Chinese herbal medicines for unexplained recurrent miscarriage

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the effectiveness and safety of Chinese herbal medicines for the treatment of unexplained recurrent miscarriage.

Background

Description of the condition

Recurrent miscarriage has been defined as three or more consecutive spontaneous miscarriages in early pregnancy (Cunningham 2010). It affects 1% to 3% of women of reproductive age. Some experts have suggested that two consecutive pregnancy losses are sufficient to define recurrent miscarriage (Branch 2010; Kiwi 2006), because the risk of subsequent loss after two is similar to that following three (Cunningham 2010). Most recurrent miscarriages occur before the 10th week of gestation and around the same gestational week in subsequent miscarriages. However, most pregnant women may not recognise a miscarriage until uterine bleeding and cramping occurs after the 10th week of pregnancy (Wilcox 1988). The risk of repeat miscarriage after one or more pregnancy losses is still unknown. The chance of having a successful pregnancy varies (Brigham 1999). The best available data suggest that pregnancy rate after one miscarriage is about 85% (Love 2010), and it significantly decreases to 70% after two miscarriages but remains approximately the same (70% to 67%) after three miscarriages (Ford 2009).

Major causes of recurrent miscarriage

The aetiology of recurrent miscarriage remains elusive; both maternal and fetal factors may contribute to the causes (ASRM 2008). The identified causes include chromosomal anomalies, mostly translocations (Therapel 1985) and aneuploidy (ACOG 2001); anatomical defects, including uterine and cervical abnormalities (Salim 2003); ovarian factors, including reduced ovarian reserve and luteal phase defect (ACOG 2001); endocrinological factors (Arredondo 2006), including thyroid disease, progesterone deficiency, polycystic ovarian syndrome, diabetes mellitus, and hypothyroidism; immunological factors (Yetman 1996), including autoimmune and alloimmune factors; and inherited thrombophilia or abnormal clotting factor (ACOG 2001). Timing of the pregnancy losses may provide a clue to the underlying cause. For instance, genetic factors most frequently result in first-trimester losses, whereas autoimmune and anatomical abnormalities more likely result in second-trimester losses (Schust 2002). Unfortunately, the underlying cause of more than 50% of recurrent miscarriages cannot be identified and they are classified as unexplained recurrent miscarriage. Infection has been associated with recurrent pregnancy loss, though the role of infection is still unclear. Physical or emotional trauma, such as depression (Sugiura-Ogasawara 2002), may lead to recurrent miscarriage. Advanced maternal age, history of previous miscarriages, habits such as smoking, caffeine, alcohol, drug abuse, and environmental toxin exposure all increase the risk of recurrent miscarriage (ACOG 2001; Lyttleton 2004). Nevertheless, paternal age and increased DNA damage in sperm may also contribute to recurrent miscarriage (Vagnini 2007).

Current treatment

For recurrent miscarriage with known cause, empirical treatments targeting the underlying cause are effective. However, there is no universal recommendation for treatment of unexplained recurrent miscarriage. If undetected or untreated, the affected women with an initial pregnancy loss are at increased risk not only of another miscarriage (Hathout 1982), but also of complications in the subsequent pregnancy, including preterm birth, induced labour, postpartum haemorrhage and maternal distress (Bhattacharya 2008). Empirical treatments include weight reduction, caffeine avoidance (Christiansen 2005; van den Boogaard 2010), stress reduction (Craig 2001; Li 2012b), antenatal counselling and psychological support (Musters 2011a), folic acid and vitamin B supplements (Nadir 2007; Sikora 2007), progesterone (Sonntag 2012; Watanabe 2012) and low-dose aspirin (Alalaf 2012; Robinson 2010; Tan 2012). To avoid recurrent causes, pre-implantation genetic diagnosis (Musters 2011b), heparin, metformin (Tan 2012) and immunotherapy (Bansal 2012) have been applied successfully, whereas leucocyte immunisation (Szekeres-Bartho 2009) and immunoglobulin (IVIG) therapy (Kotlan 2009) have not proven to be beneficial.

