike mainstream WesternMedicine, Chinese Medicine has a unique medical theory tounderstandmiscarriage. Tomake the diagnosis and guide thetreatment, “Qi” and “Blood” are the two basic elementsinvolved.Themajor causes of threatened miscarriage include“Kidney Deficiency,” “Qi Deficiency,” “Blood Deficiency,”“Blood Heat,” “External Injury,” and “Wei Jia” (refers to ec-topic pregnancy, which is considered as a cause of threatenedmiscarriage in Chinese Medicine). The diagnosis and treat-ment are based on different causes and varied a lot in differentpatients.

The principle [14] of treatments is to supplement and reg-ulate the balance of maternal “Qi,” “Blood,” and the systemconcerned and enhance the survivals of fetuses, so as to re-lieve clinical signs, promote pregnancy, and prevent inevi-table miscarriage. Besides its application as expectant man-agement for threatened and recurrent miscarriages, ChineseMedicine is also used as active managements for missed,incomplete, and complete miscarriages [20], which mainlyaccelerate the blood circulation so as to stimulate uterinecontractions and empty the uterus.

However, there is only limited information about theapplication of Chinesemedicines formiscarriage in a few sys-tematic reviews recently [21]. Besides, the efficacy and safetyclaims of Chinese medicines still have no scientific proof.The aimof this studywas to access and review the available lit-erature on the clinical applications of Chinese medicine formiscarriage during early pregnancy, in order to provide scien-tific evidences and valuable references to clinical workers andresearchers for practices and studies. The specific objectiveswere

(i) to identify the most common therapeutic approachand clinical application of Chinese Medicine for mis-carriage;

(ii) to evaluate themost commonly used formulae and in-dividual Chinesemedicines for miscarriage and com-pared the clinical dose and dosing with the recom-mendations in Chinese Pharmacopeia;

(iii) to analyze the effectiveness and adverse outcomes ofChinese medicines as treatment for miscarriage.

2. Materials and Methods

2.1. Search Method. We used subject heading, keyword, andabstract including Chinese Medicine, pregnancy, and mis-carriage/abortion and searched all published clinical trials ofChinese Medicine for miscarriage. The following databaseswere searched: Cochrane Central Register of ControlledTrials, mainly Cochrane Database of Systematic Reviews andCochrane Database of Abstracts of Reviews of Effects (from1996 to April 2013); EMBASE (from 1980 to April 2013);Cumulative Index to Nursing and Allied Health Literature(CINAHL) (from 1982 to April 2013); Chinese BiomedicalDatabase (CBM) (from 1978 to April 2013); Medline (andPreMedline) (from 1950 to April 2013); China Journal Net(CJN) (from 1915 to April 2013); China National KnowledgeInfrastructure (CNKI) (from 1915 to April 2013); Wiley InterScience (from 1966 to April 2013); and Wan Fang Database(Chinese Ministry of Science and Technology) (from 1980 toApril 2013).

We also screened bibliographies of the selected articlesand searched by hand for any internet inaccessible articles.We also explored the searches in the reference parts whichwere listed in these clinical trials and reports identified.

2.2. Systematic Review

2.2.1. Inclusion Criteria

(i) Types of Studies. All clinical studies reporting theapplications of Chinese Medicine to any miscarriage

Evidence-Based Complementary and Alternative Medicine 3

during early pregnancy were included. All the titlesand abstracts were further reviewed.

(ii) Participants. All women, regardless of the age, gesta-tional age, parity, and nationality of the participants,receiving Chinese Medicine for miscarriage are in-cluded.

(iii) Diagnosis. All the studies included for meta-analysisapplied the same inclusion criteria—the standard dia-gnosis and exclusion criteria for threatened miscar-riage according to the textbook “Obstetrics & Gynae-cology” [18]. Most of the patients received treatmentin early pregnancy, around 3rd month of gestation.And there is no significant difference in the baseline ofstudies. However, as the treatment was individuallyapplied based on the presentation of patients and theexperience of Chinese Medicine practitioners, thedurations of treatments varied a lot in the includedclinical trials, and it is hard to make a comparison orcarry out a baseline analysis on this issue.

(iv) Interventions. Chinese Medicine was administered asinterventions in the clinical trials. Only Chinesemed-icines recorded by the Chinese Pharmacopeia withwell-characterized principles of pharmacological andmedicinal applications were included. Other phar-manutrients from various herbal agents and productswere excluded. Since Chinese medicines are crudedrugs of plant, animal, and mineral origins, not onlythose Chinese medicines originated from plants orherbs but also those from animals and minerals wereincluded. All types of Chinese medicines in eitherstandard or combined formulas are used in the treat-ment of threatened miscarriage regardless of the doseor duration of administration.

(v) OutcomeMeasures.The therapeutic approach and cli-nical application of Chinese Medicine for miscar-riage; the commonly used formulae and individualChinese medicines and the clinical dose and dosing;the effectiveness and efficacy of the intervention likelive birth rate, premature birth rate, miscarriage rate,and the safety of the intervention like side effects andadverse events were studied.

(vi) Publications. No restriction on the languages wasapplied. Publications without full text but with ab-stracts only were also included.

2.2.2. Exclusion Criteria

(i) Other Participants. Nonpregnancy related and othergynaecology illness, and complications were ex-cluded.

(ii) Combined Therapies. If the intervention combinedChinese medicines with other therapies, the clinicaltrial was included but analyzed seperately.

(iii) Other Type of Studies. Case reports, commentarystudies, and review articles were excluded.

2.2.3. Data Extraction and Quantitative Analysis. We de-signed extraction forms to extract data from the selectedpublications quantitatively. The numbers of the publicationin different databases within each decade were counted. Thetotal numbers of included studies were summarized.The totalnumbers of excluded papers and the exclusion criteria werepresented in flow charts. To identify the common clinicalapplications of Chinese medicines during pregnancy, the cli-nical indication of each clinical study was recorded and com-pared. To identify the commonly used Chinese medicine for-mulae and individual Chinese medicines, the frequency ofeach formula or individualmedicine used in the clinical stud-ies was calculated. The clinical daily dose and dosing of theformula and individual Chinese medicines and their effectiverate were recorded and analyzed.

2.3. Meta-Analysis

2.3.1. Effectiveness Study

Study Inclusion(i) Types of Studies. Only randomized controlled clinical

trials evaluating the effectiveness of Chinese medi-cines for the treatment of threatenedmiscarriagewereincluded. Quasirandomized controlled clinical trials(quasirandommethod of allocating participants wereused) and cluster-randomized trials (participants arerecruited in randomized groups) were also studied.

