Hum. Reprod. Update 2012 Li 504 24

Human Reproduction Update, Vol.18, No.5 pp.
504 524, 2012

Advanced Access publication on June 2, 2012 doi:10.1093/humupd/dms025
Adverse outcomes of Chinese

medicines used for threatened
miscarriage: a systematic review
and meta-analysis
Lu Li1, Li Xia Dou2,3, James P. Neilson 3, Ping Chung Leung 4
and Chi Chiu Wang 1,*
*Correspondence address. Tel: +852-2632-2810; Fax: +852-2636-0008; E-mail: ccwang@cuhk.edu.hk
Submitted on March 3, 2012; resubmitted on April 20, 2012; accepted on May 2, 2012
table of contents
...........................................................................................................................
Introduction
Threatened miscarriage
Chinese medicines for threatened miscarriage
Methods
Study characteristics
Study design
Search strategy
Data extraction
Results
Identication of articles
Study designs and methods
Chinese medicines, type and compliance
Baseline, exclusion and follow-up
Adverse outcomes
Adverse effects and toxicity of Chinese medicines
Failure of the intervention and complications
Adverse pregnancy outcomes
Adverse perinatal outcomes
Discussion
Summary of evidence
Limitations
Difculties
Conclusions and recommendations
background: Threatened miscarriage is very common in early pregnancy. Chinese medicines have been widely used to prevent spontaneous pregnancy loss. However, the safety of Chinese medicines is still unknown. A systematic review was performed to identify and describe adverse events of Chinese medicines used for threatened miscarriage.
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1
Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, 1st Floor, Block E, Prince of Wales Hospital, Shatin,
New Territories, Hong Kong 2School of Public Health, Peking University, Beijing, China 3Cochrane Pregnancy and Childbirth Group, Institute
of Translational Medicine, University of Liverpool, Liverpool, UK 4Institute of Chinese Medicine, The Chinese University of Hong Kong, Prince
of Wales Hospital, Shatin, New Territories, Hong Kong
505
methods: Clinical studies of Chinese medicines for threatened miscarriage were selected. Primary outcomes were occurrence of adverse
effects or toxicity of Chinese medicines. Secondary outcomes were failure of treatment and adverse pregnancy and perinatal outcomes.
results: Thirty-two relevant articles included 9 randomized controlled trials, 1 quasi-randomized controlled trial and 2 controlled trials
comparing Chinese medicines alone or combined medicines with pharmaceuticals and 20 case series with no controls. Sample sizes of each
study were generally small. There was variation in Chinese medicine formulation, dosage and duration of treatment. In the pooled randomized controlled trials, dry mouth, constipation and insomnia (2 10%) and intervention failure (3.1 22.3%), diabetic complications (3%),
preterm delivery (5%) and neurodevelopmental morbidity (1.8%) were recorded. Meta-analysis demonstrated that intervention failure
was signicantly lower in the combined Chinese medicines groups than in the Western medicines controls (relative risk 0.46; 95% condence interval: 0.30 0.70, I 2 0%). No signicant differences were found between these groups for adverse effects and toxicity or for
adverse pregnancy and perinatal outcomes.
conclusions: Studies varied considerably in design, interventions and outcome measures, therefore conclusive results remain elusive.
In the absence of placebo-controlled trials, the safety of Chinese medicines for the treatment of threatened miscarriage is unknown. Rigorous
scientic and clinical studies to assess the possible risks of Chinese medicines are needed.
Key words: Chinese medicines / miscarriage / adverse events / outcomes
Threatened miscarriage
Threatened miscarriage is a spontaneous miscarriage present with
vaginal bleeding or any bloody vaginal discharge during the rst half
of pregnancy (Cunningham et al., 2005). It is the most common complication in early pregnancy. About a quarter of recognized pregnancies have this symptom and half of those will end in miscarriage
(Everett, 1997). The causes of spontaneous miscarriage are diverse
and comprise chromosomal, genetic, anatomical, immunological, hormonal, infectious and psychological factors (Bulletti et al., 1996). In
many cases, however, the specic underlying causes have not been
identied (Orvieto et al., 1991). The risk of miscarriage increases
with parity as well as maternal and paternal age. After the age of
30 35 years, fertility declines and the rate of spontaneous miscarriage
increases with a signicant social and economic impact (Brock and
Holloway, 1990).
The vaginal bleeding in threatened miscarriage is frequently slight
and will subside spontaneously. Clinical care typically includes pelvic
examination to exclude inevitable miscarriage, ultrasound to conrm
viable intrauterine pregnancy and laboratory studies to monitor
growth of the fetus. The vaginal bleeding may persist for days or
weeks and progress no matter what is done. Expectant and medical
management has not been shown to provide an additional benet;
bedrest, progesterone or chorionic gonadotrophin supplements do
not signicantly prevent pregnancy loss (Aleman et al., 2005; Hass
and Ramsey, 2008; Devaseelan et al., 2010).
Chinese medicines for threatened

miscarriage
For more than 5000 years, Traditional Chinese Medicine has
employed a range of unique clinical practices to maintain health (Giovanni, 1997). The practices include acupuncture (inserting ne needles
into specic points namely acupoints on the body), moxibustion
(burning dried mugwort on the acupoints in conjunction with acupuncture), food therapy (individualizing dietary recommendations for a
health condition), Chinese medicines (a collection of crude medicines,
prepared drugs in slices, patent medicines and simple preparations),

cupping (creating vacuum in several glass spheres on the body),
Qigong (breathing and meditation exercise) and Tuina (body
massage akin to acupressure). Most of these approaches have been
disseminated to other countries since the sixth century BC (Unschuld,
1985). Traditional Chinese Medicine is currently well accepted as a
mainstream of medical care throughout East Asia and is considered
a complementary or alternative medicine in the Western world
(Basics, 2010).
Chinese medicine is a common name for Chinese Materia Medica,
which has therapeutic properties for medical treatment and healing
(Read, 1976). It is considered as a primary modality of internal medicine in Traditional Chinese Medicine (Holland, 2000). Nowadays
Chinese medicines and other herbal medicines are commonly used
to promote maternal and fetal health and to relieve medical problems
during pregnancy worldwide (Hemminki et al., 1991; Wang et al.,
1995; Gharoro and Igbafe, 2000; Gibson et al., 2001; Hollyer et al.,
2002; Mantani, 2003; Nordeng and Haven, 2004; Ong et al., 2005;
Della et al., 2006; Chuang et al., 2009; Holst et al., 2009). Chinese
medicines are frequently used in threatened miscarriage (Li, 2011) in
order to prevent pregnancy loss (Liu, 2002).
Chinese medicines are regarded by the public and some health-care
providers as gentle and safe (Marcus and Snodgrass, 2005). Although
there is no scientic basis for the safety claim, 3050% of pregnant
women use Chinese medicines to maintain good health and reduce
the need for Western medication (Westfall, 2001; Ong et al.,
2005). Despite the potential benecial effects of Chinese medicines
in threatened miscarriage (Li et al., 2012), no data are available to
conrm the safety of Chinese medicines and no regulations have
been established to monitor and control its clinical applications in
pregnancy. In our animal studies of the commonly used Chinese medicines for threatened miscarriage, we worried about the identied reproductive toxicity, including fetal resorption, growth restriction and
congenital malformations (Li et al., 2011; Wang et al., 2012). We
hypothesized that Chinese medicines may also be associated with
adverse outcomes in human pregnancy. In this study, we have
focused on threatened miscarriage and aimed to identify and describe
the adverse events of Chinese medicines by systematic review and
Introduction
506
meta-analysis, which included adverse effects or toxicity of medicine,
failure of intervention and adverse pregnancy and perinatal outcomes.
This has not been done previously.
Materials and Methods
Li et al.
of review articles and eligible studies were hand searched to identify