Description of the intervention

Traditional Chinese medicine employs a range of unique clinical practices to maintain health, which include acupuncture (inserting fine needles into specific points namely acupuncture points (acupoints) on the body), moxibustion (burning dried Mugwort on the acupoints in conjunction with acupuncture), food therapy (individualising 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). 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. Chinese medicine is a common name for Chinese Materia Medica, which has therapeutic properties for medical treatment and healing. It is considered as a primary modality of internal medicine in Traditional Chinese medicine.

Chinese medicines have been applied to pregnancy for more than 3000 years (Ma 2006). Chinese medicines are products mostly made of or from plants, namely Chinese herbal medicines. Chinese herbal medicines are principally used in China and some Asian countries, and have become popular worldwide to promote both mothers' and fetuses' health and treat common pregnancy disorders and complications, including recurrent miscarriage (Li 2012a). For recurrent miscarriage, Chinese herbal medicines can improve pregnancy and live birth rate by preventing inevitable miscarriage and promoting the continuation of pregnancy. Some classical Chinese herbal medicine formulae are for example BuShen GuChong Pill (Deng 1971), Taishan Panshi San (Zhang 1959) and Liang Di Soup (Fu 1978). In recent decades, new formulae have also been developed to improve effectiveness and reduce side effects, for example Bushen Gutai San, Jisheng Peiyu Soup, An Tai Pill, San Qing Decoction and Huoxue Huayu Soup (He 2010). Chinese herbal medicines have also been commonly applied as complementary to Western medicines in the treatment of recurrent miscarriage (Erman 2011).

How the intervention might work

Unlike Western medicine, Chinese medicine has a unified clinical theory in diagnosis and treatment of recurrent miscarriage. "Qi" and "Blood" are the two basic elements in the pathology of recurrent miscarriage (Ma 2006). "Qi" is equivalent to vital energy. "Blood" is sustenance of the body. The common causes of recurrent miscarriage in Chinese Medicine are "Qi" deficiency in "Kidney" or combined "Qi" and "Blood" deficiency (Ma 2006). "Kidney" is responsible for growth, development and reproduction as it stores the essential "Qi" that warms and activates all the other systems in the body (Li 2005). With sufficient "Qi" and "Blood" in "Kidney", the womb will be a warm, safe and comfortable environment where an embryo or fetus could survive and develop. When "Qi" and/or "Blood" are insufficient, the embryo or fetus can not be sustained and is subsequently miscarried.

The principle of Chinese medicines to treat recurrent miscarriage is to correct the deficiency. Chinese herbal medicines such as Radix Codonopsis Pilosulae (Szechwon Tangshen Root), Rhizoma Atractylodis Macrocephala (Largeheaded Atractylodes Rhizome) and Radix Rehmanniae (Preserved Rehmania Root) are commonly used to correct "Qi" and "Blood" deficiency (He 2010; Ma 2006; Zhang 1959). Chinese herbal medicines are combined as formulae to enhance the therapeutic functions of individual herbs and which as a result, work together to create a more harmonious effect on the body for systemic treatment (Ma 2006; Zhang 1959).

Why it is important to do this review

So far, modern therapies have limited effectiveness in preventing and treating early pregnancy loss due to recurrent miscarriage. Chinese herbal medicines have been traditionally used to prevent recurrent miscarriage in Asian countries for centuries and have become an alternative medicine in Western countries in recent years. Many clinical trials have been carried out to assess the therapeutic effects of Chinese herbal medicines as the prevention and treatment of recurrent miscarriage. A list of commonly used Chinese herbal medicines as treatment for recurrent miscarriage is given (Appendix 1). Despite its wide application, there are at present no systematic reviews evaluating the efficacy of Chinese herbal medicines for recurrent pregnancy loss.

Objectives

To assess the effectiveness and safety of Chinese herbal medicines for the treatment of unexplained recurrent miscarriage.

Methods

Criteria for considering studies for this review

Types of studies

Randomised and quasi-randomised controlled trials, as well as cluster-randomised trials, comparing Chinese herbal medicines (alone or combined with other intervention or other pharmaceuticals) with placebo, no treatment, other intervention (including bed rest and psychological supports) or other pharmaceuticals as treatments for recurrent miscarriage. Trials, with or without full text, will be included. No language restrictions will be applied.