(ii) Types of Participants. All women in the clinical trialshad a viable pregnancy complicated with threatenedmiscarriage, regardless of its underlying causes. Notreatment was given before interventions. Fetal viabil-ity was assessed by ultrasound to exclude the inevit-able, incomplete, or missed miscarriage. Vaginableeding after the 20th week of pregnancy and recur-rent miscarriage were excluded. We included womenregardless of whether the pregnancy was singleton ormultiple and irrespective of the maternal age andparity.

(iii) Types of Interventions. All types of Chinese medicinesin either standard or new formulae for the treatmentof threatened miscarriage regardless of the dose orduration of administration were compared with otherinterventions, including no treatment, bed rest, pla-cebo, and other pharmaceuticals.

(iv) Types of OutcomeMeasures. Effectiveness of interven-tion was defined as either continuation of pregnancyafter 28 weeks of gestation or continuation of preg-nancy immediately after treatment.

Study Exclusion(i) Types of Studies. Clinical trials without randomization

were excluded from this review, but if the randomiza-tionmethodwas not clearly stated or was doubted, wecontact the author for confirmation.

(ii) Types of Interventions. Other therapeutic approachesof Chinese Medicine were excluded.The intervention


combined Chinese medicines and other therapieswere also excluded from our study.

(iii) Types of Outcome Measures. If the trials concludedthat Chinesemedicines were effective but no data wasshown, we also exclude the studies.

2.3.2. Safety Study

Additional Literature Search. Since we assumed that theadverse events of Chinese Medicine are very rare, in additionto the above search strategy, we performed additional lit-erature search. To collect the extrainformation on safety ofChinese medicines, several online national and public re-sources on World Wide Web were also referred, includingCenter for Food Safety and Applied Nutrition (CFSAN) fromU.S. Food and Drug Administration (FDA, http://www.fda.gov/), National Center for Complementary and AlternativeMedicine (NCCAM) from U.S. National Institute of Health(NIH, http://nccam.nih.gov/), Agricultural Research Service(ARS) from U.S. Department of Agriculture (USDA, http://www.ars-grin.gov/duke/), Medical Dictionary for RegulatoryActivities (MedDRA) from International Federation of Phar-maceutical Manufacturers and Associations (IFPMA, http://www.ifpma.org/), National Council Against Health Fraud(NCAHF) from a private health agency (http://www.ncahf.org/),Quackwatch fromanAmericannonprofit organization(http://www.quackwatch.com/), HerbMed from AlternativeMedicine Foundation (http://www.herbmed.org/), and Con-sumerLab from an independent laboratory (http://www.consumerlab.com/), accessibility verified until 15 April 2013[22].

Inclusion and Exclusion of Study(i) Types of Studies. All published clinical studies that

evaluated the safety of Chinese medicines for threat-enedmiscarriage were considered. Studies of Chinesemedicines in animal, chemical, and basic researcheswere excluded. Case reports, commentary articles,and nonsystematic reviews were also excluded. Clin-ical studies with incomplete records or no evaluationof adverse pregnancy outcome were further excluded.Only case controlled studies with or without random-ization were included for meta-analysis. Randomizedstudies, blinded randomized, quasirandomized, andcluster-randomized, were included. Clinical studieswithout case controlled, including observational andprospective cohorts, were also included for pooledanalysis if there are no or too few case controlledstudies for invalid meta-analysis.

(ii) Types of Outcome Measures. Adverse pregnancy out-comes in both mothers and fetuses/infants will be re-corded. Maternal outcomes included toxicity, sideeffects, pregnancy loss, and pregnancy complications.Fetal outcomes included perinatal mortality, toxicity,congenital malformations, and other neonatal com-plications.

2.3.3. Assessment of Risk of Bias in Included Studies. Weassessed the risk of bias, including the sequence generation to

check for possible selection bias, the allocation concealmentto check for possible selection bias, the blinding to check forpossible performance bias, the incomplete outcome data tocheck for possible attrition bias through withdrawals, drop-outs, protocol deviations, the selective reporting bias, andother sources of bias from compliance and baseline similarity.

2.3.4. Measures of Treatment Effect. Statistical analysis wasperformed by using ReviewManager Version 5.1 (RevMan 5).We presented results as summary risk ratio with 95% confi-dence intervals for dichotomous data.

2.3.5. Unit of Analysis Issues. Trials with up to three arms(Chinese medicines alone, and Western medicines alone,combined Chinese and Western medicines) were analyzed.We input the data separately for meta-analysis.

2.3.6. Dealing with Missing Data. For included studies, wenoted levels of attrition and explored the impact of includedstudies with high levels of missing data for the overall assess-ment of treatment effect by using sensitivity analysis. For alloutcomes we carried out analyses on an intention-to-treatbasis; we attempted to include all participants randomized toeach group in the analyses. The denominator for each out-come in each trial was the total number of participants ran-domized minus any participants whose outcomes wereknown to be missing.

2.3.7. Assessment of Heterogeneity. We assessed statistical het-erogeneity in each meta-analysis using the 𝑇2, 𝐼2, and 𝜒2 sta-tistics. We regarded heterogeneity as substantial if 𝑇2 wasgreater than zero and either 𝐼2 was greater than 30% or therewas a low 𝑃 value (<0.01) in the 𝜒2 test for heterogeneity.

2.3.8. Data Synthesis. We carried out statistical analysisusing RevMan5 and used fixed-effect inverse variance meta-analysis for combining data when the studies were estimatingthe same underlying treatment effect and the populations andmethods of the trials were judged sufficiently similar. Forclinical heterogeneity sufficient to expect that the underlyingtreatment effects differ between trials, or if substantial sta-tistical heterogeneity was detected, we used random-effectsmeta-analysis to produce an overall summary if an averagetreatment effect across trials was considered clinically mean-ingful.We treated the random-effects summary as the averagerange of possible treatment effects and we discussed the clin-ical implications of treatment effects differing between trials.For the average treatment effect which is not clinically mean-ingful, we did not combine trials. For random-effects analy-ses, we presented the results as the average treatment effectwith its 95% confidence interval and the estimates of 𝑇2 and𝐼2.

For dichotomous safety outcomes, we counted the num-ber of adverse events and the involved participants in eachstudy. For continuous safety outcomes, we calculated themean and standard deviation of the measures if appropriate.Dichotomous data were expressed as relative ratio (RR) with


Table 1: Number of literature studies on clinical application of Chinese Medicine.

