Received: 28 August 2017 Revised: 11 December 2017 Accepted: 11 December 2017

DOI: 10.1002/ptr.6020

REVIEW

Pregnancy and herbal medicines: An unnecessary risk for

women's health—A narrative review
Luciana O. Bruno1 | Ricardo Santos Simoes2 | Manuel de Jesus Simoes3 |

Manoel João Batista Castello Girão1 | Oliver Grundmann 4,5

1
Department of Gynecology, Federal
University of São Paulo (UNIFESP), São Paulo The indiscriminate use of herbal medicines to prevent or to heal diseases or even the use for
04021‐001, Brazil questionable purposes such as weight loss has received both interest and scrutiny from the sci-
2
Department of Obstetrics and Gynecology, entific community and general public alike. An increasing number of women put their own and
University of São Paulo (USP), São Paulo
the unborn child's health at risk due to a lack of knowledge about the phytochemical properties
05508‐010, Brazil
3
and adequate use of herbal medicine (phytomedicines or herbal supplements) and lack of com-
Department of Morphology and Genetics,
Federal University of Sao Paulo (UNIFESP), munication with their healthcare provider. The purpose of this narrative review was to summa-
São Paulo 04021‐001, Brazil rize the use of herbal medicines during pregnancy and their potential toxic effects to highlight
4
Department of Medicinal Chemistry, College the importance of caution when prescribing herbal medicines or supplements for women,
of Pharmacy, University of Florida (UFL), because, in addition to suffering interactions and a great amount of information obtained in
Gainesville 32611FL, USA
5
preclinical predictive studies, assessment of nephrotoxicity, neurotoxicity, hepatotoxicity,
Department of Biobehavioral Nursing
Science, College of Nursing, University of
genotoxicity, and teratogenicity of traditional medicinal herbs still remains scarce in the clinical
Florida (UFL), Gainesville 32611FL, USA setting.
Correspondence
Luciana de Oliveira Bruno, Department of KEY W ORDS
Gynecology, Federal University of São Paulo,
R. Botucatu, 740 – Vila Clementino, São Paulo,
herbal medicine, pregnancy risks, teratogenicity, toxicity
04021‐001 Brazil; or Department of
Morphology and Genetics, Federal University
of São Paulo, R. Botucatu, 740 – Vila
Clementino, São Paulo, 04021‐001 Brazil.
Email: lbrunovet@gmail.com

Funding information
National Council for Scientific and Technolog-
ical Development

1 | I N T RO D U CT I O N contain as active ingredients parts of plants, other plant materials, or

Currently, 65–80% of the world population, especially in developing
countries, rely on herbal medicines in the treatment of diseases, thus
medicinal plants are seen as an essential and often the only way to
treat diseases in the absence of available conventional Western
medicine (Silveira, Bandeira, & Arrais, 2008).
Women often use herbal dietary supplements and herbal medi-
cines during pregnancy, typically based on the belief that the use of
such products is safe (Eisenberg et al., 1993; Fakeye, Adisa, & Musa,
2009; Hall, Griffiths, & McKenna, 2011; Hall, Griffiths, & McKenna,
2013; Kennedy, Lupattelli, Koren, & Nordeng, 2016; World Health
Organization [WHO], 2017). Herbal medicines have been defined by
the World Health as “any medicinal product based on herbs, herbal
materials, herbal preparations and finished herbal products that
combinations thereof” (Andrew & Izzo, 2017; WHO, 2017). According
to a study done in Nigeria (Fakeye et al., 2009), where the use of herbal
medicines in women's health is very common, the reasons and beliefs
are diverse, but among them are the following: medicinal plants have
better efficacy than pharmaceutical drugs (22.4%); herbal medicines
are natural and therefore viewed as safer than conventional drugs dur-
ing pregnancy (21.1%); low effectiveness of conventional medicines
(19.7%); the easy access to herbal medicines (11.2%); the traditional
and cultural belief that herbal medicines can heal many diseases
(12.5%); and comparatively, the low cost of herbal medicines (5.9%).
More than half of respondents (56.6%) did not support the use of com-
bining herbal medicines with conventional drugs to prevent drug–herb
interactions. About one‐third (33.4%) of respondents believed that
herbal medicines have no side effects, whereas only 181 women