Types of participants

All pregnant women diagnosed with unexplained recurrent miscarriage, regardless of maternal age, gestational age and parity, will be studied. In this review, the criteria for recurrent miscarriage will be considered as two or more consecutive spontaneous miscarriages before the 20th week of gestation. No treatment will be given before interventions. In this review, only recurrent miscarriage with unknown underlined causes will be studied. Trials involving women with recurrent miscarriage with identified causes will be excluded. Any studies in which prior miscarriages at ≧ 14 weeks are included and which cannot be separated from first trimester miscarriages will be excluded, as only a minority of embryonic or fetal losses are after 14 weeks.

Types of interventions

All types of Chinese herbal medicines either standalone or in combination with other treatment for recurrent miscarriage, regardless of the dose, dosing or duration of administration, compared with other treatments will be compared. The following comparisons will be studied.

  • Chinese herbal medicines versus placebo.

  • Chinese herbal medicines versus no treatment.

  • Chinese herbal medicines versus other intervention (including bed rest and psychological supports).

  • Chinese herbal medicines alone versus other pharmaceuticals (mainly Western medicines).

  • Combined Chinese herbal medicines and other pharmaceuticals versus other pharmaceuticals (mainly Western medicines).

Types of outcome measures

Primary outcomes

(1) Effectiveness of intervention:

  • pregnancy rate;

  • live birth rate.

Pregnancy rate will be defined as successful rate of continuation of pregnancy after 20 weeks of gestation after the treatment. It will be presented as the number of pregnancies alive after 20 weeks of gestation over the total number of participants as a percentage.

Live birth rate will be defined as successful rate of pregnancy with live birth after 28 weeks of gestation. It will be presented as the number of live birth after 28 weeks of gestation over the total number of participants as a percentage.

(2) Safety of intervention:

  • maternal adverse effect and toxicity rate;

  • perinatal adverse effect and toxicity rate.

Adverse effect and toxicity refer to harmful and undesired side-effects and/or toxic effects resulting from the treatment. Specific outcomes of maternal adverse effect and toxicity may include maternal death and all reported obstetric and other complications. The rate will be presented as the number of maternal adverse or toxic events over the total number of participants as a percentage.

Specific outcomes of perinatal adverse effect and toxicity may include perinatal death and all reported complications, premature infant and congenital malformations. The rate will be presented as the number of perinatal adverse or toxic events over the total number of newborns as a percentage.

Secondary outcomes
Mother

(3) Obstetric complications (haemorrhage, hypertension, etc).

(4) Other complications (e.g. dry mouth, gastrointestinal discomfort, etc).

Child

(5) Fetal death within 14 weeks.

(6) Fetal death after 14 weeks.

(7) Premature infant (< 37 weeks).

(8) Perinatal complications (small-for-gestational age: birthweight < 10th percentile for gestational age, intrauterine growth restriction, physiopathological jaundice, etc).

(9) Congenital malformations (e.g. limb anomaly such as polydactyly (congenital abnormality of having an extra finger), heart anomaly such as patent ductus arteriosus, nervous system anomaly for example, spina bifida, etc).

Search methods for identification of studies

Electronic searches

We will search the Cochrane Pregnancy and Childbirth Group’s Trials Register by contacting the Trials Search Co-ordinator.

The Cochrane Pregnancy and Childbirth Group’s Trials Register is maintained by the Trials Search Co-ordinator and contains trials identified from: 

  1. monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);

  2. weekly searches of MEDLINE;

  3. weekly searches of EMBASE;

  4. handsearches of 30 journals and the proceedings of major conferences;

  5. weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.

Details of the search strategies for CENTRAL, MEDLINE and EMBASE, the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service can be found in the ‘Specialized Register’ section within the editorial information about the Cochrane Pregnancy and Childbirth Group

Trials identified through the searching activities described above are each assigned to a review topic (or topics). The Trials Search Co-ordinator searches the register for each review using the topic list rather than keywords.   