other potentially eligible studies. Abstracts from conference proceedings
were also considered to identify further studies that were not yet published. The search terms, adapted when required for each database, to
identify Chinese medicines interventions in threatened miscarriage are
presented in Supplementary data, Table SI.
Study characteristics
This systematic review focused on clinical studies involving women with
threatened miscarriage, the most common application of Chinese medicine
during pregnancy (Li, 2011). All published and unpublished studies that evaluated the adverse effects of Chinese medicines for threatened miscarriage
were considered for review. Clinical studies included both uncontrolled
studies and controlled studies, which compared Chinese medicines or combined medicines to a comparison group receiving no therapy (placebo),
minimal therapy (hospitalization or bedrest only) or another therapy/treatment, were considered. Outcome measures included adverse events in
mothers and fetuses.
Studies included both experimental and observational studies: (i) randomized control trials (RCTs), (ii) quasi-RCTs if the randomization
methods were not adequate, (iii) controlled trials if no randomization
was carried out; (iv) cohort studies if the study methods were not specied or assessed by RCTs and (v) case series and case reports. Observational studies were considered in this review because many adverse events
are very uncommon and also take a long period to be observed. An intervention period of at least 1 week with either short-term or long-term
follow-up and Chinese medicines, or in conjunction with any other intervention, as an independent factor on outcomes of health, were included
for this study. The intervention duration of at least 1 week was based
on capturing as many potentially effective interventional studies as possible. The primary outcome was adverse effects or toxicity of the
Chinese medicines. Adverse effects and toxicity of Chinese medicines
were dened as harmful and undesired side effects and toxic effects
resulting from the treatment. Secondary outcomes were failure of the
interventions, and adverse pregnancy and perinatal outcomes. Failure of
intervention for threatened miscarriage was dened as inevitable miscarriage presented with vaginal bleeding and pregnancy loss. Adverse pregnancy outcomes were dened as pregnancy complications, and maternal
morbidity and mortality, such as preterm labor, post-date delivery, gestational diabetics and hypertension and maternal death. Adverse perinatal
outcomes were dened as prenatal and post-natal morbidity and mortality, including intrauterine infection, asphyxia, neurodevelopmental consequence, congenital malformation and neonatal death. Studies were
excluded if (i) no ultrasound examination was provided to conrm the
viable pregnancy, (ii) complicated or recurrent miscarriage were included
for intervention, (iii) various herbal agents and products were included,
e.g. green tea and ginger, which are widely used as daily pharmanutrients
for general health and (iv) the study was not published in either English or
Chinese.
Search strategy
A systematic review of the literature was conducted in December 2011
across the following databases: MEDLINE, PubMed, Cochrane Library,
International Clinical Trials Registry Platform (ICTRP), EMB Reviews (including Cochrane Central Register of Controlled Trials (CENTRAL),
Cochrane Database of Systematic Reviews, Cochrane Methodology Register, ACP journal club), EMBASE, CINAHL, NHS Evidence, Wiley InterScience, Chinese Clinical Trial Registry, China Journal Net and WanFang
database, with no time limit applied to any database. The reference lists
Two co-authors (L.L. and L.X.D.) independently extracted data from a

subset of the articles into data summary tables. Data regarding the
study design, population(s) studied, assessment of interventions,
measure of adverse events (short-term and long-term adverse outcomes),
timing of measurement(s) and prevalence of outcomes were extracted
from each included study. Quality analysis was performed based on the
Cochrane Handbook of Systematic Reviews and Quality of Reporting of
Meta-Analysis checklist. A formal assessment of study quality was performed for each study using a standardized quality assessment form
adopted from Newcastle Ottawa Quality Assessment Scale (Stang,
2010). The intent was to perform a quantitative synthesis of the data
where possible, dependent on the quality and diversity of the data.
Meta-analysis was performed for RCTs and quasi-RCTs, otherwise controlled trials were included when there were not enough RCTs or
quasi-RCTs. Sensitivity analysis was carried out to explore the effect of
trial quality on overall result. Particularly, xed-effect meta-analyses
would be used for combining data in the absence of heterogeneity. In
the presence of heterogeneity (I 2 . 50%), where results were being
pooled from studies examining different interventions, or where it was
not clear that the same outcome was being measured in all studies,
random-effects meta-analyses would be used. Descriptive methods were
applied to report and summarize the adverse outcomes of Chinese medicines for case reports and case series.
Results
Identication of articles
Figure 1 shows the study selection according to PRISMA guidelines
(Moher et al., 2009). In total, 591 publications on Chinese medicines
for threatened miscarriage were identied from the database search,
but none were obtained from other sources. After screening the
titles and abstracts, 65 commentary and 67 review articles were
excluded. One hundred and eight-seven duplicated publications
were also excluded. Full texts of remained 272 clinical studies were
assessed for study eligibility. Adverse effects of Chinese medicines
were not reported as an outcome measure in 232 studies. Adverse
effects were not due to the intervention (outcomes before intervention) in one study (An, 2000), pregnancies of gestational age over
30 weeks were recruited in four studies (Wang et al., 2008; Jiang,
2009; Meng, 2009; Bi, 2010), recurrent miscarriage was included in
one study (Pan, 2008), different pharmaceuticals were compared in
one study (Lu et al., 2007) and Chinese medicines were included in
the control group in one study (Zhang, 2009). These 240 studies
were also excluded, leaving 32 clinical studies with full records on
the adverse effects of Chinese medicines for threatened miscarriage.
These were selected for quantitative or qualitative synthesis for the
review.
Study design
Data extraction
507
Figure 1 Study exclusion and inclusion.
Study designs and methods

Table I and Supplementary data, Table SII shows the characteristics
and main results of 32 selected clinical studies (total participants
3412). The studies, all from China, were published between 1987
and 2010. There were 9 RCT studies (total participants 1542), 1
quasi-RCT study (total participants 105), 2 non-randomized controlled trials (total participants 115) and 20 case series (total
participants 1650). No cohort studies, case control studies and
case reports were identied. Table II and Supplementary data,
Table SV summarized the quality of the selected studies. Quality
scores were 4 6 out of 9 in all the RCTs, quasi-RCT and controlled
trials (Supplementary data, Table SIV). Two RCTs clearly indicated the
randomization methods (Li et al., 2006; Zhang et al., 2000), while the
other 7 RCTs did not report details of the randomization methods
(Yang, 1992; Zhang et al., 2005; He and Che, 2007; Teng and Wu,
2008; Zhao et al., 2008, 2010; Yue et al., 2009). The randomization
method of the quasi-RCT was inadequate by the visiting date of the participants only (Song and Zhu, 2007). Two studies both did not mention
if any randomization method was used and were classied as nonrandomized controlled studies (Gong and Chen, 1993; Zhou, 2006).
The RCTs, quasi-RCT and non-randomized controlled studies consisted of two or three intervention groups, Chinese medicines alone,
508
Li et al.
Table I Summary of study characteristics and adverse events.

