Overview of Contraindicated Chinese Medicines for Pregnancy Overview of Contraindicated Chinese Medicines for Pregnancy

Chinese medicines should be classified into drugs, which have both beneficial and harm - ful effects. For centuries, Chinese medicines have been widely used to relieve many symp toms and to treat complications during pregnancy. It is not clear how safe the Chinese medicines are being used during pregnancy and if there is any adverse effects to embryo-fetal development and prenatal and postnatal growth. Some Chinese medicines are indi - cated that they cannot be used in pregnancy. In this chapter, we will conduct a systematic review to summarize and characterize in details the Chinese medicines classified as con - traindicated, not recommended and cautiously used for pregnancy in most updated ver sion of Pharmacopeia of the People’s Republic of China. Clinical reports including clinical trials, case reports, case series and animal studies including short-term and long-term tox -icity, specific organ toxicity and different species of the Chinese medicines will be studied. Unlike those pharmaceutical drugs not recommend for use during pregnancy because of known or suspected adverse or teratogenic effects evident by animal studies and/or clini - cal trials, most of the Chinese medicines were utilized for long history in culture which, however, has very limited scientific data regarding the adverse pregnant outcomes.


Application in China
Chinese medicines have become very popular and are widely applied to different kinds of medical conditions during pregnancy [1]. It promotes both mothers' and fetuses' health, relieves and cures common disorders in women [1]. It has been used as a main stream medicine in China with a longer history than Western medicines.
The first record of Chinese medicines treatment related to reproductive was first explained in A Chinese Bestiary 3000 years ago during Xia, Shang and Zhou era [2,3]. Since then, Gu Rong was commonly used for contraception [2,3]. In the following centuries, considerable progress was achieved in both clinical theory and practice while lots of milestones have been developed in Obstetrics and Gynecology. Due to historical factors of the late Qing Dynasty, and the influence of Western Medicine under the Renaissance, development of Chinese Medicine was less prominent [4]. After the establishment of People's Republic of China, with the great efforts of lots of Chinese Medicine practitioners and researchers, 6th edition of the textbook "Traditional Chinese Medicine in Obstetrics and Gynecology" [4] and lots of reference books and monographs have been published and used for daily teaching, training and self-learning. Apart from medical educations in Chinese Medicine, researches in collaborations with Chinese medicines and Western medicines have been raised to a new level and lots of meaningful conclusions have been drawn. For example, it was reported that combined Chinese medicines and Western medicines for ectopic pregnancy were more effective than conventional treatment [5,6], and the method of combined medicines has been well studied and applied widely since then.

Development in foreign countries
Chinese Medicine in China has a long history, but its development for pregnant women in other countries is just within recent centuries. In foreign nations, the most common treatments are Acupuncture and Chinese herbal medicines (CHMs). Other therapies of Chinese Medicine, which could be used during pregnancy, began to spread to the world in very late twentieth century, such as Tui Na Massage and Die Da [4].
Chinese herbal medicines (CHMs) spread to the world earlier than acupuncture but only widely applied lately, due to the early advancement and modernization of Western medicines in foreign countries [7]. For instance, the "European Pharmacopoeia" had been locally well-developed, and Chinese herbs as medicines were not attractive to the practitioners and patients. With the advantages of Chinese medicines, including less side effects and greater effectiveness in some chronic diseases (such as infertility and irregular menstruation) than Western medicines, it was gradually accepted by foreigners and now has been spread to over 160 countries [3]. More and more foreign researchers and clinical doctors seriously have interests in it and come to China for further study.