In addition, we will search the following databases: EMBASE (1980 to current) ; Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to current) ; Chinese Biomedical Database (CBM) (1978 to current); China Journal Net (CJN) (1915 to current); China Journals Full-text Database (1915 to current); and WanFang Database (Chinese Ministry of Science & Technology) (1980 to current). See Appendix 2; Appendix 3 and Appendix 4 for search strategies.

Searching other resources

(1) References from published studies

We will search the reference lists of relevant trials and reviews identified. We will also screen bibliographies of all located articles for any unidentified articles.

(2) Unpublished literature

If necessary, we will contact the authors for more details about the published trials/ongoing trials and the pharmaceutical companies for more information of medicines/relevant products.

(3) Personal communications

We will contact organisations, individual experts working in the field, and medicinal herbs manufacturers in order to obtain additional references.

We will not apply any language restrictions.

Data collection and analysis

Selection of studies

Two review authors will independently assess for inclusion all the potential studies. We will resolve any disagreement through discussion or, if required, we will consult a third review author.

Data extraction and management

We will design a form to extract data. For eligible studies, two review authors will independently extract the data using the agreed form. We will resolve discrepancies through discussion or, if required, we will consult a third review author. We will enter data into Review Manager software (RevMan 2011) and check for accuracy.

When information regarding any of the above is unclear, we will attempt to contact authors of the original reports to provide further details.

Assessment of risk of bias in included studies

Two review authors will independently assess risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve any disagreement by discussion or by involving a third assessor.

(1) Random sequence generation (checking for possible selection bias)

We will describe for each included study the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.

We will assess the method as:

  • low risk of bias (any truly random process, e.g. random number table; computer random number generator);

  • high risk of bias (any non-random process, e.g. odd or even date of birth; hospital or clinic record number);

  • unclear risk of bias.

(2) Allocation concealment (checking for possible selection bias)

We will describe for each included study the method used to conceal allocation to interventions prior to assignment and will assess whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.

We will assess the methods as:

  • low risk of bias (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);

  • high risk of bias (open random allocation; unsealed or non-opaque envelopes; alternation; date of birth);

  • unclear risk of bias.

(3.1) Blinding of participants and personnel (checking for possible performance bias)

We will describe for each included study the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. We will consider that studies are at low risk of bias if they were blinded, or if we judge that the lack of blinding would be unlikely to affect results. We will assess blinding separately for different outcomes or classes of outcomes.

We will assess the methods as:

  • low, high or unclear risk of bias for participants;

  • low, high or unclear risk of bias for personnel.

(3.2) Blinding of outcome assessment (checking for possible detection bias)

We will describe for each included study the methods used, if any, to blind outcome assessors from knowledge of which intervention a participant received. We will assess blinding separately for different outcomes or classes of outcomes.

We will assess methods used to blind outcomes assessment as:

  • low, high or unclear risk of bias.

(4) Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data)

We will describe for each included study, and for each outcome or class of outcomes, the completeness of data including attrition and exclusions from the analysis. We will state whether attrition and exclusions were reported and the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information is reported, or can be supplied by the trial authors, we will re-include missing data in the analyses which we undertake.

We will assess methods as:

  • low risk of bias (e.g. no missing outcome data or less than 20% missing; missing outcome data balanced across groups);

  • high risk of bias (e.g. number or reasons for missing data imbalanced across groups; 'as treated' analysis done with substantial departure of intervention received from that assigned at randomisation);

  • unclear risk of bias.

(5) Selective reporting (checking for reporting bias)

We will describe for each included study how we investigated the possibility of selective outcome reporting bias and what we found.

We will assess the methods as:

  • low risk of bias (where it is clear that all of the study's pre-specified outcomes and all expected outcomes of interest to the review have been reported);

  • high risk of bias (where not all the study's pre-specified outcomes have been reported; one or more reported primary outcomes were not pre-specified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);

  • unclear risk of bias.

(6) Other bias (checking for bias due to problems not covered by (1) to (5) above)

We will describe for each included study any important concerns we have about other possible sources of bias.