Study
TCM
intervention
WM comparison
Adverse
effects and
toxicity
Intervention
failure and
outcomes
Adverse
pregnancy
outcomes
Adverse perinatal
outcomes
.............................................................................................................................................................................................
Formula: ZSRGF po
Dose: not reported
Dosing: BID
Duration: until 10th
gestational week
Progesterone im
Dose: 20 mg
Dosing: QD
gestational week
Not reported
Not reported
Outcome: inevitable
abortion, missed
abortion (overall
14.8%)
Not reported
Outcome: preterm
labor
TCM 0%
WM 0%
Yue et al.
(2009)
Formula:
TSPSP + STP po
Dose: 6 30 g
Dosing: BID
gestational week
Vitamin E po
Dose: 100 mg
Dosing: TID
gestational week
Progesterone im
Dose: not reported
Dosing: PRN
Duration: not
reported
Not reported
Combined TCM and

WM 9%
Outcome: not
reported
WM 31%
Outcome: therapeutic
abortion (14.3%)
Combined TCM 0%
WM not reported
Combined TCM 0%
WM not reported
Teng and
Wu
(2008)
Formula: BSYQD po
Dose: 5 20 g
Dosing: BID
Duration: 14 days
Progesterone im
Dose: 20 mg
Dosing: QD
Duration: 14 days
Combined TCM
and WM 0%
WM not
reported
Combined TCM and

WM 7%
Outcome: not
reported
WM 20%
Outcome: not
reported
Not reported
Not reported
Zhao
et al.
(2008)
Formula: ZSRGF po
Dose: not reported
Dosing: BID
gestational week
Progesterone im
Dose: 20 mg
Dosing: QD
gestational week
Not reported
Not reported
TCM/WM 5%
Outcome: stillbirth
(groups not reported)
TCM/WM 5%
Outcome: fetal
ventriculomegaly (groups
not reported)
He and
Che
(2007)
Formula: JWATD po
Dose: 3 30 g
Dosing: BID
Duration: 10 days
Allylestrenol po
Dose: 5 mg
Dosing: BID
Duration: 10 days
Not reported
Combined TCM and

WM 8%
Outcome: not
reported
WM 20%
Outcome: not
reported
Combined TCM 3%
Outcome: preterm
delivery
WM 2% Outcome:
preterm delivery 1%
Postdate pregnancy 1%
Combined TCM 0%
WM 0%
Li et al.
(2006)
Formula: BSGTD po
Dose: 5 30 g
Dosing: BID
Duration: 10 days
HCG im
Dose: 2000 U
Dosing: QD
Duration: 10 days
Progesterone im
Dose: 20 mg
Dosing: QD
Duration: 10 days
Not reported
Combined TCM and

WM 22.2%
Outcome: not
reported
WM 29.5%
Outcome: not
reported
Combined TCM and

WM 3%
Outcome: diabetic
complications
WM 3.7%
Outcome: preterm
delivery
Combined TCM 0%
WM 0%
Zhang
(2005)
Formula: ZSYTP po
Dose: 5 g
Dosing: TID
Duration: 14 days
HCG im
Dose: 2000 U
Dosing: QD
Duration: 14 days
TCM 10%
Outcome:
dry mouth 8%
thick moss 4%
constipation 4%
insomnia 2%
Combined TCM
and WM: not
reported
WM: not
reported
TCM 13%
Outcome: not
reported
Combined TCM and
WM 7.4%
Outcome: not
reported
WM 15%
Outcome: not
reported
Not reported
Not reported
Continued
Zhao
et al.
(2010)
509
Table I Continued
Study
TCM
intervention
WM comparison
Adverse
effects and
toxicity
Intervention
failure and
outcomes
Adverse
pregnancy
outcomes
Adverse perinatal
outcomes
.............................................................................................................................................................................................
TCM 1: YAD po
Dose: 615 g
Dosing: TID
Duration: 10 days
TCM 2: STP po
Dose: not reported
Dosing: TID
Duration: 10 days
Progesterone im
Dose: 10 20 mg
Dosing: QD
Duration: 1 week
after symptom
subsided
Vitamin E po
Dose: 100 mg
Dosing: QD
Duration: 1 week
after symptom
subsided
Not reported
TCM 1: 3.1%
Outcome: not
reported
TCM 2: 14%
Outcome: not
reported
WM 44%
Outcome: not
reported
Not reported
TCM 1: 0%
TCM 2: not reported
WM not reported
Yang
(1992)
Formula: TSPSP po
Dose: not reported
Dosing: not reported
Duration: not
reported
Vitamin E,
Progesterone,
Chlordiazepoxide
Dose: not reported
Duration: not
reported
Not reported
Not reported
Not reported
TCM 1.8%
Outcome:
neurodevelopmental
morbidity
WM 7.4%
Outcome:
neurodevelopmental
morbidity
Song and
Zhu
(2007)
Formula: ZXBTD po
Dose: 210 g
Dosing: TID
Duration: 7 days
Progesterone im
Dose: 20 mg
Dosing: QD
Duration: 7 days
Vitamin E po
Dose: 100 mg
Dosing: TID
Duration: 7 days
TCM 0%
WM 0%
TCM 18.5%
Outcome: not
reported
WM 56.9%
Outcome: not
reported
Not reported
TCM 0%
WM 0%
Zhou
(2006)
Formula: STP + SXP

po
Dose: 615 g
Dosing: QD
Duration: 7 14 days
HCG im
Dose: 2000 U
Dosing: QD
Duration: 14 days
Progesterone im
Dose: 20 mg
Dosing: QD
Duration: 14 days
Not reported
TCM 5%
Outcome: not
reported
Combined TCM and
WM 0%
Outcome: not
reported
WM 30%
Outcome: not
reported
TCM 0%
WM 0%
Combined TCM and
WM 5%
Outcome: preterm
delivery
TCM 0%
WM 0%
Combined TCM and WM
(5%)
Outcome: neonatal death
due to prematurity
Gong
and
Chen
(1993)
Formula: GSATD po
Dose: not reported
Dosing: QD
Duration: not
reported
Vitamin E po
Dose: 60 mg
Dosing: QD
Duration: not
reported
Vitamin C po
Dose: 300 mg
Dosing: QD
Duration: not
reported
Not reported
TCM 16.6%
Outcome: not
reported
Combined TCM and
WM 10.4%
Outcome: not
reported
WM 33.3%
Outcome: not
reported
Not reported
Not reported
Gu et al.
(2008)
Formula: LYND po
Dose: 10 ml
Dosing: TID
Duration: 15 30
days
No comparison
TCM 0%
TCM 11.4%
Outcome: not
reported
Not reported
Not reported
Xu
(2008)
Formula: ZNBTF po
Dose: 520 g
Dosing: BID
Duration: 1 2
months after
symptom subsided
No comparison
Not reported
TCM 9.2%
Outcome: not
reported
Not reported
TCM 0%
Continued
Zhang
et al.
(2000)
510
Li et al.
Table I Continued
Study
TCM
intervention
WM comparison
Adverse
effects and
toxicity
Intervention
failure and
outcomes
Adverse
pregnancy
outcomes
Adverse perinatal
outcomes
.............................................................................................................................................................................................
Formula: YSGCD po
Dose: 10 30 g
Dosing: BID
Duration: 4 7 weeks
No comparison
Not reported
TCM 7.1%
Outcome: not
reported
Not reported
TCM 0%
Luo et al.
(2007)
Formula: TEAP po
Dose: 10 g
Dosing: TID
Duration: 20 days
No comparison
Not reported
TCM 5.2%
Outcome: not
reported
TCM 1.7%
Outcome: preterm
delivery due to
hypertension
TCM 0%
Chou
(2002)
Formula:
STP + WZD po
Dose: 10 30 g
Dosing: TID
Duration: till fourth
to fth month of
gestation/till delivery
No comparison
Not reported
TCM 3.6%
Outcome: not
reported
TCM 0%
TCM 0.9%
Outcome: malformation
(not specied)
Chen
et al.
(2001)
Formula: ZSYTP po
Dose: 5 g
Dosing: TID
Duration: .2 weeks
No comparison
TCM 6.1%
Outcome:
nausea (3.9%)
Dry mouth,
anorexia,
constipation
(0.9%)
TCM 8.1%
Outcome: not
reported
Not reported
Not reported
Xu
(2001)
Formula: STP po
Dose: 10 30 g
Dosing: BID
Duration: 1 week
after symptom
subsided
No comparison
Not reported
TCM 6.9%
Outcome: not
reported
Not reported
TCM 0%
Wang
and Li
(2000)
Formula: JPBSATD
po
Dose: 5 15 g
Dosing: BID
Duration: 3 10
weeks
No comparison
Not reported
TCM 5.5%
Outcome: not
reported
TCM 0%
TCM 0%
Chen
and Yun
(1999)
Formula: BYD po
Dose: not reported
Duration: not
reported
No comparison
Not reported
TCM 11.7%
Outcome: not
reported
TCM 0%
TCM 0%
Cui
(1998)
Formula: STP po
Dose: 10 15 g
Dosing: QD
Duration: 1 2
months
No comparison
Not reported
TCM 19.2%
Outcome: not
reported
TCM 8.5%
Outcome: preterm
delivery (6.4%)
Premature rupture of
membranes (2.1%)
TCM 8.5%
due to prematurity (6.4%)
Asphyxia (2.1%)
Kang
et al.
(1998)
Formula: STP po
Dose: not reported
Dosing: BID
Duration: 1 2 weeks
after symptom
subsided
No comparison
Not reported
TCM 9.3%
Outcome: not
reported
TCM 0%
TCM 0%
Chen
(1997)
Formula: STP po
Dose: 10 30 g
Dosing: QD
Duration: not
reported
No comparison
Not reported
TCM 5%
Outcome: not
reported
Not reported
TCM 0%
Ye and
Qiu
(2008)
Continued
511
Table I Continued
Study
TCM
intervention
WM comparison
Adverse
effects and
toxicity
Intervention
failure and
outcomes
Adverse
pregnancy
outcomes
Adverse perinatal
outcomes
.............................................................................................................................................................................................
Formula: STP po
Dose: 630 g
Dosing: QD
Duration:14 30 days
after symptom
subsided
No comparison
Not reported
TCM 7%
Outcome: not
reported
Not reported
TCM 0%
Zhou
(1997)
Formula: ATD po
Dose: 612 g
Dosing: BID/TID
Duration: not
reported
No comparison
Not reported
Combined TCM and

