Traditional Chinese medicines for ectopic pregnancy
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To determine about the effectiveness and safety of traditional Chinese medicine in the treatment of EP.
Background
Description of disease
Ectopic pregnancy (EP) is defined as the implantation of an early pregnancy anywhere other than in the uterine cavity (Bankowski 2002). It can occur in sexually active woman of reproductive age. The majority of EPs occur in the fallopian tube (97%), and the remainder are in the ovary, in the cervix, or rarely in the abdomen. Although these non‐tubal and interstitial EP are rare, they represent nearly 20% of deaths due to EP. Ectopic pregnancies may rupture causing massive blood loss and if untreated maternal death.
EP is a life‐ and fertility‐threatening condition that is commonly seen in emergency departments, it is the leading cause of pregnancy‐related deaths in the first trimester of pregnancy. The classic symptom triad of EP is pain, amenorrhoea, and vaginal bleeding. However these symptoms are present in only about 50% of patients, and is most typical in patients in whom an EP has ruptured. Abdominal pain is the most common presenting complaint, but the severity and nature of the pain vary widely.
Risk factors for EP that should be recognised include: use of assisted reproductive technology, a history of ectopic pregnancy, surgery in the pelvis, pelvic infection, IUD (intrauterine device) use, destruction of the uterine cavity or lining, DES exposure in utero and endometriosis. In addition, EP is concerned with sexually transmitted disease (STD) and associated salpingitis (such abnormalities of the tubes prevent normal transport of the fertilized egg to the uterus). IUD use marginally increases the ectopic risk, but if pregnancy does occur despite IUD use, the likelihood of ectopic is substantially higher than normal. At conception, maternal smoking may have an effect on the occurrence of ectopic pregnancy. In eleven case‐control studies, ten of them found a relationship between tobacco smoking and ectopic pregnancy (increased relative risk) (Dekeyser 2005). Epidemiological findings indicate that the two principal risk factors for EP as reproductive rather than contraceptive failure are a history of genital infection or tubal surgery and smoking. Quantitatively, their role in the risk of EP is similar: each explains approximately one‐third of EP. They have a causal role in EP risk. The other risk factors are the woman's age and her history of spontaneous or elective abortion. These risk factors together explained 76% of EP (Fernandez 2004).
Reported worldwide incidence of EP has increased to between 1% and 2% of pregnancies (Lehner 2000). This may in part be explained by earlier diagnosis, which in turn explains falling mortality rates over the same timeframe and has allowed the possibility of considering medical alternatives to surgical treatment (Luciano 2001).
Management of EP
At present, there are several options for managing EP: surgical treatment, medical treatment and expectant treatment. (Hajenius 1999) Medical treatment includes methotrexate, mifepristone and prostaglandins. Methotrexate is an antimetabolite, it can interfere with the production and maintenance of DNA, inhibit the proliferation of the trephocyte of the embryo, destroy chorionic villus, thus cause the necrosis, exfoliation and absorption of the embryonic tissue, so methotrexate is used to treat early unruptured ectopic pregnancy. Mifepristone is a progestogen antagonist, it can block the actions of the naturally occurring hormone progesterone, which is necessary for pregnancy to continue. Prostaglandin is a contraceptive agent, is used in early pregnancy, to stimulate the contraction of the uterus, enlarge the cervix and induced abortion of the ectopic pregnancy. A Cochrane systematic review (Hajenius 2000) indicate that the systematic treatment with methotrexate administered as single dose intramuscular injection is less effective than laparoscopic salpingostomy,whereas methotrexate primarily given in a multiple dose intramuscular regiment has a similar efficacy but is associated with a greater impairment of the health related quality of life and is more expensive because of surgical interventions for tubal rupture, prolonged hospitalisation, and loss of productive.