We will assess whether each study was free of other problems that could put it at risk of bias:

  • low risk of other bias;

  • high risk of other bias;

  • unclear whether there is risk of other bias.

(7) Overall risk of bias

We will make explicit judgements about whether studies are at high risk of bias, according to the criteria given in the Cochrane Handbook (Higgins 2011). With reference to (1) to (6) above, we will assess the likely magnitude and direction of the bias and whether we consider it is likely to impact on the findings. We will explore the impact of the level of bias through undertaking sensitivity analyses - see Sensitivity analysis.

Measures of treatment effect

Dichotomous data

For dichotomous data, we will present results as summary risk ratio with 95% confidence intervals.

Continuous data

For continuous data, we will use the mean difference if outcomes are measured in the same way between trials. We will use the standardised mean difference to combine trials that measure the same outcome, but use different methods.

Unit of analysis issues

Cluster-randomised trials

We will include cluster-randomised trials in the analyses along with individually-randomised trials. We will adjust their sample sizes using the methods described in the Cochrane Handbook (Higgins 2011) using an estimate of the intracluster correlation co-efficient (ICC) derived from the trial (if possible), from a similar trial or from a study of a similar population. If we use ICCs from other sources, we will report this and conduct sensitivity analyses to investigate the effect of variation in the ICC. If we identify both cluster-randomised trials and individually-randomised trials, we plan to synthesise the relevant information. We will consider it reasonable to combine the results from both if there is little heterogeneity between the study designs and the interaction between the effect of intervention and the choice of randomisation unit is considered to be unlikely.

We will also acknowledge heterogeneity in the randomisation unit and perform a subgroup analysis to investigate the effects of the randomisation unit.

Studies with more than two treatment groups

If we identify any multi-arm trials, we will include these if any pair-wise comparisons of the intervention groups are relevant to the review and meet our inclusion criteria. We will report all the intervention groups involved in the study in the 'Characteristics of included studies', but we will include only those intervention groups relevant to the review in the analysis. We will address pair-wise comparisons in multi-trials in relevant meta-analyses if they are eligible for the analysis, and we will ensure that data from any individual are included only once when pooling data. If there are multiple intervention groups in a particular meta-analysis, we will combine all relevant experimental intervention groups of the study into a single intervention group and combine all relevant control intervention groups into a single control group (Higgins 2011).

Dealing with missing data

For included studies, we will note levels of attrition. We will explore the impact of including studies with high levels of missing data in the overall assessment of treatment effect by using sensitivity analysis.

For all outcomes, we will carry out analyses, as far as possible, on an intention-to-treat basis, i.e. we will attempt to include all participants randomised to each group in the analyses, and all participants will be analysed in the group to which they were allocated, regardless of whether or not they received the allocated intervention. The denominator for each outcome in each trial will be the number randomised minus any participants whose outcomes are known to be missing.

Assessment of heterogeneity

We will assess statistical heterogeneity in each meta-analysis using the T2, I2 and Chi2 statistics. We will regard heterogeneity as substantial if the T2 is greater than zero and either an I2 is greater than 30% or there is a low P value (less than 0.10) in the Chi2 test for heterogeneity.

Assessment of reporting biases

If there are 10 or more studies in the meta-analysis, we will investigate reporting biases (such as publication bias) using funnel plots. We will assess funnel plot asymmetry visually, and use formal tests for funnel plot asymmetry. For continuous outcomes we will use the test proposed by Egger 1997, and for dichotomous outcomes we will use the test proposed by Harbord 2006. If asymmetry is detected in any of these tests or is suggested by a visual assessment, we will perform exploratory analyses to investigate it.

Data synthesis

We will carry out statistical analysis using the Review Manager software (RevMan 2011). We will use fixed-effect meta-analysis for combining data where it is reasonable to assume that studies are estimating the same underlying treatment effect: i.e. where trials are examining the same intervention, and the trials' populations and methods are judged sufficiently similar. If there is clinical heterogeneity sufficient to expect that the underlying treatment effects differ between trials, or if substantial statistical heterogeneity is detected, we will use random-effects meta-analysis to produce an overall summary, if an average treatment effect across trials is considered clinically meaningful. The random-effects summary will be treated as the average range of possible treatment effects and we will discuss the clinical implications of treatment effects differing between trials. If the average treatment effect is not clinically meaningful, we will not combine trials.