Chinese Medicineapproaches

Clinical application inall medical fields

Clinical applicationfor pregnancy

Clinical applicationfor miscarriage

Chinese medicines 241,237 (80.0%) 3,338 (90.5%) 1,444 (91.1%)Acupuncture 28,754 (9.5%) 208 (6.2%) 96 (6.2%)FoodTherapy 13,382 (4.5%) 96 (2.9%) 32 (2.0%)Qi Gong 11,671 (3.9%) 7 (0.2%) 2 (0.1%)Tui Na 3,061 (1.0%) 16 (0.5%) 2 (0.1%)Tai Chi 1,646 (0.5%) 7 (0.2%) 2 (0.1%)Cupping 864 (0.3%) 8 (0.2%) 2 (0.1%)Die Da 529 (0.2%) 8 (0.2%) 2 (0.1%)Gua Sha 403 (0.1%) 1 (<0.1%) 3 (0.2%)Total 301,547 (100%) 3,689 (100%) 1,585 (100%)

95% confidence intervals (CI), while continuous data wereexpressed as weightedmean differences (WMD) by themeta-analysis.

2.3.9. Subgroup Analysis and Investigation of Heterogeneity.To identify the potential factors of the efficiency outcomes,we also carried out subgroup analyses on maternal age, par-ity, different trimesters, standard and nonstandard herbalmedicines, treatment duration, and quality of included trials.For fixed-effect meta-analyses, we conducted planned sub-group analyses classifying whole trials by interaction tests asdescribed [23]. For random-effectsmeta-analyseswe assesseddifferences between subgroups by inspection of the sub-groups’ confidence intervals; non-overlapping confidenceintervals indicated a statistically significant difference intreatment effect between the subgroups.

2.3.10. Sensitivity Analysis. We also carried out sensitivityanalysis to explore the effect of trial quality for importantoutcomes in the review. Sensitivity analyses on results wereperformed on look at the possible contribution of high risk ofbias in the allocation of participants to groups associated witha particular study [24] or high levels of missing data [21].

3. Results and Discussion

3.1. Chinese Medicine for Pregnancy. Up to 15 April 2013,339,792 literature reported studies of ChineseMedicine for allapplications were identified (Figure 1). Amongst all the stud-ies, only 12,912 (3.8%) literature studied ChineseMedicine forpregnancy or pregnancy related applications (Table 1). Chi-nese medicines for other disorders for nonpregnancy appli-cations (91.9%) were excluded (Figure 2). Most of the piecesof literature were mainly found in CNKI and CJN Full-TextDatabase and WanFang Database but much less in PubMed,Cochrane Library, EMBASE, MEDLINE, and WILEY Inter-science (Figure 3). Most of the pieces of literatures (78.6%)were published in Chinese, whilst few of the pieces of litera-ture (21.4%) were published in English and other languages.

In China, it is considered not only as a primary medicinefor treatment but also as a supplementary therapy to promotehealth in general population. Chinese medicines (56.2%)

59 2267 7600

100485

191136

0

5

10

15

20

25×104

1911–1979 1971–1980 1981–1990 1991–2000 2001–2010Num

ber o

f pi

eces

of

liter

atur

e

Figure 1:The pieces of literature of ChineseMedicine for all medicalfields published in decades. Numbers on the top: total numbers ofliterature in each decade.

were the most common therapeutic approach of ChineseMedicine for pregnancy, while acupuncture (40.8%) was thesecond. Amongst all the pieces of literature studied Chi-nese medicines for pregnancy, human studies (46.3%) wereincluded, while animal studies (31.9%), chemical studies(12.7%), genetic studies (5.9%), and microbiology studies(3.3%) were excluded. Most Chinese medicines are derivedfrom nature, including plants, animals, and minerals. Herbalmedicines from plants are much more commonly appliedthan the others. 2,858 (85.0%) studies used herbal medicinesfor intervention were included. Other studies usedmedicinesoriginated fromanimals (9.5%) andminerals (4.8%)were alsoincluded. Othermedicines not included by the Chinese Phar-macopeia (0.3%) and included the pharmanutrients fromvar-ious herbal biological agents and products (0.3%) were fur-ther excluded. In total, 3,338 pieces of literature were includedfor systematic review (Figure 3).

3.2. Chinese Medicines for Miscarriage. Amongst all pieces ofliterature of Chinese medicines for pregnancy, miscarriage(43.3%) was the most common clinical indication of the Chi-nese medicines for pregnancy [25] (Table 2). Less commonclinical indications included infertility (27.9%), therapeuticabortion (11.7%), immunological disorders (6.2%), hyper-tensive disorders (3.8%), infection (2.6%), fetal growthrestriction (2.2%), preterm labor (1.5%), postdate (0.3%),


Traditional Chinese Medicinefor all clinical applications

(with either chinese or english abstracts)

Other disorders

excluded

Women disorders(non pregnancy)

excluded

Pregnancy disorders

included

Other therapeutic approaches

excluded

Acupuncture

excluded

Chinese medicines

included

Basicstudies

Genetic studies

Microbiology studies

excluded

Chemicalstudies

excluded

Animalstudies

excluded

Humanstudies

included

Others

Non chinese Pharmacopeia

pharmanutrients

excluded

Other medicines

Animal origin

metal origin

included

Herbal medicines

Herb origin

included

3,338 paperssystematic review

N = 339,792

N = 312,269 N = 14,611(4.3%)

N = 12,912(3.8%)

N = 388(3.0%)

N = 5,268(40.8%)

N = 7,256(56.2%)

(91.9%)

N = 427 (5.9%)

N = 237 (3.3%)

N = 921(12.7%)

N = 2,312(31.9%)

N = 3,359(46.3%)

N = 10 (0.3%)

N = 11 (0.3%)

N = 320 (9.5%)

N = 160 (4.8%)

N = 2,858(85.0%)

Figure 2: Study inclusions and exclusions for systematic review (Chinese medicines for pregnancy).

0

2

4

6

8

10

12×104

1911–1979 1971–1980 1981–1990 1991–2000 2001–2010Num

ber o

f pie

ces o

f lite

ratu

re

Chinese journals net fulltext databaseWang FangMedlineCochrane

PubMedEMBASEWiley

Figure 3: The pieces of literatures of Chinese Medicine for preg-nancy published in various databases.

gestational diabetes mellitus (0.6%), puerperium (0.1%), andother obstetric complications. Among different types of mis-carriage, threatened miscarriage was the most common onefor Chinese medicines (Figure 4).