Effectiveness and efficacy
With a long history of application of Chinese medicines to treat pregnant disorders, large amounts of case reports and clinical trials have been reported [8]. However, until now, limited data are available to overview Chinese medicines for pregnancy. Our team has reported in a systematic review [9] about the general applications, including common formulae, common individual CHMs, dosage and dosing, frequency, therapeutic efficacy, clinical indications and so on.
Chinese medicines are prescribed in formulae, and the Chinese medicine practitioners decide the formula according to the clinical presentation. Based on medical knowledge and personal experience, some use original or traditional formula, the others have individual prescription as personalized medicine. The prescribed formulae vary a lot, some formulae even lack unified theory and scientific evidence. Therefore, under a long-term collaboration with Cochrane Review Pregnancy and Childbirth Group, our team has conducted two systematic reviews with meta-analyses to study the claimed efficacy of Chinese herbal medicines for pregnancyrelated disorders [10,11]. The results showed that combined Chinese herbal medicines and other pharmaceuticals are more beneficial than other pharmaceuticals alone for threatened miscarriage [10] and unexplained recurrent miscarriage [11], but the evidence on the effectiveness and safety of Chinese herbal medicines alone as treatment is still insufficient, due to the poor qualities of the included clinical trials.

Safety
Safety is always the biggest issue in daily medical practice, and the issue is also a major concern to pregnant women. Chinese herbal medicines have been used to treat diseases and complications during pregnancy, and it is apparently well accepted as with fewer side effects.
There are 31 Chinese herbal medicines that were classified as toxic and contraindicated during pregnancy, which have been listed in many textbooks. The website of Chinese Medicine Council of Hong Kong (CMCHK) recently released another five CHMs, which contain aristolochic acid, which could induce abortion, kidney damage and cancer. Further studies of these Chinese herbal medicines have been carried out in the last 20 years and have demonstrated their adverse effects on both/either mothers and/or newborns. For example, Kansui Root (Radix Kansui, Gan Sui) is prohibited in pregnancy because it can poison the fetus and stimulate uterine contraction [12].
On the other hand, numbers of clinical trials have also been carried out to assess the safety of some Chinese herbal medicines in pregnancy and associated conditions, or to compare the adverse effects of Chinese herbal medicines with other medicines. Among the commonly used Chinese medicines, there are not too many studies of their potential harmful effects however. Our team has carried out a systematic review [13,14] with meta-analyses to record the potential adverse effects and safety issues of CHMs as treatment for threatened miscarriage, but conclusive results remain elusive, as studies varied considerably in design, interventions and outcome measures. In the absence of placebo-controlled trials, the safety of Chinese medicines for the treatment of threatened miscarriage is unknown. Rigorous scientific and clinical studies to assess the possible risks of Chinese medicines are needed.
In conclusion, it is not clear how safe the Chinese medicines are being used during pregnancy and if there is any adverse effects to embryo-fetal development and prenatal and postnatal growth.

Chinese pharmacopeia
Unlike those pharmaceutical drugs not recommend for use during pregnancy because of known or suspected adverse or teratogenic effects evident by animal studies and/or clinical trials, most of the Chinese medicines were utilized for long history in culture which, however, has very limited scientific data regarding the adverse pregnant outcomes.
"Chinese Pharmacopeia", acknowledged by World Health Organization (WHO) as the official pharmacopeia for Chinese medicines, records 1146 different Chinese medicines [15]. It provides information on the herbs with their characteristics, identity, impurity, contents, extractum, analysis, property and channel, therapeutic action, pharmacological data, dose and dosing, precautious, storage, authentication methods and so on.
Among all this valuable information, we will obtain the most specific safety information for pregnancy from the Chinese Pharmacopeia and provide to the doctors, scholars and patients as scientific evidence on the safe application of Chinese medicines during pregnancy.

Objective
In this chapter, we will conduct a systematic review to summarize and characterize in details the Chinese medicines classified as contraindicated, not recommended and cautiously used for pregnancy in the most updated version of Chinese Pharmacopeia. Clinical reports including clinical trials, case series, case reports and animal studies including short-term and long-term toxicity, specific organ toxicity and different species of Chinese medicines will be studied.

Search in Chinese pharmacopeia
Two review assessors carried out the word-by-word study in Chinese Pharmacopeia to identify the study medicines. First, they read all the recorded individual Chinese medicines and the formulae one by one and recorded in a list of the medicines remarked with application in pregnancy. Second, they checked the details of pharmaceutical effects and clinical functions and indications of these list-out medicines. If any adverse effects related to pregnancy were reported, the reference study would be traced and more details of the adverse outcomes were recorded, for further summaries and analyses. Third, they carried out the same rules to expand the search in different online databases, if the details of the adverse outcomes could not be accessed from the Chinese Pharmacopeia or the reference study. Finally, they extracted and summarized the specific safety information on three classifications of these Chinese medicines.