If we use random-effects analyses, the results will be presented as the average treatment effect with its 95% confidence interval, and the estimates of T2 and I2.

Subgroup analysis and investigation of heterogeneity

If we identify substantial heterogeneity, we will investigate it using subgroup analyses and sensitivity analyses. We will consider whether an overall summary is meaningful, and if it is, use random-effects analysis to produce it.

We plan to carry out the following subgroup analyses:

  1. maternal age: below 35 versus 35 and above;

  2. gestational age at intervention with Chinese herbal medicines started: < 14 weeks versus ≧ 14 weeks;

  3. numbers of prior recurrent miscarriage: two consecutive miscarriages versus more than two consecutive miscarriages;

  4. type of herbal medicines: standard herbal medicines versus non-standard herbal medicines, according to the formulary stated in the Chinese Pharmacopeia;

  5. timing of intervention: before pregnancy versus after pregnancy;

  6. duration of intervention: short-term treatment (one course only) versus long-term treatment (more than one course);

  7. study design: quasi-randomised clinical trials versus randomised clinical trials;

  8. main types of recurrent miscarriage in Chinese Medicine: "Qi" deficiency in Kidney versus combined "Qi" and "Blood" deficiency.

We will use the following outcomes in subgroup analysis:

  • pregnancy rate and live birth rate.

We will assess subgroup differences by interaction tests available within RevMan (RevMan 2011). We will report the results of subgroup analyses quoting the X2 statistic and P value, and the interaction test I2 value.

Sensitivity analysis

We will carry out sensitivity analysis to explore the effect of trial quality on important outcomes in the review. Where there is a high risk of bias in the allocation of participants to groups associated with a particular study or high levels of missing data, we will explore this by sensitivity analysis (Higgins 2011).

We will use the following outcomes in sensitivity analysis:

  • effectiveness of intervention: pregnancy rate and live birth rate;

  • pregnancy loss (before and after 14 weeks);

  • preterm delivery (less than 37 weeks);

  • multiple pregnancy;

  • obstetric complications (haemorrhage, hypertension, intrauterine growth retardation);

  • maternal morbidity;

  • prenatal morbidity.

Acknowledgements

We appreciate the help from the staff in the editorial office of the Cochrane Pregnancy and Childbirth Group.

As part of the pre-publication editorial process, this protocol has been commented on by three peers (an editor and two referees who are external to the editorial team), a member of the Pregnancy and Childbirth Group's international panel of consumers and the Group's Statistical Adviser.

The National Institute for Health Research (NIHR) is the largest single funder of the Cochrane Pregnancy and Childbirth Group. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, NHS or the Department of Health.

Appendices

Appendix 1. List of Chinese herbal medicines (CHMs) used as treatment for recurrent miscarriage*