Phytotherapy Research. 2018;1–15. wileyonlinelibrary.com/journal/ptr Copyright © 2018 John Wiley & Sons, Ltd. 1
2 BRUNO
(30.4%) had the opinion that side effects of some herbal medicines
could be dangerous (Fakeye et al., 2009; Gohil & Patel, 2007; Hall
et al., 2011; Izzo, Hoon‐Kim, Radhakrishnan, & Williamson, 2016).
In a multinational study, conducted in 18 countries that included
women from Western, Northern, or Eastern Europe, North America,
and Australia, where they chose to use herbal dietary supplements
and herbal medicines (Andrew & Izzo, 2017) during pregnancy because
they consider them safer than pharmaceutical drugs, where the latter
are perceived to have more potential for toxicity to living beings
including humans. Their toxicity includes cardiovascular toxicities and
neurotoxicity and causes diarrhea, cramps, dermatitis, allergic reac-
tions, and so forth (Hall et al., 2011, 2013; Kennedy et al., 2016; Tian
et al., 2011). A study conducted in Canada including 27 pregnant
women selected at random found that they felt more secure about
herbal medicines than pharmaceuticals. Because supplements are
“softer,” “more natural,” “simpler and more familiar,” or “caused fewer
side effects”, it was noticed that the majority of herbal advice (69% in
the presented study) was received by word‐of‐mouth (Hall et al.,
2011; Westfall, 2003).
According to the WHO, 85% of people in the world use medicinal
plants for healing, and 80% of people in developing countries rely on
traditional and/or complementary medicine for their primary health
care needs (Eisenberg et al., 1993; Kennedy et al., 2016; WHO,
2017). In developed countries, traditional medicine adaptations are
called “complementary and alternative medicine” (CAM) that are used
in the maintenance of health and in the prevention, diagnosis, improve-
ment, or treatment of physical and mental illness even if not approved
as such by the regulatory agencies (WHO, 2017).
A narrative review of the literature was conducted by all authors
independently in the following databases: MEDLINE and COCHRANE,
using as strategy of research specific MeSH terms as follows: “Preg-
nancy risks” AND “Herbal Medicine,” “Phytotherapy” AND “Pregnant
Women,” or “Complementary and Alternative Medicine” AND “Preg-
nancy” AND “Toxicity.”
2 | S P E C I F I C C O N S I D E R A T I ON S F O R TH E
U S E OF H E R B A L M E D I C I NE S D U RI N G
PREGNANCY
2.1 | Restrictions for the use of herbal medicine or
medicinal plants for pregnant patients
The indiscriminate use of herbal medicines in combination with or in
place of conventional medicines can be problematic and costly, and it
may lead to altered pharmacokinetics or increased toxicity of certain
drugs (Blumenthal, Goldberg, & Brinckmann, 2000; Bunchorntavakul
& Reddy, 2013; Kristanc & Kreft, 2016; Licata, Macaluso, & Craxì,
2013; Navarro & Seeff, 2013; Silva et al., 2013; Yoon, Horne, & Adams,
2004). Because side effects and teratogenic potential of most herbal
medicines are poorly understood and do not have to be provided to
consumers, herbal dietary supplements are often mistaken as harmless
unless proven otherwise. In addition, herbal dietary supplements or
drug manufacturers usually offer a wide range of semitherapeutic or
general health claims which are powerful temptations for consumers
ET AL.
who think that herbal medicines are better and safer alternatives to
conventional medicines prescribed by their doctors. Previous studies
have shown that many patients had used herbal medicines with good
therapeutic results, although the benefits were later discovered to be
based on the presence of prescription drugs that were added without
declaration (Silva et al., 2013; Kristanc & Kreft, 2016; Teschke &
Schulze, 2013). Patients may even develop significant organic disor-
ders such as renal failure and hepatic or neurological disorders among
other undesirable effects because of the use of adulterated products
(Bunchorntavakul & Reddy, 2013; Silva et al., 2013; Smeriglio,
Tomaino, & Trombetta, 2014).
The consumption of products derived from soy, for example, raises
concerns related to potential effects of phytoestrogen hormones pres-
ent in the extract and potential interference with gestational periods.
Experimental animal studies show that soy isoflavones (foremost the
isoflavonoid genistein) dietary exposure reduced the litter in subse-
quent generations who were continuously exposed to the same diet
and also lead to decreased weight gain in preweaned puppies. In
females, hyperplasia of the mammary gland and calcification of renal
tubules were noted (Delclos & Newbold, 2007; National Toxicology