Search in other databases
To further supplement the pharmacological and toxicology data of the Chinese medicines, several online national and public resources on World Wide Web were also referred.

Toxicity
Or could be included or replaced by similar words:

Therapy
Only clinical trials, which assessed the adverse pregnant outcomes of the Chinese medicines, were further selected for meta-analysis.

Types of studies
All published studies (list in Chinese Pharmacopeia and reference and reference of reference) that evaluated the safety of Chinese medicines for pregnancy were included. Studies of Chinese medicines for other clinical applications and in animal, chemical and basic research were included. (Non)/Randomized control trials, case controlled studies, case series, case reports, commentary articles and non-systematic reviews were excluded. Studies with no evaluation or incomplete records of adverse pregnancy outcome were also included.
Language of the publications was restricted to English and Chinese. Literature with either English or Chinese abstract should be available for initial search. No translation was required for Chinese articles as all review assessors can read Chinese and understand Traditional Chinese Medicine and Chinese medicines thoroughly. Translations were only sought from the language facilities of the university for articles written in English and Chinese.

Types of participants
There was no strict for types of participants, as we collected all safety information then further extracted for the summary table ( Table 1).

Types of interventions
Since Chinese medicines are crude drugs of plant, animal and mineral origins, not only those Chinese medicines originated from plants or herbs but also those from animals and minerals were included. All types of Chinese medicine in either standard or combined formulas used during pregnancy or on pregnancy model animals regardless of the dose or duration of administration.

Types of outcome measures
General and specific adverse effects of the study Chinese medicines were recorded. Adverse reproductive outcomes in both mothers and fetuses/infants (both human and animals) will be recorded. Maternal outcomes included (1) toxicity (e.g. renal failure, liver failure, neurological impairment and death); (2) side-effects (e.g. anaphylaxis, gastrointestinal disturbance, hypertension/hypotension, cardiac arrhythmia, gestational diabetes and so on); (3) pregnancy loss (e.g. late abortion, intrauterine death and still birth) and (4) pregnancy complications (e.g. preterm/postdate labor, placenta previa, placenta abruption and so on). Fetal outcomes included (5) perinatal mortality (including prenatal and postnatal death); (6) toxicity (e.g. fetal compromise, neurological consequences, hydrops fetalis and so on); (7) congenital malformations and (8) neonatal complications (e.g. jaundice, infection, hypoglycemia and so on). Both long-and short-term adverse outcomes were reported and summarized.

Data collection and analysis
For each reference study to be involved in this review, all review assessors first screened the titles, abstract sections and keywords of every record to exclude the duplicates and obvious false positive. Second, full text of eligible studies was assessed for further inclusion or exclusion. If there was sufficient information and it met the inclusion criteria, the study was included in the analyses and summaries. Two review assessors assessed the studies for inclusion independently; any disagreement was resolved by discussion among all the review authors. The study authors were contacted for clarification if there were doubts about the eligibility of the study and the disagreement could not be resolved. The review authors were not blinded to the journal of origin or institution.

草乌 (Cao Wu)
After preparation To restore yang, to improve fire, and to disperse cold. Being used in: sweating profusely with body temperature dropping; muscle spasm in cholera; instant sweating, afraid of cold in cases of yangxu (yang deficient); pain and cold in chest and abdomen, chronic diarrhea due to pixu (spleen deficient), chronic muscle or joint pain due to wind cold dampness, tightness and pain in joints and muscles; edema and coldness in the lower legs due to shenyangxu (kidney yang deficient) Contraindicated 2 Aconiti radix Aconitum carmichaelii Debx.