No. English names Biological names Chinese names (Pinyin)
1Largehead Atractylodes Rhizome Rhizoma Atractylodis MacrocephalaeBai Zhu
2Chinese Dodder Seed Semen CuscutaeTu Si Zi
3Himalayan Teasel Root Radix DipsaciXu Duan
2Chinese Taxillus Twig Herba TaxilliSang Ji Sheng
3Liquorice Root Radix AstragaliHuang Qi
4Mongolian Milkcetch Root Radix Paeoniae AlbaBai Shao
3White Paeony Root Radix Angelicae SinensisDang Gui
4Chinese Angelica Radix Et Rhizoma GlycyrrhizaeGan Cao
5Baical Skullcap Root Radix ScutellariaeHuang Qin
4Eucommia Bark Cortex EucommiaeDu Zhong
5Steamed Rehmannia Root Radix Rehmanniae PraeparataShu Di Huang
6Szechwon Tangshen Root Radix CodonopsisDang Shen
5Common Yam Rhizome Rhizoma DiosscoreaeShan Yao
6Villous Amomrum Fruit Fructus AmomiSha Ren
7Rehmannia Root Radix RehmanniaeSheng Di Huang
6Szechuan Lovage Rhizome Rhizoma ChuanxiongChuan Xiong
7Chinese Mugwort Leaf Folium Artemisiae ArgyiAi Ye
8Tangerine Peel Pericarpium Citri ReticulataeChen Pi
7Danshen Root Radix Et Rhizoma Salviae MiltiorrhizaeDan Shen
8Heterophylly Falsestarwort Root Radix PseudostellariaeTai Zi Shen
9Perilla Stem Caulis PerillaeZi Su Jin
8Ramie Root Radix BoehmeriaeZhu Ma Gen
9Gin Seng Radix Et Rhizoma GinsengRen Shen
10Largetrifoliolious Bugbane Rhizome Rhizoma CimicifugaeSheng Ma
9Chinese Thorowax Root Radix BupleuriChai Hu
10Red Paeony Root Radix Paeoniae RubraChi Shao
11Glossy Privet Fruit Fructus Ligustri LucidiNv Zhen Zi
10Hairyvein Agrimonia Herb and Bud Herba AgrimoniaeXian He Cao
11Bamboo Shavings Caulis Bambusae in TaeniaZhu Ru
12Chinese Angelica Radix Et Rhizoma GlycyrrhizaeZhi Cao
11Common Macrocarpium Fruit Fructus CorniShan Zhu Yu
12Polished Glutinous Rice Abelia ChinensisRuo Mi
13Malaytea Scurfpea Fruit Radix CurcumaeYu Jin
12Hiraute Shiny Bugleweed Herb Herba LycopiZe Lan
13Indian Buead PoriaFu Lin
14Barbary Wolfberry Fruit Fructus LyciiGou Qi
13Nutgrass Galingale Rhizome Rhizoma CyperiXiang Fu
14Cassia Twig Ramulus CinnamomiGui Zhi
15Fennel Fruit Fructus FoeniculiXiao Hui Xiang
14Garden Burnet Root Radix SanguisorbaeDi Yu
15Yan Hu Suo Rhizoma CorydalisYan Hu Suo
16Dwarf Lilyturf Tuber Radix OphiopogonisMai Dong
15Cape Jasmine Fruit Fructus GardeniaeZhi Zi
16Citron Fruit Fructus CitriXiang Yuan
17Sharpleaf Galangal Fruit Fructus Alpiniae OxyphyllaeYi Zhi Ren
16Spine Date Seed Semen Ziziphi SpinosaeSuan Zao Ren
17Chinese Magnoliavine Fruit Fructus Schisandrae ChinensisWu Wei Zi
18Round Cardamom Fruit/Java Amomum Fruit Fructus Amomi RotundusBai Dou Kou
17Tuber Fleeceflower Root Radix Polygoni MultifloriHe Shou Wu
18Amur Corktree Bark Cortex Phellodendri ChinensisHuang Bai
19Lotus Rhizome Node Nodus Nelumbinis RhizomatisOu Jie
18Tree Peony Bark Moutan CortexDan Pi
19Chinese Hawthorn Fruit Fructus CrataegiSheng Sha Zha
20Dark Plum Fruit Fructus MumeWu Mei Tan
19Desertliving Cistanche Herba CistanchesRou Cong Rong
20Tree Peony Cortex MoutanMu Dan
21Common Anemarrhena Rhizome Rhizoma AnemarrhenaeZhi Mu
20Lotus Seed Semen NelumbinisLian Zi
21Yerbadetajo Herb Herba EcliptaeHan Mo Lian
22Indian Bread with Pine/ Poriacocos WolfFU Shen
21Tuckahoe with pine Rhizoma ZingiberisGan Jiang Tan
22Dried Ginger Rhizoma Zingiberis PraeparatumPao Jiang
23Indigowoad Leaf Folium IsatidisDa Qing Ye
22Jujube Fructus JujubaeDa Zao
23Grassleaf Sweelflag Rhizome Rhizoma Acori TatarinowiiShi Chang Pu
24Dried Longan Prlp Arillus LonganLong Yan Rou
23Figwort Root Radix ScrophulariaeXuan Shen
24Chinese Wolfberry Root Bark Cortex LyciiDi Gu Pi
25Silktree Albizzia Bark Cortex AlbiziaeHe Huan Pi
24Malt Fructus Gordei GerminatusChao Mai Ya
25Thinleaf Milkwort Root-bark Radix PolygalaeYuan Zhi
26Gordon Enryale Seed Semen EuryalesQian Shi
25Reed Rhizome Rhizoma PhragmitisLu Gen
26Japanese Honeysuckle Stem Caulis Lonicerae JaponicaeRen Dong Teng
27Loquat Leaf Folium EriobotryaePi Pa Ye
26Chinese Arborvitae Twig Cacumen PlatycladiCe Bai Tan
27Honeysuckle Flower Flos Lonicerae JaponicaeJin Yin Hua
28Oriental Waterplantain Rhizome Rhizoma AlismatisZe Xie
27Officinal Magnolia Bark Cortex Magnoliae OfficinalisHou Pu
28Gambir Plant Ramulus Uncariae Cum UncisGou Teng
29Mulberry Leaf Folium MoriSang Ye
28Cyrtomium Rhizome Rhizoma Dryopteridis CrassirhizomatisGuan Zhong
29Perilla Leaf Folium PerillaeSu Ye
30Redroot Gromwell Root Radix ArnebiaeZi Cao
29Mongolian Dandelion Herb Herba TaraxaciPu Gong Ying
30Tree-of-heaven Ailanthus Bark Cortex AilanthiChun Gen Pi
31Palmleaf Raspberry Fruit Fructus RubiFu Pen Zi
30Coastal Glehnia Root (North)/Ladybell Root (South) Radix Glehniae/AdenophoraeSha Shen