Traditional Chinese medicines in the treatment for EP
Traditional Chinese medicine follows a specific theoretical and methodological pathway as to the cause of, and the treatment for EP that are different to those of Western medicine. The principle of traditional Chinese medicines in the treatment for EP is promoting blood flow. For example, E Shu (Rhizoma Curcumae) (Chu 1998) and Hong Hua (Flos Carthami) (Liu 1998a) do have anti‐implantation and against early pregnancy functions; Tian Hua Fen (Radix Trichosanthis) can induce abortion and has the anti early pregnancy function (Dai 1998); Tao Ren (Semen Persicae) contains amygdalin which may hydrolyze to produce hydrocyanic acid, it can make central nervous system of the embryo paralysed and the embryo stop developing (Gong 1998; Li 2005a); Dang Gui (Radix Angelicae Sinensis), San Qi (Radix Notoginseng) and Wu Gong (Scolopendra) have the effectiveness of enhance the immune function (Huang 1998a; Huang 1998b; Liu 1998b); Dan Shen (Ridx Salviae Miltiorrhiae) can reduce the level of the serum progesterone, inhibit specific binding of hCG/LH receptor, and has the function of promoting blood circulation to dissipate blood stasis(Liu 1998c). Single Chinese herb and Chinese herbal formulae such as fixed formula and tailored formula, or combined with Western medicines can be used for the treatment of EP, usually taking a herbal decoction of a few of the traditional Chinese medicines mentioned above orally once a day for 7 to 14 days. Traditional Chinese medicines can also be applied externally for EP, for example, spreading on the abdomen.
Rational for undertaking this review
Traditional Chinese medicines have been widely used to treat many diseases for centuries in China. They have also been used to treat EP routinely in many Chinese hospitals, from big hospitals, i.e. tertiary hospitals and university college hospitals to county hospitals. In addition, there are many traditional Chinese medical hospitals which all use traditional Chinese medicines in the treatment for EP. There are many published studies about the curative effect of traditional Chinese medicines for EP. The interest in traditional Chinese medicine is not confined to China, there is increasing public interest in, and use of, a wide range of therapies, which lie outside the "mainstream" of traditional Western medical practice. The recent House of Lords Select Committee report on Complementary and Alternative Medicine (CAM) heard that "we are now experiencing a rapid increase in the use of CAM across the Western World." (HLSC 2000). Whether we agree or disagree with their use and effectiveness, traditional Chinese medicines are widely used.
There is evidence to indicate that not all traditional Chinese medicines are risk‐free. There are concerns regarding adverse events, e.g. allergic reaction, and Chinese herbal nephropathy (CHN) (Nortier 2000; Lampert 2002; Lord 2001). However, some randomised trials have been published and have reported that traditional Chinese medicine combined with Western medicine for EP can strengthen the effects and reduce the side‐effects of the latter, shorten the time of beta‐hCG decline to normal, promote the absorption of the ectopic pregnancy mass. Currently there is insufficient evidence about the safety and efficacy of traditional Chinese medicine in the treatment of EP and therefore there is a need for a systematic review.
Objectives
To determine about the effectiveness and safety of traditional Chinese medicine in the treatment of EP.
Methods
Criteria for considering studies for this review
Types of studies
All relevant randomised controlled trials. We will exclude quasi‐randomised trials.
Types of participants
Diagnostic criteria include all of the following terms:
1. having or no trilogy of EP: amenorrhoea, abdominal pain and vaginal bleeding;
2. serum ?‐hCG assay is positive;
3. an empty uterine cavity and a pelvic mass or extrauterine sac visualised by ultrasound examination.
Women with EP. Medical management is considered inappropriate for women with abnormal liver function or with significant haemoperitoneum, or for pregnancies that have already ruptured or gone beyond eight weeks gestation, or hCG higher than 5000 IU/L. When studies include such women, we will include the study and note the inclusion criteria, and apply sensitivity analysis that omits the study from a secondary analysis.
Types of interventions
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Traditional Chinese medicine versus placebo/expectant management.
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Traditional Chinese medicine versus Western medicine.
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One type of traditional Chinese medicine versus another type of traditional Chinese medicine.
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Traditional Chinese medicine versus acupuncture or massage for EP if there is any.
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Traditional Chinese medicine and Western medicine versus acupuncture or massage if there is any.
