**4. Results**

#### **4.1. 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**.

#### **4.2. Adverse outcomes**

#### *4.2.1. 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.


*3.3.6. Data extraction, evaluation and management*

46 Chinese Medical Therapies for Diabetes, Infertility, Silicosis and the Theoretical Basis

**4.1. Chinese pharmacopeia and literature study**

kept them separately list in the summary table.

*4.2.1. General adverse effects and lethal effects*

sification in pregnancy of these 102 CHMs was reported in **Table 1**.

in this review.

**4. Results**

**4.2. Adverse outcomes**

reported.

trials and or animal studies.

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

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

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 clas-

Among these 102 CHMs for pregnancy, around 80% were reported with their safety in clinical

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



**No. CHM (English) Adverse outcomes Reproductive adverse outcomes**

Death (human)

Death (mammals)

Death (component

Anti-fertility effects: placenta damage, miscarriage

HgO3 )

**Lethal effects Maternal effects Fetal** 

pregnancy: induce miscarriage (pregnant mice, po, component 180 mg/kg); 2. Stimulation on pregnancy uterus (rabbit

pregnancy: 1. Induce miscarriage (pregnant monkeys, amniotic injection for 1–3 days, component 0.2–8 mg); 2. Stimulation on pregnancy uterus

and mice)

(rabbit)

pregnancy: 1.25 g/ kg; 2. Termination on pregnancy: (ih on pregnancy d1, d6, d10, bid, decoction 2.5–3 g/kg)

1. Recorded embryotoxicity, but no malformation on fetus (rabbit, details not available); 2. Interfere with fetal circulation

system

**effects**

**General adverse** 

48 Chinese Medical Therapies for Diabetes, Infertility, Silicosis and the Theoretical Basis

1. Diarrhea; 2. Persistent abdominal pain, nausea, vomiting, lethargy, drowsiness (human)

17 Ferulae resina 1. Termination of

18 Genkwa flos Termination of

1. Hemolysis; 2. Local mucosal irritation, damage to central nervous system, respiratory failure, death (mammals)

quadriceps (rabbit)

21 Hirudo 1. Termination on

**effects**

15 Euphorbiae semen pulveratum

16 Eupolyphaga steleophaga

19 Gleditsiae fructus abnormalis

20 Ground beetle

22 Hydrargyri

oxydum rubrum

23 Hyoscyami semen Chromosome damage 24 Kansui radix Hemolysis effect on


44 Aconiti kusnezoffii radix cocta


**No. CHM (English) Adverse outcomes Reproductive adverse outcomes**

death (mice, po, component)

intraperitoneal injection of high

dose)

mg/kg)

7 days)

details not available); 2. Death (human, po, 30 mg)

1. Death (mice, details not available); 2. Death (human, po, 30 mg)

Death (human, po)

**Lethal effects Maternal effects Fetal** 

Specific toxicity: fetal malformation on bone developemnt

Stimulation on uterus (pregnant rabbits)

1. Stimulation on nonpregnancy and early pregnancy uterus (mice); 2. Inhibition effects on both non-pregnancy and early pregnancy uterus (guinea pig); 3. Anti-fertility effect on pregnancy (mice)

**effects**

**General adverse** 

50 Chinese Medical Therapies for Diabetes, Infertility, Silicosis and the Theoretical Basis

2.5–10 g/kg), damage to brain (mice, po)

Dermatitis Death

**effects**

31 Realgar Immediate

33 Scolopendra Death (mice,

34 Scorpio Death (rabbit, iv, 0.5

35 Sparganii rhizoma Death (mice, ip for

Chronic toxicity (mammal, po)

36 Strychni semen 1. Death (mice,

30 Phytolaccae radix Vomitting (cat, po,

32 Rhododendri mollis flos

37 Strychni semen pulveratum

38 Toxicodendri resina 39 Gleditsiae sinensis fructus

41 Abelmoschi corolla 42 Achyranthis

43 Aconiti kusnezoffii folium 44 Aconiti kusnezoffii radix cocta

involucratae herba

bidentatae radix

40 Saussureae



79 Momordicae semen

**No. CHM (English) Adverse outcomes Reproductive adverse outcomes**

58 Campsis flos 1. Inhibition effects on

<sup>63</sup> Croci stigma Death (mammals) Death (mammals) Stimulation effects on

<sup>64</sup> Cyathulae radix 1. Stimulation effects on

<sup>65</sup> Dianthi herba Stimulation on

Death (mice, intraperitoneal injection, component)

poisoning symptoms, reduced activity, walking difficulties (mice, intragastric and intraperitoneal injection, decoction)