*This is not an exhaustive list, and other CHMs will be supplemented in the future literature review.

Appendix 2. Search strategy for EMBASE

1. exp PREGNANCY/

2. (spontaneous adj2 abortion*).af

3. (recur* adj3 (pregnancy ADJ loss)).af

4. (habitual* adj3 (pregnancy ADJ loss)).af

5. (abortion* adj3 recur*).af

6. (abortion* adj3 habitual*).af

7. (spontaneous adj3 (pregnancy ADJ loss)).af

8. miscarriage*.af

9. exp CHINESE HERB/

10. (chin* adj6 herb*).af

11. ((china OR chinese) AND (tradition* adj4 medicine*)).af

12. 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8

13. 9 OR 10 OR 11

14. 1 AND 12 AND 13

Appendix 3. Search strategy for CINAHL

1. exp PREGNANCY/

2. (spontaneous adj2 abortion*).af

3. (recur* adj3 (pregnancy ADJ loss)).af

4. (habitual* adj3 (pregnancy ADJ loss)).af

5. (abortion* adj3 recur*).af

6. (abortion* adj3 habitual*).af

7. (spontaneous adj3 (pregnancy ADJ loss)).af

8. miscarriage*.af

9. (chin* adj6 herb*).af

10. ((china OR chinese) AND (tradition* adj4 medicine*)).af

11. DRUGS, CHINESE HERBAL/

12. 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8

13. 9 OR 10 OR 11

14. 1 AND 12 AND 13

Appendix 4. Search Strategies for other databases

We will use a similar search strategy for Chinese Biomedical Database (CBM) (1978 to current); China Journal Net (CJN) (1915 to current); China Journals Full-text Database (1915 to current); and WanFang Database (Chinese Ministry of Science & Technology) (1980 to current).

We will document each search strategy in full in the review.

Contributions of authors

Dr Li Lu and Prof Wang Chi Chiu both wrote the initial and final versions of the protocol. Dr Dou Li Xia, Prof Leung Ping Chung and Prof Chung Kwok Hung Tony commented on the final version of the protocol.

Declarations of interest

None known.

Sources of support

Internal sources

  • Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong. Shatin, Hong Kong.

  • Institute of Chinese Medicine, The Chinese University of Hong Kong. Shatin, Hong Kong.

External sources

  • No sources of support supplied

Ancillary