Program, 2008; Smeriglio et al., 2014; L. D. Zhang et al., 2013).
2.2 | Causes of adverse reactions from the use of
herbal medicine
It is well known that many medicinal plants contain substances that
can trigger adverse reactions, either by its own active ingredients or
by the presence of contaminants (mold, bacteria, dirt, and other) or
adulterants (synthetic drugs, biologicals, etc.; Cordell & Colvard,
2005; Mohamed, Shuid, Borhanuddin, & Fozi, 2012; J. Zhang, Wider,
Shang, Li, & Ernst, 2012). The requirement of a strict quality control
program (physical–chemical and microbiological analyses) has to
include the whole manufacturing process from the cultivation, plant
collection, drying and storage, extract preparation, to the production,
and packaging of the final product. In addition, herbal preparations
may present with both pharmacokinetic and pharmacodynamics inter-
actions if taken in conjunction with other over‐the‐counter or prescrip-
tion drugs (Andrew & Izzo, 2017; Cordell & Colvard, 2005; Gohil &
Patel, 2007; Izzo et al., 2016; Mohamed et al., 2012; J. Zhang et al.,
2012). Some of these interactions are not well studied to date and
hence make healthcare providers reluctant to recommend dietary sup-
plements in general. For example, herbs with the potential to modulate
the activity of drug‐metabolizing enzymes (notable cytochrome P450
isoenzymes that are expressed in intestinal cells and the liver) or drug
transporters (P‐glycoprotein located in the intestinal barrier and the
blood–brain barrier) with clinical significant effects include ginseng
(Panax ginseng), garlic (Allium sativum), echinacea (Echinacea purpurea),
ginkgo (Ginkgo biloba), kava (Piper methysticum), and St. John's wort
(Hypericum perforatum; Alex, Michael, Milin, & William, 2004; Cordell
& Colvard, 2005; Dugoua, Mills, Perri, & Koren, 2006; Ernst, 2002;
Hu et al., 2008; John & Shantakumari, 2015; Lambrigger‐Steiner
et al., 2014; National Research Council, 2000; Orief et al., 2014; Wu,
Nair, & DeWitt, 2002). In addition, a recent review indicates that
traditional Chinese plant extract combinations have the potential to
cause adverse pregnancy outcomes and affect embryonic and fetal
BRUNO ET AL.
development; for example, a case has been reported of a 15 month old
Chinese girl with an accessory phallic urethra (about 1 cm in diameter
and 2 cm long) arising to the right of the anus (Han, Saing, Choi, &
Nicholls, 1997). There are some herbal medicines which can be used
safely during pregnancy, for example, air plant (Bryophyllum pinnatum)
for sleep quality, German chamomile (Matricaria recutita L.) as an
antiinflammatory and uterine tonic but also for anxiety, nausea, and
vomiting, peppermint (Mentha × piperita L.) is the most commonly used
for indigestion/heartburn and nausea/morning sickness, whereas echi-
nacea (Echinacea sp. L.) is used to prevent or treat cold or the flu and in
general boost the immune system; and ginger (Zingiber officinale Roscoe)
is a common herb for nausea and vomiting with potential mild adverse
effects such as drowsiness and heartburn (Araújo, Santiago, Peixoto,
de Oliveira, & de Sousa Coutinho, 2016; Bishop, Northstone, Green, &
Thompson, 2011; Broussard, Louik, Honein, & Mitchell, 2010;
Dennehy, 2011; Holst, Wright, Haavik, & Nordeng, 2011; Kolding,
Pedersen, Henriksen, Olsen, & Grzeskowiak, 2015; Moretti, Maxson,
Hanna, & Koren, 2009; Petersen, McCrea, Lupattelli, Nordeng, 2015;
Orief et al., 2014; Viljoen, Visser, Koen, & Musekiwa, 2014; Wang, Li,
San Lau, Leung, & Fung, 2013). However, clinical data concerning safety
of maternal exposure to herbal medicines during pregnancy are often
inconclusive due to small sample sizes, ethical reservations, and incom-
plete study designs. Some individual clinical trials of Chinese medicines
reported some adverse effects during pregnancy, whereas animal stud-
ies identified more significant adverse maternal and perinatal effects
and the potential for embryonic toxicity (Ernst, 2002; Posadzki, Watson,
& Ernst, 2013; Scott Jr & Treff, 2010).
2.3 | Teratogenic potential of herbal medicines
Several common complaints are reported by pregnant or lactating
women who are adept to the use of herbal medicines for common
pregnancy symptoms. As cited before, ginger is used for nausea,
Devil's claw used for back pain, kava is used for anxiety, Horse chest-
nut for varicose veins, and St. John's wort for depressive disorders
(Dennehy, 2011; Ernst, 2002; Ujházy, Mach, Navarová, Brucknerová,
& Dubovický, 2012). Many pregnant women are therefore tempted
to use phytomedicines over prescription drugs because of the per-
ceived risks of conventional drugs (John & Shantakumari, 2015; Ton,