The toxic effects of guizhi on mice have significant differences between day and night, the daytime toxic and lethal effects were significantly enhanced at night

(mice)

**Lethal effects Maternal effects Fetal** 

Stimulation effects on pregnancy uterus and anesthesia uterus (rabbit, 0.9 mg component)

mice non-pregnancy uterus (mice, 7.5 mg/ml); 2. Stimulation effects on pregnancy uterus

Stimulation effects on uterus (more obvious on pregnancy uterus than non-pregnancy one)

both non pregnancy and pregnancy uterus (mice, puinea pig, rabbit, god,

pregnant uterus (rabbit and cat); 2. Miscarriage rate 100% (mice, po for 7 days, component 2.5

pregnancy uterine (rabbit

cat)

g/kg)

and rat)

**effects**

**General adverse** 

52 Chinese Medical Therapies for Diabetes, Infertility, Silicosis and the Theoretical Basis

**effects**

po, 7.5 g/kg)

54 Bovis calculus Fewer activities (mice,

59 Carthami flos Low-spirited

60 Cinnamomi cortex 61 Cinnamomi ramulus

<sup>62</sup> Coicis semen

55 Bovis calculus artifactus 56 Bovis calculus sativus 57 Bufonis venenum



**No. CHM (English) Adverse outcomes Reproductive adverse outcomes**

Death (mice, intraperitoneal injection, decoction)

**Lethal effects Maternal effects Fetal** 

Stimulation on pregnant

uterine

**effects**

**General adverse** 

54 Chinese Medical Therapies for Diabetes, Infertility, Silicosis and the Theoretical Basis

inhibition such as temperature decreasing, reflection disappeared, reduced activity, reduced respiratory, etc. (mice, intraperitoneal injection, component)

intraperitoneal injection, decoction)

Induce cancer

Acute and chronic toxicity reported, but details not avaliable

relaxation, ataxia, piloerection and other phenomena (mice, intraperitoneal injection of 3.5 g/kg decoction)

Reduced activity, but recover on the next day (mice, intraperitoneal injection, 1 g/ml water

Different degree of peritonitis, the severity and scope and dosage showed parallel effects, 700 mg/kg dose group was administered after 6 weeks can cause white blood cell count was significantly reduced, but there were no significant changes in blood and liver and kidney function. (rats, intraperitoneal injection, conponent)

extract)

**effects**

80 Moutan cortex Some central

82 Natrii sulfas Death (mice,

86 Persicae semen Visible muscle

81 Myrrha

83 Natrii sulfas exsiccatus

85 Olibanum

87 Physochlainae radix

88 Polygoni cuspidati rhizoma et radix

84 Notoginseng radix et rhizoma


**Table 2.** Adverse outcomes of CHMs for pregnancy [15, 16].

In 2 "not recommended for pregnancy" CHMs (**Table 2**), Gleditsiae Sinensis Fructus (Moschus berezovskii Flerov, DaJiaoZao) was recorded with both general effects of chronic toxicity in oral administration to mammals and lethal effects when human took a higher dose. No obvious adverse effects were recorded to the other CHM, Saussureae Involucratae Herba (Saussurea involucrata (Kar.et Kir.) Sch.-Bip., TianShanXueLian). 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.

#### *4.2.2. 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**).

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.

#### **4.3. Animal toxicity data**

In 2 "not recommended for pregnancy" CHMs (**Table 2**), Gleditsiae Sinensis Fructus (Moschus berezovskii Flerov, DaJiaoZao) was recorded with both general effects of chronic toxicity in oral administration to mammals and lethal effects when human took a higher dose. No obvious adverse effects were recorded to the other CHM, Saussureae Involucratae Herba (Saussurea involucrata (Kar.et Kir.) Sch.-Bip., TianShanXueLian). 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

**No. CHM (English) Adverse outcomes Reproductive adverse outcomes**

101 Vaccariae semen 1. Anti-implantation

**Lethal effects Maternal effects Fetal** 

pig, rabbit)

and decrease pregnancy rate; 2. Stimulation on pregnant uterus (rat)

1. Anti-fertility effects; 2. Anti-preganncy effects: termination of pregnancy; 3. Stimulation on uterus (mice, puinea

**effects**

**General adverse** 

56 Chinese Medical Therapies for Diabetes, Infertility, Silicosis and the Theoretical Basis

**effects**

**Table 2.** Adverse outcomes of CHMs for pregnancy [15, 16].

102 Wenyujin rhizoma concisum

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

Generally speaking, more maternal adverse effects were recorded than fetal effects. But this

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

during pregnancy, so it was not recommended for pregnant women.

visceral bleeding, decreased blood pressure then acute circulatory failure.

may be due to the failure of early pregnancy of mothers.