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Traditional Chinese medicine and Western medicine versus placebo and Western medicine or Western medicine alone.
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Traditional Chinese medicine and Western medicine versus traditional Chinese medicine.
Expectant management is one of the treatments for EP, means giving no treatment but observation to allow EP patients to recover naturally.
Types of outcome measures
Primary outcome
Primary treatment success.
Primary treatment success is defined as disappearance of the symptoms, a negative serum ?‐hCG level, and diminution or disappearance of the EP mass by ultrasound after initial medical treatment. Accordingly, treatment failure is that surgical intervention was needed for aggravation of symptoms and/or rising or inadequately declining of the serum hCG level and/or increasing of the EP mass measured and/or appearance of the sign of activity bleeding after the initial medical treatment.
Secondary outcomes
1. Patency of tubal, is examined by salpingography.
2. Future fertility, measured as the rate of future intrauterine pregnancy.
3. Cost.
4. Quality of life, measured by some instruments, e.g. SF‐36, WHOQOL‐BRIEF etc. and at the end of the trials.
5. The period of hospitalisations.
Adverse events
Any serious adverse event defined according to ICH Guidelines, and we will report serious and non‐serious adverse events.
Search methods for identification of studies
We will formulate a comprehensive search strategy in order to identify all randomised controlled trials (RCTs), regardless of language or publication status (published, unpublished, in press and in progress), when necessary, non‐English‐language papers were translated so that they could be fully assessed for potential inclusion in the review.
1. Electronic searches
We will identify relevant trials from The Cochrane Library (Issue 4, 2005), MEDLINE (1966 to present), EMBASE (1980 to present); and the Chinese Biomedical Database (CBM) (1975 to present), China National Knowledge Infrastructure (CNKI)(1979 to present), VIP(1989 to present), Traditional Chinese Medicine Database System. The following search strategy will be constructed by using a combination of subject headings and text words relating to the use of traditional Chinese medicines in the treatment of EP.
A. Search strategy for MEDLINE (OVID):
a) Search strategy to locate RCTs:
#1 randomization controlled trial
#2 random allocation
#3 random* allocat*
#4 RCT
#5 #1˜#4/or
b) Search strategy to locate EP:
#6 ectopic pregnancy
#7 ectop* pregnancy
#8 ectopic pregnan*
#9 ectop* pregnan*
#10 eccyesis
#11 ectopic fetation
#12 ectopic feta*
#13 ectop* fetation
#14 ectop* feta*
#15 ectopic gestation
#16 ectop* gestation
#17 ectopic gestat*
#18 ectop* gestat*
#19 extra‐uterine pregnancy
#20 extra‐uterine pregnan*
#21 extra‐uter* pregnancy
#22 extra‐uter* pregnan*
#23 heterotopic pregnancy
#24 heterotopic pregnan*
#25 heterotop* pregnancy
#26 heterotop* pregnan*
#27 #6˜#26/or
c) Search strategy to locate traditional Chinese medicine:
#28 traditional Chinese medicine
#29 Chinese traditional medicine
#30 traditional Chinese medic*
#31 Chinese traditional medic*
#32 herbal medicine
#33 herb* medic*
#34 medic* herb*
#35 Chinese herbal medicine
#36 Chinese herb* medic*
#37 Chinese medic* herb*
#38 herbal
#39 herb*
#40 complementary
#41 alternative medicine
#42 comp*
#43 alter* medic*
#44 #28˜#43/or
#45 #5 AND #27 AND #44
B. A similar strategy will be used for EMBASE:
#1 ectopic
#2 pregnancy
#3 ectopic pregnancy
#4 ectop*
#5 pregnancy
#6 ectop* pregnancy