WM 4.6%
Outcome: not
reported
TCM 0.7%
Outcome: preterm
delivery
TCM 1.3%
due to prematurity (0.7%)
Epilepsy (0.3%),
neurodevelopmental
morbidity (0.3%)
Wu and
Ji (1994)
Formula: STP po
Dose: 630 g
Dosing: BID
Duration: 1 2
weeks/till delivery
No comparison
TCM 0%
TCM 9%
Outcome: not
reported
Not reported
Not reported
Zhu and
Li (1992)
Formula: ATD po
Dose: 615 g
Dosing: BID
Duration: not
reported
No comparison
Not reported
TCM 7.5%
Outcome: not
reported
TCM 0%
TCM 0%
Tian and
Li (1991)
Formula: ATD po
Dose: 10 30 g
Dosing: QD
Duration: not
reported
No comparison
Not reported
TCM 8.9%
Outcome: not
reported
TCM 2.9%
Outcome:
oligohydramnios and
stillbirth
TCM 0%
Li (1989)
Formula: STP po
Dose: 330 g
Dosing: QD
Duration: 15 days
No comparison
Not reported
TCM 12.5%
Outcome: not
reported
TCM 0%
Not reported
Wang
and
Wang
(1987)
Formula: STP po
Dose: 10 30 g
Dosing: BID
Duration: 1 month
on average
No comparison
Not reported
TCM 18%
Outcome: not
reported
TCM 0%
Not reported
Wu
(1987)
Formula: WZD po
Dose: 10 20 g
Dosing: QD
Duration: not
reported
No comparison
Not reported
TCM 2.4%
Outcome: not
reported
Not reported
TCM 2.4%
due to aspiration
pneumonia
Study location, designs, participants details and exclusion criteria are available in online Supplementary data, Table SII. TCM, Chinese medicines group; WM, pharmaceutical group
(mainly Western medicines); combined TCM and WM, combined Chinese medicines and pharmaceutical group. ATD, An Tai Decoction; BSGTD, Bu Shen Gu Tai Decoction;
BSYQD, Bu Shen Yi Qi Decoction; BYD, Bao Yun Decoction; GSATD, Gu Shen An Tai Decoction; JPBSATD, Jian Pi Bu Shen An Tai Decoction; JWATD, Jiu Wei An Tai Decoction;
LYND, Le Yun Ning Decoction; STP, Shou Tai Pill; SXP, Shi Xiao Pill; TEAP, Tai Er An Pill; TSPSP, Tai Shan Pan Shi Pill; WZD, Wu Zi Decoction; YAD, Yun An Decoction; YSGCD, Yi
Shen Gu Chong Decoction; ZNBTF, Zi Ni Bao Tai Formula; ZSRGF, Zi Shen Rou Gan Formula; ZSYTP, Zi Shen Yu Tai Pill; ZXBTD, Zhi Xue Bao Tai Decoction. Details of the Chinese
medicines are provided in Supplementary data, Table SIII. QD, quaque die; BID, bis in die; TID, ter in die; PRN, pro re nata; p.o., per os; i.m., intramuscular.
pharmaceuticals alone and combined Chinese medicines and pharmaceuticals. All pharmaceuticals were Western medicines, including progesterone and oestrogen derivatives, HCG and vitamins C and E. Most
case series only had a single Chinese medicines group, except one case
series included combined Chinese medicines and pharmaceuticals as
treatment group (Wang and Wang, 1987). All case series did not
have a control group for comparison.
Chinese medicines, type and compliance

Amongst the Chinese medicines studied, there were 19 kinds of
Chinese medicine formulae (Table I and Supplementary data, Table
SV). Each formula contained wide varieties of 520 different individual
Chinese medicines. Some of the studies included more than one kind
of formula in the intervention (Chou, 2002; Zhou, 2006; Yue et al.,
He
(1997)
512
Li et al.
Table II Summary of study qualities.

Study
Design
Quality
scorea
Summary
Compliance
Follow-upb
Strength
Weakness
.............................................................................................................................................................................................
RCT
Small study
Recruitment from July
2007 to March 2009
Randomized
100%
completed
Short term:
intervention failure and
outcomes only
Long term: pregnancy
and perinatal outcomes
RCT
High
compliance
Baseline
comparable
Long-term
follow-up
Small sample size

Power calculation not
reported
Randomization method
not reported
Allocation method not
reported
Exclusion not reported
Adverse effects/toxicity
not studied
Yue et al.
(2009)
RCT
Small study
Recruitment from
January 2004 to
December 2008
Randomized
100%
completed
Short term:
intervention failure and
outcomes only
RCT
High
compliance
Baseline
comparable
Long-term
follow-up
Small sample size

reported
not reported
reported
Combined TCM and WM
as subset
More than one type of
TCM and WM included
not studied
Teng and
Wu
(2008)
RCT
Small study
Recruitment from
April 2007 to
November 2007
Randomized
95.6%
completed
Short term: adverse

effects/toxicity and
intervention failure
Long term: no
RCT
High
compliance
Small sample size

reported
not reported
reported
Baseline unclear
Combined TCM and WM
as subset
Intervention failure
outcomes not studied
No long-term follow-up
Zhao et al.
(2008)
RCT
Small study
Recruitment from
January 2007 to
January 2008
Randomized
100%
completed
Short term: no
RCT
High
compliance
Baseline
comparable
Long-term
follow-up
Small sample size

reported
not reported
reported
No short term follow-up
He and
Che
(2007)
RCT
Large study
Recruitment: not
reported
Randomized
100%
completed
Short term:
intervention failure only
RCT
Large sample
size
High
compliance
Long-term
follow-up
(60%)

reported
not reported
reported
Baseline unclear
Mixed rst and second
trimesters
Combined TCM and WM
as subset
and intervention failure
outcome not studied
Continued
Zhao et al.
(2010)
513
Table II Continued
Study
Design
Quality
scorea
Summary
Compliance
Follow-upb
Strength
Weakness
.............................................................................................................................................................................................
RCT
Small study
Recruitment from
January 2003 to
September 2005
Randomized by
random number table
100%
completed
Short term:
RCT
High
compliance
Baseline
comparable
Long-term
follow-up
Small sample size

reported
reported
Combined TCM and WM
as subset
WM included
outcome not studied
Zhang
(2005)
RCT
Small study
Recruitment from
January 2002 to
December 2004
Randomized
100%
completed
Short term: adverse