*4.2.2. Maternal and fetal adverse effects*

for pregnancy" CHMs (**Table 2**).

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.




**No. CHM (English) LD50 Dosing Species Remarks**

18 Genkwa flos 9.25 g/kg<sup>2</sup> ip Rat 18 Genkwa flos 1.0–17.78 g/kg1,2 ip, ig Mouse

58 Chinese Medical Therapies for Diabetes, Infertility, Silicosis and the Theoretical Basis

20 Ground beetle 146.45 mg/kg<sup>1</sup> ip Mouse

24 Kansui radix 30–346.1 mg/kg<sup>1</sup> ip Mouse 25 Moschus 152–848 mg/kg<sup>1</sup> ip, iv Mouse 26 Mylabris 1.71–1037 mg/kg1,2 ig, ip, iv Mouse

 Papaveris pericarpium 64–600 mg/kg<sup>1</sup> iH, ip, po Rat Papaveris pericarpium 20–745 mg/kg<sup>1</sup> iH, ip, po, iv Mouse Papaveris pericarpium 18–2200 mg/kg<sup>1</sup> iH, iv, po Rabbit Papaveris pericarpium 160–237 mg/kg<sup>1</sup> po, ip Guinea pig

28 Papaveris pericarpium MLD 60 mg/kg iH Cat 29 Pharbitidis semen 37.5 mg/kg<sup>1</sup> Ih Mouse 30 Phytolaccae radix 11.87–486 mg/kg1,2 ig, ip, iv Mouse 31 Realgar 3.207 g/kg ig Mouse

33 Scolopendra 22.5–9900 mg/kg1,2 ig, ip Mouse

146.45 mg/kg<sup>1</sup> ip Mouse

21 Hirudo 15.28 g/kg<sup>2</sup> iH Male mouse Mouse, po, qd, decoction

22–120.98 mg/kg1,2 ig Mouse

0.25–5850 mg/kg1,2 ig, po, iv, ip, iH Mouse

18 mg/kg<sup>1</sup> ig Rat 0.1–1.5 g HgO<sup>2</sup>

500 and 1000 mg/kg, lower maternal weight, higher resorption rate, fetal malformation rate, higher neonatal mortality

human, death

to

14 Euphorbiae semen 15 Euphorbiae semen pulveratum

16 Eupolyphaga steleophaga

17 Ferulae resina

19 Gleditsiae fructus abnormalis

22 Hydrargyri oxydum rubrum

22 Hydrargyri oxydum rubrum

23 Hyoscyami semen

27 Nigellae semen

32 Rhododendri mollis flos



4 Raw herb.

**No. CHM (English) LD50 Dosing Species Remarks**

54 Bovis calculus 497.5–6630 mg/kg<sup>1</sup> ig, ip, iv Mouse

60 Chinese Medical Therapies for Diabetes, Infertility, Silicosis and the Theoretical Basis

maximum tolerated

773.6(night)mg/kg<sup>2</sup>

dose)

59 Carthami flos 2.35–20.7 g/kg1,2 ig, ig, iv Mouse 60 Cinnamomi cortex 42–46 g/kg1,2 ip Mouse

> (maximum tolerated dose)

63 Croci stigma 20.7 g/kg<sup>1</sup> po Mouse

71 Haematitum 12.90 g/kg<sup>2</sup> iv Mouse 72 I-borneolum 907–4960 mg/kg<sup>1</sup> ig, ip Mouse

74 Leonuri herba 0.572–60 g/kg1,2 iv Mouse 75 Limonitum 8.25 g/kg<sup>2</sup> iv Mouse

78 Meliae cortex 13.8–244.2 mg/kg<sup>1</sup> ip, iv, iH, po Mouse 78 Meliae cortex 9.8 mg/kg<sup>1</sup> iH Rat 78 Meliae cortex 4.2 mg/kg<sup>1</sup> iv Rabbit

907–4960 mg/kg<sup>1</sup> ig, ip Mouse

ig Mouse

ig Mouse

po Mouse

53 Borneolum

55 Bovis calculus artifactus 56 Bovis calculus sativus 57 Bufonis venenum

syntheticum

58 Campsis flos 50 g/kg (raw herb,

61 Cinnamomi ramulus 624.7(daytime)–

62 Coicis semen 10 ml/kg<sup>1</sup>

64 Cyathulae radix 65 Dianthi herba 66 Dichroae radix 67 Echinopsis radix 68 Euphorbiae hirtae herba 69 Ferrous sulfate 70 Gendarussae herba

73 Impatientis semen

76 Manis squama 77 Melanteritum

79 Momordicae semen

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].