3.3. Chinese Medicines for Threatened Miscarriage. Therewere 418 clinical studies of Chinese medicines for threatenedmiscarriages. However, 97 (24.1%) were case reports, 67(16.0%) were commentary articles, and 43 (10.3%) were re-view articles. Since case reports are only involved with verysmall number of participants, mostly with only one case andall less than 5 individuals, which could hardly represent thegeneral application of Chinese medicines. Commentary arti-cles focused on the theory and hypothesis without details anddata for further study. Other review articles contributed tosummary and conclusion on clinical topics, other than sys-tematically review the clinical trials. We further excluded thecase reports, commentary articles, and the review articles. Intotal, 211 clinical trials 2 duplicated papers excluded, were sel-ected for meta-analysis and quantitative analysis (Figure 5).

3.3.1. Common Formulae. Amongst all the formulae studiedfor threatened miscarriage (Table 3), “Shou Tai Pill” was themost frequently used formula (72.0%). Its main function is toenhance the function of “Kidney” and regulate the “Qi” in thehuman body, and then to improve the health condition of


Table 2: Clinical applications of Chinese medicines during pregnancy.

Pregnancy disorders Frequency∗ (%) Therapeutic applications

Spontaneous abortion 1,444 (43.3)Improve maternal healthPromote embryo-fetal developmentReduce irregular vaginal bleeding

Infertility 930 (27.9) Improve women’s healthElevate the female fertility

Induced abortion 392 (11.7)Enhance lethal effect on embryosDecrease incomplete abortion rateImprove vaginal irregular bleeding

Immunological disorders 206 (6.2) Inhibit the release of inflammatory molecules

Hypertensive disorders 126 (3.8)Promote vasodilatationIncrease blood flowDecrease platelet aggregation

Infection 87 (2.6) Decrease intrauterine transmission

Fetal growth restriction 73 (2.2) Improve uteroplacental circulationPromote fetal growth

Preterm labour 49 (1.5) Inhibit uterine contractilityPostdate or term 9 (0.3) Accelerate labor process

Gestational diabetes mellitus 20 (0.6) Improve insulin levelsEnhance glucose metabolism

Puerperium 2 (0.1)Improve hormone levelsPromote lactation and uterine contractionHeal perineum injuries

Total 3,338 (100)∗Frequency of each clinical application amongst 3,228 papers for systemic review.

Threatened

28.9%

Recurrent

22.8%

Complete

31.2%

Incomplete

12.4%

Inevitable

3.0%

Missed

1.6%

miscarriage

miscarriage

miscarriagemiscarriage

miscarriage

miscarriage

Figure 4: Clinical application of Chinese medicines for differenttypes of miscarriage.

mothers and benefit the fetus. Its basic formula includes fourindividual Chinese medicines, Chinese Dodder Seed (SemenCuscuta), Chinese Taxillus Twig (Floralia Taxillus), Hima-layan Teasel Root (Radix Dipsaci), and Donkey-hide Glue(Colla Corii Asini). The former three medicines improve the“Qi” in the body, while Donkey-hide Glue regulates the“Blood” circulation. Therefore, the therapeutic effects of“ShouTai Pill” aremainly for the pregnant women to improvebody condition of mothers and the fetuses. Supplementary ofLargehead Atractylodes Rhizome (Rhizoma Atractylodis

Macrocephalae) and Pilose Asiabell Root (Radix Codonopsis)in the formula can enhance the therapeutic effects by furtherimproving the “Qi” of pregnant women [26].

Other popular formulae (Table 3) include “Si Jun Zi De-coction,” “An Tai Yin,” “Wu Zi Decoction,” “An Dian Er TianDecoction,” and “Jiao Ai Decoction”. The therapeutic effectsof “Si Jun Zi Decoction” in the treatment of miscarriageimprove the functions of “Spleen” and “Stomach” and regulate“Qi” [27]. “AnTai Yin” improves the function of “Kidney” andthen regulates “Qi” and “Blood” [28]. “WuZiDecoction” pro-motes the luteal function by supplementing the “Qi” and“Blood” [29]. “An Dian Er Tian Decoction” relieves the cli-nical signs such as vaginal bleeding and is mainly applied forrecurrent miscarriage [30]. “Jiao Ai Decoction” enhances“Kidney” and regulates “Blood” to improve the health con-dition of mothers and also to relieve vaginal bleeding [31].Most of these regimes contain Largehead AtractylodesRhizome (Rhizoma Atractylodis Macrocephalae), Ginseng(Panax Giaseng), and Baical Skullcap Root (Scutellaria Bai-calensis), which are mostly used to nourish and regulate the“Qi”. It has been reported that the combination of LargeheadAtractylodes Rhizome and Baical Skullcap Root is highlyrecommended for their effects to benefit and survive the fetus[17].

In the literature, there were lots of modified formulae,which were not recorded in either Chinese Pharmacopeia orthe textbooks. They were prescribed according to the experi-ence of physicians and clinical presentations of the patients.For example, Rehmannia root (Radix Rehmanniae), Lyciumfruit (Fructus Lycii), and Cuscuta fruit (Semen Cuscutae) are


Table 3: Chinese medicine formulae studied for threatened miscarriage.

Order Name Frequency∗ Main composition Therapeutic actionsOther applicationsb

Dosea (g) Dosinga System/organ

1 Shou TaiPill 301 (72.0%)

Colla Corii AsiniHerba TaxilliRadix DipsaciSemen Cuscutae

5–159–159–156–12

QD/BID

Reproductivesystem

and Spleenand Kidney

Abdomen distension, lowerabdomen pain, dizziness,frequent urination, urinaryincontinence, tinnitus,lower-limb weakness.

2 Si JunziDecoction 52 (12.5%)

Ginseng, PoriaRadix GlycyrrhizaeRhizoma AtractylodisMacrocephalae

9–303–96–12

QD/BID

Immunesystem andKidney

and Spleen

Chronic gastritis, gastric ulcer,duodenal ulcer, antitumor

3 An TaiDecoction 28 (6.7%)

Cortex EucommiaeFolium Artemisiae argyiGiseng,Radix Dipsaci Poria cocosRadix Angelicae sinensisRadix AstragaliRadix Paeoniae AlbaRadix Rehmanniae Praeparata,Cyperi RadixScutellariae RhizomaAtractylodisMacrocephalaeRhizoma

6–153–99–309–156–129–306–159–156–99–306–12

QD/BID

Reproductivesystem

and Kidneyand Spleen

Vitiligo

4 Wu ZiDecoction 16 (3.8%)

Caulis PerillaeColla Corii AsiniCortex EucommiaeFructus Lycii, Fructus RubiFructus Schisandrae chinensis,Herba TaxilliRadix DipsaciRadix ScutellariaeSemen Cuscutae

5–95–156–156–123–103–69–159–159–306–12

QD/BID Kidney Uterine hypoplasia, maleinfertility

5An dianEr tianDecoction

10 (2.4%)