Long term: no
RCT
High
compliance
Small sample size

Baseline unclear
not reported
Allocation method was
not reported
Combined TCM and WM
as subset
outcome not studied
No long-term follow ups
Zhang
et al.
(2000)
RCT
Large study
Recruitment: not
reported
Randomized by
random table
100%
completed
Short term:
Long term: perinatal
outcomes only
RCT
Large sample
size
High
compliance
Baseline
comparable
Long-term
follow-up

reported
reported
TCM and WM included
outcome not studied
No pregnancy outcomes
Yang
(1992)
RCT
Large study
Recruitment: not
reported
Randomized
100%
completed
Short term: no
outcomes only
RCT
Large sample
size
High
compliance
Long-term
follow-up

reported
not reported
reported
Baseline unclear
WM included
No short-term follow-up
Song and
Zhu
(2007)
Quasi-RCT
Small study
Recruitment from
October 2005 to
August 2006
Randomized by
visiting date
100%
completed
Short term: adverse

outcomes only
RCT
High
compliance
Baseline
comparable
Long-term
follow-up
Small sample size

reported
reported
WM included
Continued
Li (2006)
514
Li et al.
Table II Continued
Study
Design
Quality
scorea
Summary
Compliance
Follow-upb
Strength
Weakness
.............................................................................................................................................................................................
Controlled
Trial
Small study
Recruitment from
January 1997 to May
2003
100%
completed
Short term:
High
compliance
Long-term
follow-up
Small sample size

Baseline unclear
Combined TCM and WM
as subset
reported
not reported
reported
TCM and WM studied
outcome not studied
Gong and
Chen
(1993)
Controlled
Trial
Small study
Recruitment: not
reported
100%
completed
Short term:
Long term: no
High
compliance
Small sample size

reported
Baseline unclear
not reported
reported
Combined TCM and WM
as subset
WM included
outcome not studied
No long-term follow-up
Gu et al.
(2008)
Case series
Small study
Recruitment from
June to December
2006
Prospective study
100%
completed
Short term: adverse

Long term: no
High
compliance
Low quality
Small sample size
reported
No control
outcome not studied
Xu (2008)
Case series
Small study
Recruitment from
2000 to 2006
Prospective study
100%
completed
Short term:
outcomes only
High
compliance
Long-term
follow-up
Low quality
Small sample size
reported
trimesters
No control
outcome not studied
Continued
Zhou
(2006)
515
Table II Continued
Study
Design
Quality
scorea
Summary
Compliance
Follow-upb
Strength
Weakness
.............................................................................................................................................................................................
Case series
Small study
Recruitment from
March 2000 to April
2006
Prospective study
100%
completed
Short term:
outcomes only
High
compliance
Long-term
follow-up
Low quality
Small sample size
reported
No control
outcome not studied
Luo et al.
(2007)
Case series
Small study
Recruitment from
September 2004 to
December 2006
Prospective study
100%
completed
Short term:
High
compliance
Long-term
follow-up
Low quality
Small sample size
reported
trimesters
No control
outcome not studied
Chou
(2002)
Case series
Small study
Recruitment from
1981 to 2001
Prospective study
100%
completed
Short term:
Long term: pregnant
No exclusion
Long-term
follow-up
Low quality
Small sample size
Allocation method was
not reported
Baseline unclear
TCM included
No control
Prolonged treatment
outcome not studied
Chen
et al.
(2001)
Case series
Large study
Recruitment from
March to September
2000
Prospective study
100%
completed
Short term: adverse

Long term: no
Large sample
size
High
compliance
Low quality
reported
Baseline unclear
No control
Xu (2001)
Case series
Small study
Recruitment: not
reported
Prospective study
100%
completed
Short term:
outcomes only
High
compliance
Long-term
follow-up
Low quality
Small sample size
reported
No control
outcome not studied
Continued
Ye and
Qiu
(2008)
516
Li et al.
Table II Continued
Study
Design
Quality
scorea
Summary
Compliance
Follow-upb
Strength
Weakness
.............................................................................................................................................................................................
Case series
Small study
Recruitment: not
reported
Prospective study
100%
completed
Short term:
High
compliance
Long-term
follow-up
Low quality
Small sample size
reported
Exclusion unclear
trimesters
No control
outcome not studied
Chen and
Yun
(1999)
Case series
Small study
Recruitment from
1995 to 1997
Prospective study
100%
completed
Short term:
High
compliance
Long-term
follow-up
Low quality
Small sample size
reported
No control
outcome not studied
Cui
(1998)
Case series
Small study
Recruitment: not
reported
Prospective study
100%
completed
Short term:
High
compliance
Long-term
follow-up
Low quality
Small sample size
Baseline unclear
reported
No control
outcome not studied
Kang et al.
(1998)
Case series
Small study
Recruitment from
January 1993 to
December 1997
Prospective study
100%
completed
Short term:
High
compliance
Long-term
follow-up
Low quality
Small sample size
reported
trimesters
No control
outcome not studied
Chen
(1997)
Case series
Small study
Recruitment: not
reported
Prospective study
100%
completed
Short term:
outcomes only
High
compliance
Long-term
follow-up
Low quality
Small sample size
Baseline unclear
reported
No control
outcome not studied
Continued
Wang and
Li (2000)
517
Table II Continued
Study
Design
Quality
scorea
Summary
Compliance
Follow-upb
Strength
Weakness
.............................................................................................................................................................................................
Case series
Small study
Recruitment from
1989 to 1993
Prospective study
100%
completed
Shortterm: intervention
failure only
outcomes only
High
compliance
Long-term
follow-up
Low quality
Small sample size
reported
No control
outcome not studied
Zhou
(1997)
Case series
Large study
Recruitment from
January 1988 to
December 1994
Prospective study
100%
completed
Short term:
Large sample
size
High
compliance
Long-term
follow-up
Low quality
reported
No control
Combined TCM and WM
outcome not studied
Wu and Ji
(1994)
Case series
Small study
Recruitment from
December 1990 to
May 1994
Prospective study
100%
completed
Short term: adverse

Long term: no
High
compliance
Low quality
Small sample size
reported
No control
Prolonged treatment
outcome not studied
Zhu and Li
(1992)
Case series
Small study
Recruitment from
April 1987 to April
1988
Prospective study
100%
completed
Short term:
High
compliance
Long-term
follow-up
Low quality
Small sample size
reported
No control
outcome not studied
Tian and
Li (1991)
Case series
Small study
Recruitment from
October 1988 to May
1990
Prospective study
100%
completed
Short term:
High
compliance
Long-term
follow-up
Low quality
Small sample size
Mixed early and late
gestation
reported
No control
outcome not studied
Li (1989)
Case series
Small study
Recruitment from
1985 to 1987
Prospective study
100%
completed
Short term:
outcomes only
High
compliance
Long-term
follow-up
Low quality
Small sample size
reported
No control
outcome not studied
No perinatal outcomes
Continued
He (1997)
518
Li et al.
Table II Continued
Study
Design
Quality
scorea
Summary
Compliance
Follow-upb
Strength
Weakness
.............................................................................................................................................................................................
Case series
Small study
Recruitment from
1983 to 1987
Prospective study
100%
completed
Short term:
outcomes only
High
compliance
Long-term
follow-up
Low quality
Small sample size
trimesters
Combined TCM and WM
as subset
reported
No control
outcome not studied
No perinatal outcomes
Wu
(1987)
Case series
Small study
Recruitment date not
reported
Prospective study
100%
completed
Short term:
outcomes only
High
compliance
Long-term
follow-up
Low quality
Small sample size
reported
Baseline unclear
No control
outcome not studied
RCT, randomized controlled trial.