#7 ectopic
#8 pregnan*
#9 ectopic pregnan*
#10 ectop*
#11 pregnan*
#12 ectop* pregnan*
#13 ectopic
#14 fetation
#15 ectopic fetation
#16 ectop*
#17 fetation
#18 ectop* fetation
#19 ectopic
#20 feta*
#21 ectopic feta*
#22 ectop*
#23 feta*
#24 ectop* feta*
#25 ectopic
#26 gestation
#27 ectopic gestation
#28 ectop*
#29 gestation
#30 ectop* gestation
#31 ectopic
#32 gestat*
#33 ectopic gestat*
#34 ectop*
#35 gestat*
#36 ectop* gestat*
#37 extra‐uterine
#38 pregnancy
#39 extra‐uterine pregnancy
#40 extra‐uter*
#41 pregnancy
#42 extra‐uter* pregnancy
#43 extra‐uterine
#44 pregnan*
#45 extra‐uterine pregnan*
#46 extra‐uter*
#47 pregnan*
#48 extra‐uter* pregnan*
#49 heterotopic
#50 pregnancy
#51 heterotopic pregnancy
#52 heterotop*
#53 pregnancy
#54 heterotop* pregnancy
#55 heterotopic
#56 pregnan*
#57 heterotopic pregnan*
#58 heterotop*
#59 pregnan*
#60 heterotop* pregnan*
#61 #1˜#60/or
The above EMBASE search is following restricted to study design as below (combine with 'AND'):
#1 explode 'clinical‐trial' / all subheadings
#2 explode 'controlled‐study' / all subheadings
#3 'randomization‐' / all subheadings
#4 'case‐control‐study' / all subheadings
#5 #2 NOT #4
#6 random* or clin*
#7 #1˜#6/or
C. A search strategy in the Cochrane Library:
#1 ECCYESIS*: ME
#2 (((ECTOP* near PREGNAN*) or FETA*) or GESTAT*)
#3 ( ECTOP* or (EXTRA‐UTER* or (HETEROTOP* near PREGNAN*)))
#4 (#2 or #3)
#5 (#1 or #4)
D. A search strategy in the Chinese Biomedical Database (CBM):
#1 ectopic pregnancy Gong Wai Yun (ectopic pregnancy)
#2 ectopic fetation Yi Wei Ren Shen (ectopic pregnancy)
#3 ectopic gestation Shu Luan Guan Ren Shen (tubal pregnancy)
#4 eccyesis Luan Chao Ren Shen (ovarian pregnancy)
#5 extra‐uterine pregnancy Gong Jing Ren Shen (cervical pregnancy)
#6 heterotopic pregnancy Fu Qiang Ren Shen (abdominal pregnancy)
#7 traditional Chinese medicine Zhong Yao (traditional Chinese medicine)
#8 Chinese herbal medicine Zhong Cao Yao (Chinese herb medicine)
#9 herb* medicine Cao Yao (Chinese herb medicine)
#10 medic* herbs Zhong Yi Yao (traditional Chinese medicine)
#11 medic* herb* Zhong Yao Zhi Liao (traditional Chinese medicine treatment)
#12 traditional medicine Zhong Yi Zhi Liao (traditional Chinese medicine treatment)
#13 (#1˜#6/or) and (#7˜#12/or)
E. The same search strategy will be used in CNKI, VIP and Traditional Chinese Medicine Database System.
All of the search terms will be translated to Chinese terms accordingly when we conduct the searching in Chinese databases.
F. We also intend to searching for ongoing trials in:
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National Research Register
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Meta‐register of Controlled Trials
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Medical Research Council Clinical Trials Directory
2. Handsearches
We will handsearch the following Chinese Journals:
Chinese Journal of Obstetrics and Gynecology
Chinese Journal of Integrated Traditional and Western Medicine
Progress in Obstetrics and Gynecology
Chinese Journal of Practical Gynecology and Obstetrics
Journal of Practical Obstetrics and Gynecology
New Journal of Traditional Chinese Medicine
Modern Traditional Chinese Medicine
Journal of Traditional Chinese Medicine
We will particularly note those journals which were not indexed in electronic databases. We will contact authors as required to obtain full details; if these cannot be obtained, we will probably exclude the trial.
3. References from published studies
We will try to identify additional studies by searching the reference lists of relevant trials and reviews.