Eucommia ulmoides OliverFructus Corni, PreparataFructus Lycii,GisengRadix GlycyrrhizaeRadix RehmanniaeRhizoma AtractylodisMacrocephalaeRhizoma Dioscoreae

6–156–126–129–303–99–156–126–1215–30

QD/BID SpleenKidney Postmenopausal bleeding

6 Jiao AiDecoction 6 (1.4%)

Colla Corii AsiniFolium Artemisiae ArgyiP. Lactiflora PallRadix Angelicae SinensisRadix GlycyrrhizaeRadix Rehmanniae Praeparata

5–153–96–156–123–99–15

QD/BIDLiverSpleenKidney

Thrombocytopenic purpura,abdominal pain

7 Others 5 (1.2%) Nonstandard Formulae 3–30 QD/TID Spleen∗% is the number of literature of each formula/total amount of literature × 100.aTherapeutic dose and dosing refer to the dose and dosing of the formulae per regime for threatened miscarriage; QD: once per day; BID: twice per day; TID:three times per day.bOther applications refer to the applications of the formulae for other disorders during pregnancy.


Chinese medicinesfor pregnancy disorders

Other clinical applications Spontaneous miscarriage

Othermiscarriages

Incomplete abortion

Inevitable abortion

Missed abortion

Recurrent miscarriage

Complete miscarriage

Threatened miscarriage

Other studies Clinical trials

Meta-analysis andquantitative analysis

Case reports N = 97 (23.2%)Commentary articles N = 67 (16.0%)Other review articles N = 43 (10.3%)

N = 211 (50.5%)Duplicates N = 2

N = 179 (12.4%)

N = 43 (3.0%)

N = 23 (1.6%)

N = 330(22.8%)

N = 451(31.2%)

N = 418 (28.9%)

N = 1,444(43.3%)

N = 3,338

Infertility N = 930 (27.9%)Induced abortion N = 392 (11.7%)

Immunological disorders N = 206 (6.2%)Hypertensive disorders N = 126 (3.8%)

Infection N = 87 (2.6%)Fetal growth restrictions N = 73 (2.2%)Preterm labor N = 49 (1.5%)Postdate N = 9 (0.3%)Diabetes mellitus N = 20 (0.6%)Puerperium N = 2 (0.1%)

Figure 5: Study inclusions and exclusions for systematic review (e.g., clinical trials of Chinese medicines for threatened miscarriage).

added into the basic formula of ShouTai pill and prescribed asa new formula, whichwas used to correct “Kidney” deficiencyin treatment of miscarriage [32].

3.3.2. Individual Chinese Medicines. According to ChinesePharmacopeia, the official Pharmacopeia for Chinesemedicines, acknowledged by World Health Organization(WHO), only 130 out of 1,150 individual Chinese medicineshad been used in the clinical trials [29] (see full list in Sup-plementary Table 1 available online at http://dx.doi.org/10.1155/2014/753856, top 10 list in Table 4).

3.3.3. Clinical Dose andDosing. A large range of clinical dosesof the Chinese medicines was recorded in the reported clin-ical trials (Supplementary Matrial Table 1). The mean andmedian daily dose for each medicine ranged from 6 g/day to23 g/day. About 90.9% of Chinese medicines, 10 to 20 g/day,was recommended, while 9.1% less than 5 g/day or more than25 g/day was recommended. For example, Fructus Amomihas been prescribed as small as 2 g/day only, while Rehmannia

Root has been used more than 30 g/day. In 95% of cases, theChinese formulae were taken once a day, while 4% twice aday and only 1% three times a day.The top 10most commonlyused single Chinese medicines included Largehead Atracty-lodes Rhizome, Chinese Dodder Seed, Himalayan TeaselRoot, Donkey-hide Glue, Chinese Taxillus Twig, MongolianMilkcetch Root, White Paeony Root, Chinese Angelica,Liquorice Root, and Baical Skullcap Root in descending order(Table 4).

3.4. Efficacy and Effectiveness

3.4.1. Efficacy. Effective rate of Chinese medicines for threat-enedmiscarriages in each clinical trial was recorded [29], andthe rate ranged from 75% to 100%. Among all the records,over 84.6% of the studies exceeded 90%, while 24.3% ex-ceeded 95%. Two studies reported 100% [33, 34]. However, nosignificant correlation was found between frequency of useand effective rate of the studied ChineseMedicine (𝑟=0.1086,𝑃 = 0.335). The top 10 Chinese medicines only had effective


Table 4: Top 10 of most commonly studied individual Chinese medicines for threatened miscarriage.

Order English name Biological name Frequency∗ Mean daily dosea Therapeutic actionsb Other applicationsc

1 LargeheadAtractylodes Rhizome

RhizomaAtractylodis

Macrocephalae59 (41%) 12.7 g Prevent miscarriage —

2 Chinese Dodder Seed Semen Cuscutae 55 (38%) 21.8 g Prevent miscarriage andprelabor

Cataract, diarrhea, spermabnormality, chronic

prostatitis.

3 Himalayan TeaselRoot Radix Dipsaci 55 (38%) 15.3 g Stop vaginal bleeding

Prevent miscarriageFractures and injuries,

Lower back pain.

4 Donkey-hide Glue Colla Corii Asini 49 (35%) 6.3 g Increase platelet count Stopvaginal spotting

Chronic bleeding, anemia,tuberculosis, uterine

fibroids, endometriosis.

5 Chinese Taxillus Twig Herba Taxilli 48 (34%) 17.9 g Prevent miscarriageLower high blood pressure

Lower back pain, tendonsatrophy.

6 Milkvetch Root Radix Astragali 48 (34%) 22.9 g — Chronic nephritis, diabetesmellitus, diuresis.

7 White Peony Root Radix PaeoniaeAlba 44 (31%) 15.5 g Regulate menstruation Abdomen and limb pain,

check sweating.

8 Chinese Angelica Radix AngelicaeSinensis 42 (29%) 10.1 g Improve blood circulation

Regulate menstruationGeneral pain, bowels

overactivity.

9 Liquorice Root Radix Et RhizomaGlycyrrhizae 40 (28%) 6.2 g —

Detoxification, dispelphlegm, coughing,spasmodic pain.

10 Baical Skullcap root Radix Scutellariae 35 (24%) 10.1 g Stop vaginal bleedingPrevent miscarriage Detoxification.

∗% is the number of literature of each formula/total amount of literature ∗ 100.aThe mean of the reported daily dose in all included clinical trials.bFunctions of Chinese herbal medicines as treatment to threatened miscarriages.cOther functions of Chinese herbal medicines as treatment to other disorders.