a
Quality score: total score obtained from the quality assessment according to Newcastle Ottawa Quality Assessment Scale (see Supplementary data, Table SIV). Short-term follow-up
include adverse effects and toxicity during intervention or intervention failure and outcomes; long-term follow-up include adverse pregnancy or perinatal outcomes.
b
Parameters and durations of the long-term and short-term follow-up are available in Supplementary data, Table SV.
2009). In addition, the dosage of the Chinese medicines varied from

the smallest 2 g in one pack per day (Song and Zhu, 2007) to the
largest 30 g in one pack per day (Li et al., 2006). The course of the
regimes ranged from 7 days (Wu and Ji, 1994; Song and Zhu, 2007)
up to term delivery (Wu and Ji, 1994; Chou, 2002), but seven
studies did not report the duration of interventions (Wu, 1987; Tian
and Li, 1991; Yang, 1992; Zhu and Li, 1992; Chen, 1997; Zhou,
1997; Chen and Yun, 1999). For the pharmaceuticals used in RCTs,
quasi-RCT and controlled trials, progesterone was commonly used together with Vitamin E for a week (Zhang et al., 2000; Li et al., 2006;
Song and Zhu, 2007; Teng and Wu, 2008; Zhao et al., 2008, 2010;
Yue et al., 2009) or HCG for 1 2 weeks (Zhang et al., 2005; Zhou,
2006). All studies reported 100% compliance to complete the interventions, except Teng & Wus study (Teng and Wu, 2008) (Table II).
Baseline, exclusion and follow-up

The number of participants in most studies was ,100 (Table I and
Supplementary data, Table SIII), only 5 studies included .200 subjects
(Yang, 1992; Zhou, 1997; Chen et al., 2001; Zhang et al., 2000; He
and Che, 2007) and 2 studies included .300 subjects (Zhou, 1997;
Zhang et al., 2000). The gestational age of participants in most
studies was ,12 weeks of pregnancy, but eight studies included pregnancies from 12 to 20 weeks (Li, 1989; Tian and Li, 1991; Kang et al.,
1998; Wang and Li, 2000; Luo et al., 2007; Gu et al., 2008; Xu, 2008;
Yue et al., 2009), two studies included up to gestational 30 weeks
(Zhang et al., 2000; He and Che, 2007) and six studies did not
report the details (Wu, 1987; Yang, 1992; Chen, 1997; Cui, 1998;
Chou, 2002; Zhou, 2006). Only 11 studies clearly excluded ectopic
pregnancy, molar pregnancy, uterine abnormalities or other medical
complications in the subject recruitment (Tian and Li, 1991; Chen,
1997; Cui, 1998; Kang et al., 1998; Chen et al., 2001; Zhang et al.,
2005; Li et al., 2006; Song and Zhu, 2007; Teng and Wu, 2008;
Zhao et al., 2008; Yue et al., 2009). In the other 21 studies, 11 did
not report the exclusion criteria (Zhu and Li, 1992; Wu and Ji,
1994; Chen and Yun, 1999; He, 1997; Zhou, 1997, 2006; Wang
and Li, 2000; Zhang et al., 2000; Xu, 2001; Chou, 2002; Luo et al.,
2007), while the other 10 studies did not provide any information
(Wang and Wang, 1987; Wu, 1987; Li, 1989; Yang, 1992; Gong
and Chen, 1993; He and Che, 2007; Gu et al., 2008; Xu, 2008; Ye
and Qiu, 2008; Zhao et al., 2008). Short-term and long-term
outcome measures were both included in most studies, except two
studies did not measure short-term outcomes (Yang, 1992; Zhao
et al., 2008), while six studies did not measure long-term outcomes
(Gong and Chen, 1993; Wu and Ji, 1994; Chen et al., 2001; Zhang
et al., 2005; Gu et al., 2008). For short-term outcomes, most
studies followed-up the subjects immediately or up to 2 weeks after
interventions. For long-term outcomes, most studies followed-up
Wang and
Wang
(1987)
519
the subjects around a month after intervention or until delivery,

except for seven studies which prolonged the follow-up to years
after delivery (Yang, 1992; Zhu and Li, 1992; He, 1997; Wang and
Li, 2000; Zhang et al., 2000; Xu, 2001, 2008).
Adverse outcomes
In these 32 selected trials, the reported adverse outcomes included
the adverse effects and toxicity of Chinese medicines, failure and complications of the intervention, adverse pregnancy outcomes and
adverse perinatal outcomes. Owing to the substantial diversity of
the selected studies with respect to quality, methodology, intervention
variations, sample characteristics and outcome reporting, only a few
studies meet the requirements for the planned quantitative data synthesis, comparing the adverse outcomes by meta-analysis. We also
provided a qualitative data synthesis, presenting the major results of
the studies in the text and summary tables.
In most studies, adverse effects and toxicity of the Chinese medicines

as one of the short-term outcome measures were not studied
(Table I). Only 2 RCT studies with 130 participants (Zhang et al.,
2005; Teng and Wu, 2008) reported adverse effects and toxicity of
combined Chinese and Western medicines or Chinese medicines
alone, but not Western medicines alone. No adverse effects were
reported under combined medicines, but minor adverse effects
were observed in 28% of women with Chinese medicine alone
treatment. The effects included dry mouth, constipation and insomnia.
No adverse effects and toxicity were identied in the quasi-RCT in
either intervention (Song and Zhu, 2007). The controlled trials did
not report adverse effects and toxicity after interventions (Gong and
Chen, 1993; Zhou, 2006). No meta-analysis was performed.
Two case series reported no adverse effect and toxicity after
Chinese medicines treatment (Wu and Ji, 1994; Gu et al., 2008).
Only one case series identied 0.9 3.9% of some gastrointestinal
effects, including nausea, dry mouth, anorexia and constipation
(Chen et al., 2001).
Failure of the intervention and complications

Two RCTs (Zhang et al., 2000; Zhang et al., 2005) and 1 quasi-RCT
(Song and Zhu, 2007) with 778 participants compared Chinese medicines alone with Western medicines alone. Failure of Chinese medicine treatment occurred in 3.1 18.5%, while failure of Western
medicine treatment occurred in 15 56.9%; however, none reported
the details of the complications of threatened miscarriage after the
failure. In these three studies, there was signicant heterogeneity
(x 2 20.46, df 2, I 2 90%, P , 0.0001), which indicated that the
magnitude of the effects among the studies was not consistent, or
the data might be at risk of allocation bias. Meta-analysis showed
that Chinese medicine alone resulted in no signicant difference in
intervention failures compared with Western medicine alone [relative
risk (RR) 0.24; 95% condence interval (CI): 0.06 1.00, I 2 90%,
random-effects model, evidence from three RCTs and quasi-RCTs,
Fig. 2a). Sensitivity analysis was carried out to explore the impact of
the quality of original trials, and the results showed no difference
whether the quasi-RCT study was included or not in the
meta-analysis.
Adverse pregnancy outcomes