4. Unpublished literature
We will identify unpublished and on‐going trials by correspondence with authors, and by contacting pharmaceutical companies who produce relevant products, if needed.
5. Other search strategies
We will contact organisations, individual researchers working in the field, and medicinal herbs manufacturers in order to obtain additional references, unpublished or ongoing trials.
Data collection and analysis
Study selection
First, we will telephone interview the original authors of possible RCTs to identify whether the randomisation procedure was correct or not. Only those studies that used adequate method to generate allocation sequence (see below) will be included. According to the empirical evidence (Jadad 1996; Juni 2001; Kjaergard 2001; Moher 1998; Schulz 1995).
We will assess the methodological quality as described by Kjaergard (Kjaergard 2001):
1. generation of the allocation sequence: adequate (computer generated random numbers, table of random numbers, or similar) or inadequate (other methods or not described);
2. allocation concealment: adequate (central independent unit, sealed envelopes, or similar) or inadequate (not described or open table of random numbers or similar);
3. double blinding: adequate (identical placebo tablets or similar) or inadequate (not performed or tablets versus injections or similar);
4. follow up: adequate (number and reasons for dropouts and withdrawals described) or inadequate (number or reasons for dropouts and withdrawals not described).
We will describe each of our criterion separately for each included study. Additionally, we will explore the influence of individual quality criteria in a sensitivity analysis. Two review authors (WD and WT) will assess each trial and extract data independently. In cases of disagreement, we will consult the third author (HuL) and make a judgement based upon consensus.
Data extraction
WD and WT will independently extract data using a data extraction form. We will extract data on study characteristics including methods, participants, interventions, and outcomes. We will list the Ping Yin name, Latin name and English name of traditional Chinese herbs in a special table. We will list the contents of all of the traditional Chinese medicine formulations, also. We will resolve any disagreements by referring to the trial report and through discussion. If data from the trial reports are insufficient or missing, we will contact the authors for additional information.
If possible we will extract data to allow an intention‐to‐treat analysis (the analysis should include all the participants in the groups to which they were originally randomly assigned). If the number randomised and the numbers analysed are inconsistent, we will calculate the percentage loss‐to‐follow up and report this information in an additional table. For binary outcomes, we will record the number of participants experiencing the event in each group of the trial. For continuous outcomes, for each group we will extract the arithmetic means and standard deviations. If the data are reported using geometric means we will extract standard deviations on the log scale. Medians and ranges will be extracted and reported in tables.
Data analysis
We will analyse the data using Review Manager (Version 4.2). We will compare outcome measures for binary data using risk ratio. For continuous data, we will use the weighted mean difference. If continuous data have been reported using geometric means, we will combine the findings on a log scale and report on the original scale. We will report medians and ranges in tables only. We will assess heterogeneity amongst trials by inspecting the forest plots and using the Chi‐squared test for heterogeneity with a 10% level and I squared with an equally 50% level of statistical significance.
If it is appropriate to pool data and heterogeneity is detected, we will use the random‐effect model. We do not intend to combine results of trials with different traditional Chinese medicine formulations or different comparator drugs. Potential publication bias will be tested for using the funnel plot or other corrective analytical methods depending on the number of clinical trials included in the systematic review (Egger 1997).
Subgroup analyses
We will use subgroup analyses to explore the following potential sources of heterogeneity:
1. the contents of traditional Chinese medicines used in the experimental group;
2. the intervention measure used in the experimental group (only traditional Chinese medicines or combination of traditional Chinese medicine with Western medicine);
3. the degree of severity of disease: we will stratify the ectopic pregnancies as hCG < 5,000 and > 5,000 but < 10,000 and size < 3 cm and > 3 cm but < 5 cm, if possible, depends on data.
4. different time point for testing outcomes, for example, short term effects < 3 months, long term effects > 3 months, depends on data.
Sensitivity analyses
We will explore reasons for heterogeneity in studies and, if necessary, use sensitivity analyses to examine the effects of excluding study subgroups, for example, those studies with lower methodological quality.