川乌 (Chuan Wu)
After preparation To restore yang, to improve fire, and to disperse cold. Being used in: sweating profusely with body temperature dropping; muscle spasm in cholera; instant sweating, afraid of cold in cases of yangxu (yang deficient); pain and cold in chest and abdomen, chronic diarrhea due to pixu (spleen deficient), chronic muscle or joint pain due to wind cold dampness, tightness and pain in joints and muscles; edema and coldness in the lower legs due to shenyangxu (kidney yang deficient)

5-10
Hei pu huang is pu huang that has been stir fried till dark color. It is being used in stopping bleeding. Raw pu huang possesses double effects of stopping bleeding and promoting circulation.
For treatment of: angina: blood clot in the brain, high blood lipids, inflammation of the intestine and difficulty in urination: pu huang 50 g, xiong huang 10 g, bing pian 3 g, fresh white part of green onion 200 g,(wash the part of green onion and boil in water for 3 minutes. Smash all herb past it to the lower abdomen while still warm. Bleeding and abdomen ache due to chronic colitis: pu huang 3 g, wu ling zhi 3 g (wrap in cloth), baked ge gen 10 g, baked rou dou kou 3 g. Make into decoction and use as tea.

Data extraction, evaluation and management
Extraction form was designed and used to extract data. For eligible studies, two review authors extracted the data, any discrepancy was resolved through discussion or the third person was consulted. For each selected literature, publication year, study population, participant numbers, maternal age, gestation age, symptoms and signs, clinical diagnosis, examination and laboratory results, disease course, study intervention, standard or modified Chinese medicine formulas, individual medicine, immediate and follow-up outcomes were recorded. But only the data related to the safety classification and adverse outcomes would be reported in this review.

Chinese pharmacopeia and literature study
There were 105 CHMs in Chinese pharmacopeia remarked with potential toxicity classification for pregnant women, of which 38 were "contraindicated", 2 were "not recommended" and 65 were "cautiously used" during pregnancy. Three of them were repeated under different common names, so we studied and collected information of 102 CHMs ( Table 1) [15]. Some of the CHMs were origin from the same part of a plant, but they were prepared and applied in different format. Although their properties and safety outcomes were similar, we kept them separately list in the summary table.
An extension search on the cited references was carried out, and data of around another 600 studies were further extracted [15,16]. A summary included the common name (English name), the biological name (Latin name), the original name (Chinese name), the recommended dose range in Chinese Pharmacopeia, clinical effects/indications and the safety classification in pregnancy of these 102 CHMs was reported in Table 1.

General adverse effects and lethal effects
Among these 102 CHMs for pregnancy, around 80% were reported with their safety in clinical trials and or animal studies.
In those 38 "contraindicated" CHMs, 28 (73.7%) of which reported either general adverse effects or lethal effects ( Table 2). About 16 of 38 (42.1%) CHMs were recorded with general adverse outcomes such as gastrointestinal discomfort including nausea, vomiting, lethargy, abdominal pain, diarrhea; nervous system problems such as drowsiness, headache, dizziness, respiratory failure, shock, dermatitis and ulcers, damage to multi-organ/systems, and so on. About 18 of 38 (47.4%) CHMs were recorded with lethal effects in human and mammals like mice, rats and rabbits. Immediate death was reported when Realgar Tragacanth (a component of Realgar) was orally administrated to mice, but details of the dose and dosing were not reported. . Although it has great therapeutical function of improve the immune system, due to its pharmacological effects to enhance the blood circulation and stimulate the contraction of uterus, it may induce abortion during pregnancy, so it was not recommended for pregnant women.
In 65 "cautiously used" CHMs, 33 (50.8%) of which reported either general adverse effects or lethal effects ( Table 2). About 24 of 65 (36.9%) CHMs were recorded with same general adverse outcomes such as gastrointestinal discomfort, nervous system problems, skin disorders and multi-organ damage. Other adverse effects such as muscle necrosis, pelvic congestion and cancer were also recorded. A total of 9 of 38 (13.8%) CHMs were recorded with lethal effects in human and mice. One study also reported that Meliae Cortex (Melia toosendan Sieb.et Zucc.; Melia azedarach L, KuJianPi) could cause death of rabbits, dogs and monkeys after oral administration of high dose of Toosendanin (a component), and the main reason is visceral bleeding, decreased blood pressure then acute circulatory failure.