80

85

90

95

100

0 5 10 15 20 25 30 35 40

Effec

tiven

ess (%

)

Usage frequency (%)

Top 10 medicinesOther medicines

Figure 6: Efficacy of individual Chinese medicines.

rates from 91.3% to 93.2% (Figure 6). It suggests that com-monly used Chinese medicines might not result in a betterefficacy.

To evaluate the relationship between dosage and efficacyof Chinese Medicines in the treatment of threatened miscar-riage, the daily dose of the studied Chinese medicine wascorrelated with the effective rate of the intervention. Chinesemedicines with 95% or higher efficacy were less commonlyused, 0.72%–7.91%. The Chinese medicines in 20 g or highermean daily dose, the efficacy ranged from 83.33% to 95.83%.However, there was still no significant correlation betweenmean daily dose and efficacy (𝑟 = 0.2324, 𝑃 = 0.513)(Figure 7). It suggests that increased dose might not result ina better efficacy.

There were also different dosing records in differentclinical studies. The effective rate of dosing once per day haslowest effective rate, while dosing twice per day has highesteffective rate, but dosing three times per day did not furtherincrease the effective rate.There was no significant differencebetween effective rate and the daily dosing times (Figure 8). Itsuggests that increasing dosing could not increase the efficacy.

3.4.2. Effectiveness. With a long history of application of Chi-nese medicines to treat pregnant disorders, large amounts ofcase reports and clinical trials have been reported [35]. How-ever, until now, no data are available to overview the effect-iveness of Chinese medicines for pregnancy.

In our previous review [36], no placebocontrolled trialwas found.The effectiveness of Chinese medicine treatments


80

85

90

95

100

5 10 15 20 25

Effec

tiven

ess (%

)

Mean daily dose (g/day)Top 10 medicinesOther medicines

Figure 7: Dosage and efficacy.

can be compared only through the comparisons amongstChinesemedicines,Westernmedicines, and combinedmedi-cines. However, most Western medicines included tocolyticdrugs (e.g., salbutamol and magnesium sulfate), hormonalsupplementations (e.g., human chorionic gonadotrophin andprogesterone), immunotherapy (e.g., IgG immunization andantiphospholipid antibodies) and supportive supplements(e.g., vitamin E and folic acid), which have no proved benefits.The meta-analysis in limited randomized clinical trials didnot support that Chinesemedicines aloneweremore effectivethan Western medicines. But it showed that combined Chi-nese and Western medicines were more effective than West-ern medicines alone to prevent inevitable miscarriage andcontinue pregnancy after 28weeks of gestation.Meta-analysisin other clinical trials indicated that Chinese medicines aloneor Chinese medicines combined with Western medicineswere more effective than Western medicines alone to treatthreatened miscarriage in relieving the clinical signs, includ-ing vaginal bleeding, low back pain, and abdominal pains.The result confirmed the therapeutic effects of Chinesemedi-cines alone and combined with other pharmaceuticals forthreatened miscarriage. In current update study, only onenew randomized clinical trial was included [37] formeta-ana-lysis; the new analysis resulted in same conclusion (Figure 9).

Due to insufficiency of data, analysis for all designed sub-groupswas not employed.Meanmaternal age and/or range ineach group were not reported. Comparison between the par-ticipants of below 35 years old and above 35 years old cannotbe performed. All the clinical trials reported the overall parityof all participants but did not provide details about the parityin each groups, so further comparisons were not possible.Gestational age at threatened miscarriage was not availableeither. Comparison between first trimester and second tri-mester could not be carried out due to insufficient informa-tion. All of the Chinese medicines and the supplements werestandard formulae as stated in the Chinese Phamacopeia, so

90

91

92

93

94

95

96

97

98

99

100

Effec

tiven

ess (%

)

0 QD BID TIDMean daily dosing

Mean

QD: once per dayBID: twice per dayTID: three time per day

Figure 8: Dosing and efficacy.

no subgroup analysis between standard formula and non-recorded formula was carried out. As to the treatment course,only one study [38] reported the termination of intervention(with unknown reason), while the other three studies [39–41]did not report the details on the total amount of the coursesfor the treatment. Therefore, it is difficult to extract the dataand carry out analysis on the duration of intervention for theeffectiveness. No trials had any high risk of bias in the alloca-tion of participants to groups or significanty of missing datawas identified, so the sensitivity analysis was not carried out.If a sufficient number of trials are found in the future update,we will further specify sensitivity analyses.

Though the result favored Chinese medicines for threat-enedmiscarriage, itmust bementioned that differentChinesemedicines were used in different studies.Most ChineseMedi-cine practitioners slightly modify the standard prescriptionsdepending on the presentations of each patient. In the clinicaltrials, most of the trials used a common prescription of “ShouTai Pill” as basic formula, while the others used different pre-scriptions. However, some Chinesemedicines have been sup-plemented into or removed from the standard formula duringthe treatment. Therefore, the effectiveness of the studiescould only represent the general effects of Chinese medicinesbut not the effects of the Chinese formula or individual Chi-nesemedicines. Besides, the success rate formany of the clini-cal trials was higher than that in the general population (oftenover 90%). This indicated that many of the patients includedwere likely relatively far along in the pregnancy (when lossrates are lower).

As in most cases, doctors would suggest the patients tohave bed rest first, although it also has no significant effects inaltering the course and progress of miscarriage [5]. However,no study compared Chinese medicines treatment to bed restin this review.Westernmedicineswere not considered as clas-sical therapies for threatened miscarriage [7, 8]. So the con-clusion of the effectiveness of Chinese medicines is limited.Therefore,more placebocontrolled trials are necessary to eva-luate the effectiveness of Chinese medicines.

3.4.3. Limitations and Difficulties. In the early years of Chi-nese Medicine studies, the pieces of literature could be onlyobtained from Chinese databases. With the development of


Study or subgroup

Cui 2002Kuang 2007Liu 2008Liu 2009Song 2005Song 2007Sun 2003Wang 2007Zhang 2007Zhong 2002

Total events

Events49415327974434466727

485

Total50605830

1265436486930

Events13383710512225432722

288

Total20604915

1175136483930

Weight8.2%

9.7%

11.8%

7.1%

10.5%

7.8%

10.5%

13.4%

10.9%

10.0%

M-H, random, 95% CI1.51 [1.09, 2.08]1.08 [0.83, 1.40]1.21 [1.01, 1.45]1.35 [0.93, 1.97]1.77 [1.41, 2.22]1.89 [1.34, 2.65]1.36 [1.08, 1.71]1.07 [0.96, 1.20]1.40 [1.13, 1.74]1.23 [0.96, 1.57]

Chinese medicines Pharmaceuticals Risk ratio Risk ratioM-H, random, 95% CI

0.001 0.1 1 10 1000Favours chinese medicines Favours pharmaceuticals

Total (95% CI) 561 465 100.0% 1.34 [1.17, 1.54]

Heterogeneity: 𝜏2 = 0.03; 𝜒2 = 33.78, df = 9 (P < 0.0001); I2 = 73%

Test for overall effect: Z = 4.12 (P < 0.0001)

Figure 9: Efficacy of Chinese medicines versus pharmaceuticals.