Adverse pregnancy outcomes were only reported in ve RCT studies
(Li et al., 2006; He and Che, 2007; Zhao et al., 2008; Yue et al., 2009;
Zhao et al., 2010) and one controlled trial (Zhou, 2006). However,
the incidents were not described separately in either intervention
group in two RCT studies (Zhao et al., 2008, 2010) and in the
Western medicines group in another RCT study (Yue et al., 2009).
One RCT study (He and Che, 2007) and the controlled trial (Zhou,
2006) compared the adverse pregnancy outcomes in Chinese medicines alone and Western medicines alone; and the remaining one
RCT study compared the adverse pregnancy outcomes of combined
medicines and Western medicines alone (Li et al., 2006). The
adverse pregnancy outcomes included preterm labour (1.7 5%),
postdate delivery (1.7%) and diabetic pregnancy (3.7%). Results
from one RCT comparing Chinese medicines alone versus Western
medicines alone (He and Che, 2007) and one RCT comparing combined medicines versus Western medicines alone (Li et al., 2006) on
the adverse pregnancy outcome were not conclusive. Since insufcient
RCT studies were available for meta-analysis, controlled trials were
also included for further analysis. Meta-analysis of a single RCT
study (Li et al., 2006) and a single controlled trial (Zhou, 2006) on
the adverse pregnancy outcome of Chinese medicines alone and
Western medicines alone (RR 1.65, 95% CI: 0.22 12.07, I 2 0%,
xed-effect model, evidence from 1 RCT and 1 controlled trial,
Fig. 2b) or combined medicines and Western medicines alone
(Fig. 2b) could not be conclusive.
Adverse effects and toxicity of Chinese medicines
Five RCTs studies (Zhang et al., 2005; Li et al., 2006; He and Che,
2007; Teng and Wu, 2008; Yue et al., 2009) with 482 participants
compared combined medicines with Western medicines. Failure of
combined treatment occurred in 7 22.3%, while failure of Western
medicine treatment occurred in 15 31%; however, no details of the
complications of threatened miscarriage were available. In these ve
studies, there was no signicant heterogeneity (x 2 2.86, df 4,
I 2 0%, P 0.58). Meta-analysis showed the incidence of intervention failure in combined medicines was signicantly lower than that
in Western medicines alone (RR 0.46; 95% CI: 0.30 0.70, I 2
0%, xed-effect model, evidence from 5 RCTs and quasi-RCTs,
Fig. 2a).
Two controlled trials (Gong and Chen, 1993; Zhou, 2006) with 115
participants compared combined medicines, Chinese medicines alone
and Western medicines alone. The incidences of intervention failure
were recorded as 010.4, 5 16.6 and 30 33%, respectively. In
these two studies, there were no signicant heterogeneity in either
comparison (x 2 0.77 1.20, df 1, I 2 017%, P 0.27 0.38).
Meta-analysis showed that there was no signicant difference
between Chinese medicines alone and Western medicines alone
interventions (RR 0.30; 95% CI: 0.09 0.99, I 2 0%, xed-effect
model, evidence from two controlled trials, Fig. 2a) or between combined medicines and Western medicines alone interventions (RR
0.21; 95% CI: 0.06 0.67, I 2 17%, xed-effect model, evidence
from two controlled trials, Fig. 2a).
Twenty case series with 1532 participants studied Chinese medicines alone. Chinese medicines intervention failed to improve miscarriage symptoms and prevent miscarriage in 220% cases; however,
their clinical outcomes after the intervention failure had not been followed at all.
520
Li et al.
Figure 2 Adverse outcomes of Chinese medicines for threatened miscarriage. (A) Outcome: failure of the interventions. Study design: RCT and
quasi-RCT . (B) Outcome: failure of the intervention. Study design: controlled trials. (C) Outcome: adverse pregnancy outcomes. Study design: RCT
and controlled trials.
521
Most case series did not report adverse pregnancy outcomes. Only
seven cases series reported no adverse pregnancy outcome after
Chinese medicine treatment (Wang and Wang, 1987; Li, 1989; Zhu
and Li, 1992; Kang et al., 1998; Chen and Yun, 1999; Wang and Li,
2000; Chou, 2002). Another four case series identied adverse pregnancy outcomes after Chinese medicine treatment (Tian and Li, 1991;
Zhou, 1997; Cui, 1998; Luo et al., 2007). Preterm deliveries were also
identied in three case series (Zhou, 1997; Cui, 1998; Luo et al., 2007)
in 0.7 6.4%. Other adverse maternal outcomes were identied in two
case series, including premature rupture of membranes in 2.1% in one
case series (Cui, 1998) and stillbirths in 2.9% in other case series (Tian
and Li, 1991).
Adverse perinatal outcomes
Discussion
Summary of evidence
In this review, adverse events of Chinese medicines for threatened
miscarriage, including adverse effects or toxicity, failure of intervention, adverse pregnancy and perinatal outcomes, were studied. Data
were pooled from studies that were clinically very heterogeneous;
there were large differences across studies in study design, interventions and outcome measures. Furthermore, data were often statistically herterogeneous as reected by an I 2 value .50%. As a
consequence the results presented should be considered with care.
Meta-analysis demonstrated that intervention failure was signicantly
lower in the combined Chinese medicines groups than in the
Western medicines controls. No signicant differences were found
Limitations
Very few clinical studies of Chinese medicines for threatened miscarriage were eligible for this review. Over 90% of the identied studies
did not include adverse effects as one of the study outcome measures.
It may be because the incidence of adverse events was indeed too rare
or because the awareness on the adverse effects was actually too low.
In our qualitative analysis, a low rate of adverse events after maternal
exposure to Chinese medicines for threatened miscarriage was
recorded, but the incidences were not too low to be easily missed.
Hence, lack of awareness on the safety issue of Chinese medicines
in general could be the main reason of limited studies being available
for systematic review.
Apart from limited records in adverse outcomes, study designs
were also restricted. No RCTs were placebo controlled and one
RCT had non-placebo controls (Yang, 1992). Of the RCTs, only
two were adequately randomized, while the other RCTs only mentioned with participants were randomly received different treatments. The quasi-RCT used an inadequate randomization method
Adverse perinatal outcomes were reported in seven RCT studies

(Yang, 1992; Zhang et al., 2000; Li et al., 2006; He and Che, 2007;
Zhao et al., 2008, 2010; Yue et al., 2009), one quasi-RCT study
(Song and Zhu, 2007) and one controlled trial (Zhou, 2006).
However, the incidents were not described in the control group in
three RCT studies (Zhang et al., 2000; Zhao et al., 2008; Yue et al.,
2009). In four RCT and one quasi-RCT studies (Li et al., 2006; He
and Che, 2007; Song and Zhu, 2007; Zhao et al., 2008, 2010), no
adverse perinatal outcomes were identied in either intervention
group. No meta-analysis was performed. Neurodevelopmental morbidity was conrmed in one RCT study (Yang, 1992), the incidence
was 1.8 and 7.4% with Chinese medicines alone and with Western
medicines alone, respectively. Neonatal death due to prematurity
was identied in the controlled study (Zhou, 2006), the incident
was 5% in the combined medicines group, but not in the Chinese
medicines alone and Western medicines alone groups.
Most case series reported adverse perinatal outcomes after
Chinese medicines treatment, except ve case series (Wang and
Wang, 1987; Li, 1989; Wu and Ji, 1994; Chen et al., 2001; Gu
et al., 2008). No adverse perinatal outcomes were reported in the
11 case series, but neonatal death due to prematurity, asphyxia or infection were identied in three case series with an incidence rate
ranging from 0.7 to 6.4% (Wu, 1987; Zhou, 1997; Cui, 1998), while
an unspecied malformation was recorded in one case series with
an incidence rate of 0.9% (Chou, 2002) and epilepsy and abnormal intellectual development in one case series with an incidence rate of
0.3% (Zhou, 1997).
in adverse effects and toxicity, or in adverse pregnancy and perinatal