Maternal and fetal adverse effects
Generally speaking, more maternal adverse effects were recorded than fetal effects. But this may be due to the failure of early pregnancy of mothers.
In those 38 "contraindicated" CHMs, 2 (5.3%) of which reported adverse effects on both mothers and fetuses ( Table 2). A total of 12 of 38 (31.6%) CHMs were recorded with maternal adverse outcomes such as lower pregnancy rate (mainly due to anti-implantation), miscarriage (mainly due to effects on uterus), placenta damage and so on. About 3 of 38 (7.9%) CHMs were recorded with fetal adverse effects on bone development, circulation system and malformation.
No obvious maternal and fetal adverse effects were reported in those two "not recommended for pregnancy" CHMs (  Table 2. Adverse outcomes of CHMs for pregnancy [15,16]. In those 65 "cautiously used" CHMs, 1 (1.5%) of which reported adverse effects on both mothers and fetuses ( Table 2). About 20 of 65 (30.8%) CHMs were recorded with same maternal adverse outcomes as the "contraindicated" CHMs, and the study animals included mice, guinea pigs, rats and rabbits. Only 1 of 65 (1.5%) CHMs, Typhae Pollen (Typha angustifolia L, PuHuang), was recorded with mouse fetal death under oral administration of a 10-21 g/kg decoction.

Animal toxicity data
In Table 3, we summarized the toxicity data of those 102 CHMs from different animal studies and provided the information of LD50, dose, doing and species [15]. About 21 of 102 (20.6%) CHMs have more than one LD50 data, by applying raw herb, main/active components, water extraction and decoction or applying different species of animals. But 35 of 102 (34.3%) CHMs did not have a LD50 record. One implied reason is the CHM is too safe to test a LD50 data. Another reason is that half of these CHMs without a LD50 data were mineral origin, and there have been no study carried out to test their LD50 so far. Herbal water extraction. 3 Decoction. 4 Raw herb. ip: peritoneal injection; ig: intragastrical administration; iv: intravenous injection; iH: hypodermic injection; po: oral administration; im: intramuscular injection. Table 3. Animal toxicity data of CHMs for pregnancy [15,16].

Chinese medicines are not free of risk
The active ingredients of the Chinese medicines are chemicals that are similar to prescribed drugs. Chinese medicines are not free of risk and they have the same potential to cause adverse effects.
In this overview of Chinese medicines for pregnancy with well-characterized reproductive toxicity, though these Chinese medicines are not commonly used in clinical practice, some of them could result in severe consequences when given in over dosages or even normal dosages. In the communities which use Chinese medicines, special attention should be paid and precautions should be taken to prevent mistaken overdoses of the Chinese medicines.

International guideline is necessary
It should be acknowledged that some of the studies from animals may not be comparable to human responses, both referring to Chinese medicines and Western medicines. Despite variations in clinical practice and therapeutic prescription, Chinese medication in Traditional Chinese Medicine should comply with modern pharmacological principles as in Western Medicine. Chinese medicines may be beneficial but may also adversely affect both mothers and fetuses in utero. International regulations have not been designed or specified to categorize the Chinese medicines for use in pregnancy. Until now, no detailed/well-designed reproductive toxicity and pharmacotoxicity studies are available to assess the potential risk of Chinese medicines during pregnancy, as much as true that conventional medications are not well tested in pregnancy too.
Before the detailed studies become available, here we take the initiative in gathering information about the adverse effects and potential toxicity of the Chinese medicines for pregnancy from Chinese Pharmacopeia and the extensive literature studies.

Recommendations
We hope more comprehensive and systematic experiments will be carried out. Until more reliable and scientific research data become available, clinicians should appraise both the risk and benefit before recommendations to pregnant women or women who plan to be pregnant.
Both Chinese and Western physicians should explicitly elicit and document the history of the use of any Chinese medications. This is to prevent and recognize potential serious problems associated with their use and should encourage their discontinuation. More studies and clinical trials in humans with a larger sample size are obviously mandatory. We do recommend more systematic basic investigation of the safety use of Chinese medicines for pregnancy.