Chinese Medicine and its spread to foreign countries, moreand more western scientists and clinical workers have inter-ests in Chinese Medicine, and various studies have been car-ried out and could be identified in English databases since thelate 70s. An increasing trend is that Chinese Medicine wasstudied by foreign researchers in the following decades. From2000 onwards, more English database recorded ChineseMedicine in different areas and topics, covering clinical trialsfor various applications, animal studies for toxicity tests, lab-oratory research on chemical components, and commentaryarticles for theories of Chinese Medicine. Due to the differ-ences in language and theory, most pieces of literature of Chi-nese Medicine studies are still identified in Chinese database,however. There are some major limitations in identifying thepublications from various databases. As there are some dis-crepancies in the translation of Chinese Medicine from Chi-nese to English, and lots of medical terms of Chinese Medi-cine are difficult to interpret, literature searches are alwaysinefficient when searched by an English subject headings andkeywords in Chinese database. On the other hand, 80% ofthe pieces literature were overlapped in two famous Chinesedatabases, China National Knowledge Infrastructure (CNKI)and WanFang, and it is time consuming to double checkbecause of limited resources and tools. As the mainstreammedicine is inChina, over 86%of the publicationswere foundin Chinese databases only. This largely limits the researchersand scientists in western countries to obtain the informationand knowledge. Although some of the publications were withEnglish abstracts, inmost cases English full texts are not avai-lable. It is very difficult for foreigners to understand theChinese Medicine.

Regarding the design of the clinical studies in Chinesemedicines for threatened miscarriage, there are still somelimitations. Firstly, well-conducted randomized controlledtrials are important for meta-analysis. Most of the selectedtrials have inadequatemethodology quality. Furthermore, thequality of each clinical trial was obviously not at the same

level. Therefore, it would be greatly helpful to improve thequality of analysis if the authors were adequately trained tocarry out and report such clinical trials according to theinternational standard, including sufficient randomizationmethod and adequate allocation concealment, double-blinded participants and researchers or outcome assessors,participants’ classifications, and effects assessments. Sec-ondly, a better clinical trial should also provide some essentialinformation, such as the average days or weeks of the treat-ments, the changes in the medicines dosage and composi-tions, the amount of participants with a successful pregnancytill 28 weeks or afterwards, and the mortality and follow-upsof newborns, whichwould be helpful to examine the effects ofChinese medicines in the treatment. Thirdly, all the com-parisons in these clinical trials were made between Chinesemedicines and other medicines, which were not the recom-mended and the most effective treatment for threatened mis-carriage. So it is hard to draw a conclusion on the the-rapeuticeffects of Chinese medicines, and we suggest more placebo-controlled trials to be involved in the future clinical trials.Last but not least, small numbers of qualified clinical trialsand insufficient information in this review did limit us to con-duct further subgroup analysis; more details and informationof the clinical trials are essential to further understand theeffects of Chinese medicines in the analysis.

3.5. Safety and Adverse Outcomes

3.5.1. Safety. So far, Chinese medicines are claimed to be safeif applied properly, and in the last 3000 years of practices,most of the medicines have been applied in the same way astheir first records. In fact, all Chinese Medicine practitionersagree that Chinese medicines are with their potential sideeffects, which could be reduced or eliminated by prescribingin formula, shortening the course of treatment and correctlyadjusting the dose and constitutes of Chinese medicines.However, the scientific evidence of its safety is still lacking.


Study or subgroup

Song 2007Zhong 2002

Total eventsHeterogeneity: not applicableTest for overall effect: not applicable

Events00

0

Total5419

Events00

0

Total5114

Weight M-H, random, 95% CINot estimableNot estimable

Chinese medicines Pharmaceuticals Risk ratio Risk ratioM-H, random, 95% CI

0.01 0.1 1 10 100Favours chinese medicines Favours pharmaceuticals

Total (95% CI) 73 65 Not estimable

Figure 10: Adverse outcome of Chinese medicines versus pharmaceuticals.

Despite case reports of adverse effects accused by Chinesemedicines, evidences of adverse events in the use of Chinesemedicines for threatened miscarriage are limited. In mostclinical trials, adverse effects and toxicity of the Chinesemedicines were not studied. Only very few studies reportedno adverse effect and toxicity aftermaternal exposure [42–44]and some gastrointestinal effects, including nausea, drymouth, anorexia, and constipation were reported [43]. Clini-cal outcomes of threatened miscarriage were not followed inabout 2%–20% cases, if Chinese medicines interventionfailed. Even if the intervention was successful and pregnan-cies were maintained, adverse pregnancy and/or perinataloutcomeswere not studied inmost studies. Pretermdeliverieswere reported in some studies with incidence rate 0.7%–6.4%[45–48], while premature rupture of membranes and still-birth were identified in a separate study [46]. Neonatal deathdue to prematurity, asphyxia, or infection was identified insome studies [45–47, 49], while an unspecified malformationwas recorded in a study [35] and epilepsy andmental retarda-tion in a study [47]. However, all the clinical studies did notfurther study and explain the possible causes for these adverseeffects, and there was limited evidence for us to find a dir-ect relation between the adverse outcomes with Chinesemedicines.

3.5.2. Adverse Outcomes. In our previous review [21], thirty-two relevant articles included 9 randomized controlled trials,1 quasirandomized controlled trial, and 2 controlled trialscomparing Chinese medicines alone or combined medicineswith pharmaceuticals and 20 case series with no controls werestudied and analyzed. However, sample sizes of each studywere generally small. There was variation in Chinese medi-cine formulation, dosage, and duration of treatment. In thepooled randomized controlled trials, drymouth, constipationand insomnia (2–10%), intervention failure (3.1–22.3%), dia-betic complications (3%), preterm delivery (5%), and neu-rodevelopmental morbidity (1.8%) were recorded. Meta-ana-lysis demonstrated that intervention failure was significantlylower in the combined Chinese medicines groups than in theWestern medicines controls (relative risk = 0.46; 95% confi-dence interval: 0.30–0.70, I2 = 0%).No significant differenceswere found between these groups for adverse effects andtoxicity or for adverse pregnancy and perinatal outcomes(Figure 10). In current update study, no new randomizedclinical trial was included for meta-analysis.