outcomes.
This review identied the adverse maternal and perinatal outcome
of Chinese medicines for threatened miscarriage. Preterm premature
rupture of membranes (PPROM) was recorded in a study with incidence of 2.1%. Prematurity and associated neonatal mortality were
recorded in several studies with an incidence ranging from 0.7 to
6.4%. It is well known that threatened miscarriage is associated with
the risk of suboptimal pregnancy outcome (van Oppenraaij et al.,
2009; Saraswat et al., 2010). Women with threatened miscarriage
have a signicantly higher incidence of antepartum haemorrhage
(overall 1.2%). They are also more likely to experience PPROM
(overall 1.9%), preterm delivery (overall 11.0%) and to have babies
with an intrauterine growth restriction (overall 8.3%). First-trimester
bleeding is also associated with signicantly higher rates of perinatal
mortality (overall 1.8%) and low and/or very low birthweight babies
(overall 11.0%, odd ratios . 2.0). In comparison, after treatment of
threatened miscarriage with Chinese medicines, no antepartum haemorrhage, intrauterine growth restriction or low birthweights were
recorded and the prematurity rate was relatively lower, but the
PPROM rate was slightly higher. The neonatal death rate due to prematurity with respect to rst trimester bleeding is 2.68.5% (Williams et al., 1991), which is comparable to our current review.
These results suggest that Chinese medicines treatment for threatened miscarriage may not be associated with an increased risk of
preterm delivery and neonatal mortality.
On the other hand, malformations were reported in 0.9% of babies
whose mothers had taken Chinese medicines for threatened miscarriage. Unfortunately, the details of the malformations were not specied. Although at least half of threatened miscarriages are associated
with chromosomal anomalies of the conceptus, the risk of birth
defects does not appear to be increased signicantly. The overall incidence rates of congenital anomalies in women with and without
vaginal bleeding in rst trimester are 3.2 and 2.7%, respectively (Saraswat et al., 2010). The results suggest that Chinese medicines for
threatened miscarriage may not be associated with increased risk of
congenital malformation.
522
by visiting date. All 20 case series studies had no controls for comparison, allocation methods were not described and their quality
scores were not high. Furthermore, the study results were questionable. Though all the studies had high compliance and drop-out rates
were not high, sample sizes of the selected studies were still very
small. Some important demographic data and study exclusion criteria
were not provided. Different studies used different Chinese medicine
formulae to treat threatened miscarriage and also there were large
variations in the dose, dosing and duration of the intervention
amongst the studies. Most studies followed-up the pregnancy until delivery, but the outcome parameters in the pregnancy and perinatal
complications were rather inconsistent. Few studies monitored
adverse effects and toxicity of Chinese medicines, and complication
of miscarriage was unknown. Owing to the limited number of RCTs
and the clinical heterogeneity between studies, additional metaanalysis to evaluate the adverse effects of Chinese medicine for threatened miscarriage was not available.
Li et al.
Difculties
Unlike Western herbalism, Chinese medicines include many animal
materials and even mineraloid remedies as well as medicinal herbs
(National Phamacopoeia Committee, 2005). In addition, Chinese
medicines are formulated and individualized. A typical formula may
contain 325 Chinese medicines. Most of the formula are processed
by decoction in boiling water for hours and are orally administered as a
soup (Scheid, 2002), though it can be supplied as powders, soluble
granules and tablets nowadays. As each Chinese medicine has its
own properties and potential interactions, the application of formulized and individualized medication enhance the therapeutic actions
of some herbs and all the herbs collaborate in each other for the treatment. However, the adverse effects and toxicity of Chinese medicines
may vary in different combinations, preparations and individuals. It is
difcult to identify which Chinese medicine contributes to a specic
adverse effect.
Conclusions and recommendations

This is the rst systematic review to evaluate the clinical studies of
Chinese medicines for threatened miscarriages in identifying their potential adverse effects on mothers and fetuses. Unfortunately, the evidence regarding the use of Chinese medicines for threatened
miscarriage on adverse effects/toxicity, and adverse pregnancy and
perinatal outcomes, is limited. Studies vary considerably in design,
interventions and outcome measures; therefore, conclusive results
remain elusive. Rigorous scientic and clinical studies are necessary
to conrm the risk of Chinese medicines.
The active ingredients of the Chinese medicines are also chemicals
that are similar to prescription pharmaceuticals. Chinese medicines
are not free of risk; similar to Western pharmaceutical medicines,
they have the potential to cause adverse effects. Thus, Chinese medicines in Traditional Chinese Medicine may not only result in maternal
manifestations that indirectly affect fetal health, but they may also
harm the fetus directly. Despite variations in clinical practice and
therapeutic prescription, Chinese medication in Traditional Chinese
Medicine should comply with the same modern pharmacological principles as Western Medicine. Chinese medicines may be benecial, but
may also adversely affect both mothers and fetuses in utero.
Supplementary data
Supplementary data are available at http://humupd.oxfordjournals.
org/.
Authors roles
L.L. and L.X.D. are responsible as rst and second assessors for study
identication, screening, eligibility and inclusion, data acquisition and
statistical analysis and drafting of the manuscript. C.C.W. is responsible as third assessor for study eligibility and inclusion, conception
of the project, design of the study, research funding and drafting the
manuscript. J.P.N. and P.C.L. were responsible for interpreting the
results and approving the nal manuscript.
Funding
The study is partially supported by the Health and Health Service Research Grant from Food and Health Bureau, Hong Kong Special Administration Region (HHSRF 06070511 and 10110901) to C.C.W.
and P.C.L. L.L received the Hop Wai Scholarship and Zi Ying Scholarship from the Institute of Chinese Culture and Postgraduate Student
Grants for Overseas Academic Activities from the Graduate School,
The Chinese University of Hong Kong to attend Cochrane training
workshops in Oxford and Freiburg and to study in the Cochrane Pregnancy and Childbirth Group at University of Liverpool and the Yu To
Sang Memorial Scholarship 2008/2009 and 2009/2010 from the
Chinese University of Hong Kong to pursue her PhD study.
Conict of interest
None.
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Human Reproduction Update, Vol.18, No.5 pp.

504 524, 2012

Adverse outcomes of Chinese

*Correspondence address. Tel: +852-2632-2810; Fax: +852-2636-0008; E-mail: ccwang@cuhk.edu.hk

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Chinese medicines for threatened miscarriage

Chinese medicines for threatened

prepared drugs in slices, patent medicines and simple preparations),

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Materials and Methods

of review articles and eligible studies were hand searched to identify

Two co-authors (L.L. and L.X.D.) independently extracted data from a

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Chinese medicines for threatened miscarriage

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Figure 1 Study exclusion and inclusion.

Study designs and methods

Table I Summary of study characteristics and adverse events.

Combined TCM and

Combined TCM and

Combined TCM and

Combined TCM and

Combined TCM and

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Chinese medicines for threatened miscarriage

Formula: STP + SXP

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Chinese medicines for threatened miscarriage

Combined TCM and

Chinese medicines, type and compliance

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Table II Summary of study qualities.

Small sample size

Small sample size

Short term: adverse

Small sample size

Small sample size

Power calculation not

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Chinese medicines for threatened miscarriage

Small sample size

Short term: adverse

Small sample size

Power calculation not

Power calculation not

Short term: adverse

Small sample size

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Small sample size

Small sample size

Short term: adverse

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Chinese medicines for threatened miscarriage

Short term: adverse

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Chinese medicines for threatened miscarriage

Short term: adverse

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RCT, randomized controlled trial.

2009). In addition, the dosage of the Chinese medicines varied from

Baseline, exclusion and follow-up

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