Chinese medicines are not free of risk; similar toWesternpharmaceutical medicines, they have the potential to causeadverse effects. The active ingredients of Chinese medicinesare also chemicals that are similar to prescription pharmaceu-ticals.Thus, Chinesemedicines in ChineseMedicinemay notonly result in maternal manifestations that indirectly affectfetal health, but theymay also harm the fetus directly. Despitevariations in clinical practice and therapeutic prescription,Chinesemedication inChineseMedicine should complywiththe same modern pharmacological principles as WesternMedicine. Chinese medicines not only may be beneficial butmay also adversely affect both mothers and fetuses in utero.

3.5.3. Limitations and Difficulty. Over 90% of the clinicaltrials did not include adverse effect as one of study outcomemeasures. It may due to the incidence of adverse events beindeed too rare or the awareness on the adverse effects wasactually too low.The low rate of adverse events after maternalexposure to Chinese medicines for threatened miscarriagewas recorded, however.The incidences were not too low to beeasily missed. Hence lack of awareness on the safety issue ofChinese medicines in general could be the main reason forlimited safety studies available.

Apart from limited records in adverse outcomes, studydesigns were also restricted.There were no placebocontrolledtrial and only 1 controlled trial was with adequate random-ization method. Whilst all other cohorts had no controls forcomparison, allocationmethods were not described and theirquality was relatively low. Nevertheless, the study results werequestionable. Though the drop-out rates were not high, sam-ple sizes of the selected studies were still very small. Someimportant demographic data and study exclusion criteriawere not provided. Different studies used different Chinesemedicine formulae to treat threatened miscarriage and alsothere were large variations in the dose, dosing, and durationof the intervention amongst the studies. Most studies fol-lowed up the pregnancy until delivery, but the outcome para-meters in the pregnancy and perinatal complications wererather inconsistent. Few studies monitored adverse effectsand toxicity of Chinese medicines, and complicated miscar-riagewas unknown.Owing to the limited number of random-ized controlled trials and the clinical heterogeneity betweenstudies, additional meta-analysis to evaluate the adverseeffects of Chinese medicine for threatened miscarriage wasnot available.


Unlike Western herbalism, Chinese medicines includemany animal materials and even mineraloid remedies as wellas medicinal herbs [50]. Most of the formulae are processedby decoction in boiling water for hours and are orally admin-istered as a “soup” [51], though it can be supplied as powders,soluble granules, and tablets nowadays. As each Chinesemedicine has its own property and potential interaction,the application of formulated and individualized medicationenhances the therapeutic actions of some herbs and collabo-rates all the herbs to balance disharmony of each individualfor treatment. However, the adverse effects and toxicity ofChinese medicines may vary in different combinations, pre-parations, and individuals. It is difficult to identify whichChinese medicine attributes to the specific adverse effects.

4. Conclusions

Chinese medicines, as the most common therapeuticapproach of ChineseMedicine, have become popular for the-rapeutic and complementary use in healing diseases andmaintaining health, not only in China but also around theworld. In this study, we focused on the Chinese medicines forpregnancy providing background information for overall un-derstanding on the clinical applications of Chinese Medicineduring pregnancy, and scientific evidences on their efficacyand safety for pregnancy use.

The results showed that (1) 339,792 pieces of literaturewere identified, mostly fromChinese databases, and only fewclinical studies were selected for systematic review; (2) Chi-nese medicine is the most common therapeutic approach formiscarriage, and the most common clinical indication wasthreatened miscarriage; (3) the most commonly prescribedformula to prevent miscarriage and promote the pregnancywas Shou Tai Pill, and the most frequently used individualChinese medicine was Largehead Atractylodes Rhizome;(4) the Chinese medicines for threatened miscarriage weremostly single dose per day, but the range of the dose was quitelarge; (5) the overall effectiveness rate of Chinese medicinesfor threatenedmiscarriage was over 90%; however, there is nodirect correlation between efficacy and usage frequency, andbetween efficacy and dose and dosing; (6) no placebo wasincluded in either efficacy or safety study, and only few studieswith high quality were conducted formeta-analysis; (7) basedon limited clinical trials, a combination of Chinesemedicinesand Western medicines was more effective than Chinesemedicines alone. No specific safety problemwas reported, butpotential adverse and toxic effects by certain medicines wereidentified.

It is suggested that Chinese medicines combined withWestern medicines may be effective to treat miscarriage andrelieve the clinical signs, while Chinese medicines alone maynot be effective. However, large scales of randomized con-trolled trials and more scientific evidences, especially place-bocontrolled trials, are still necessary to confirm the effec-tiveness of Chinese medicines. In most of the pieces of lit-eratures, Chinese medicines are 90% effective, and our meta-analysis also supports the therapeutic application of Chinesemedicines. However, most of the studies are so flawed that

meaningful conclusions cannot be made; there is a desperateneed for better clinical studies on Chinese medicines. Poten-tial adverse effects of Chinese medicines on mothers andfetuses during pregnancies are lacking, and the evidences ofadverse events in the use of Chinesemedicines for threatenedmiscarriage are limited. Studies vary considerably in design,interventions, and outcome measures; therefore conclusiveresults remain elusive. Rigorous scientific and clinical studiesare necessary to confirm the risk of Chinese medicines.

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of the paper.

Authors’ Contribution

Lu Li is responsible for study identification, screening, eligi-bility and inclusion, data acquisition, and statistical analysis.Chi Chiu Wang is responsible for study eligibility andinclusion, conception of the project, design of the study, andresearch funding. Lu Li and Chi Chiu Wang both wrote theinitial and final versions of the review. Ping Chung Leung andTony Kwok Hung Chung were responsible for commentingand approving the final paper.

Acknowledgments

Lu Li received the Hop Wai Scholarship and the Zi YingScholarship from the Institute of Chinese Culture and Post-graduate Student Grants for Overseas Academic Activitiesfrom the Graduate School, The Chinese University of HongKong, to attend Cochrane training workshops in Oxford andFreiburg and to study in the Cochrane Pregnancy and Child-birth Group at University of Liverpool and the Yu To SangMemorial Scholarship 2008/2009 and 2009/2010 from theChinese University of Hong Kong during her Ph.D. study. LuLi has received fellowships from Deutscher AkademischerAustausch Dienst (DAAD) and Research Fellowship Scheme(RFS) for her research project in Germany and Hong Kong,respectively.

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