Lin, & Willett, 2006).
As previously mentioned, side effects and the possibility of terato-
genic effects of herbal medicines in pregnant women are not clear
because of insufficient clinical data. A teratogenic agent is defined as
any substance, organism, physical or chemical agent, or nutritional
deficiency, present through the embryonic or fetal development that
produces a change in the structure or function of the offspring (Bishop
et al., 2011; Dugoua, Mills, et al., 2006; Dugoua, Perri, Seely, Mills, &
Koren, 2008; Dugoua, Seely, Perri, Koren, & Mills, 2006; Dugoua,
Seely, Perri, Koren, & Mills, 2008; Moretti et al., 2009; Ouedraogo
et al., 2012; Ton et al., 2006).
A review of clinical studies attempted to summarize and alert
healthcare professionals to the fact that herbal medicines are not
entirely free of risks for pregnant or lactating women. Tables 1 and 2
summarize common herbal medicines and their potential adverse
effects during pregnancy which include teratogenic, mutagenic,
3
genotoxic, emmenagogue, abortifacient, uterine stimulant, oxytocic,
and other effects (Baum, 2007; Blumenthal et al., 2000; Brinker,
2010; Broussard et al., 2010; Buehler, 2003; Ernst, 2002; Goel, Prabha,
Kumar, Dorababu, & Prakash, 2006; Han et al., 1997; Kolding et al.,
2015; Kristanc & Kreft, 2016; National Research Council, 2004;
Ouedraogo et al., 2012; Petersen et al., 2015; L. D. Zhang et al., 2013).
Despite a plethora of information obtained in predictive preclinical
studies, the nephrotoxicity, neurotoxicity, hepatotoxicity, genotoxicity,
and teratogenicity assessment of traditional herbal medicines remains
scarce in the clinical setting. There have been advances with
researchers in the postgenome era having dedicated their focus to
the development of rigorous methods, considering the reliability and
interpretation of endpoints, with the intent of regulating the integra-
tion of conventional methods for toxicity assessments with new
“omics” technologies (Ernst, 2002; Ouedraogo et al., 2012). This has
not yet been fully implemented and extended through the field of
herbal medicines.
In this section, we will focus on teratogenic effects. This area of
research has been advanced because of the proteomics and metabolomics
studies combining the clinical signs and histopathological approaches
available. Hopefully, the omics technologies have the potential for
the development of molecular markers allowing for detection of early
changes in signal transduction, regulation, and biochemistry during cell
division with high sensitivity and specificity (Ouedraogo et al., 2012).
Toxins that can lead to developmental abnormality or fetal death
are described by the term “teratogens”; the teratogenicity is the capac-
ity of a chemical or phytochemical compound to cross the placental
barrier in sufficient concentration to be active at a specific time during
the pregnancy (Ernst, 2002; Blumenthal et al., 2000; Brinker, 2010;
Ouedraogo et al., 2012; Ton et al., 2006). A majority have identified
that the teratogenic mechanisms rely on neural crest cell disruption,
endocrine disruption, vascular disruption, folate antagonism, oxidative
stress, and specific receptor‐ or enzyme‐mediated teratogenesis
(van Gelder et al., 2010; Lather, Valecha, & Sharma, 2011). Although
the literature details copious lists of herbs that are supposedly contra-
indicated during pregnancy (Lather et al., 2011), most herbal supple-
ments and medicines have never been assessed and may contribute
to the baseline birth defect rate described below. The baseline birth
defect rate is about 6% globally but varies considerably between 2%
and 8% with respect to type of defect, time, place, and other demo-
graphic, genetic, and environmental factors (Keeler, 1984). It is not
known if this baseline rate is a normal frequency of errors in the highly
complex developmental process or the consequence of as yet uniden-
tified environmental or dietary factors. Between 1% and 3% of all birth
defects have been suggested to be due to exposure to chemicals and
drugs, but this figure is a rough estimate (Wang et al., 2013). A compar-
ison between the major methods developed for teratogenicity assess-
ment is shown in Table 3 (Ouedraogo et al., 2012).
The current tests employed for teratogenicity assessment with
examples have been employed in various herbal medicines point to a
diverse range of applications based on susceptible cell lines as in the
case of dihydroartmeisinin and red blood cells in the whole embryo
culture test. The most commonly employed preclinical teratogenicity
test is the zebrafish test due to its high success rate of true positives
and its ease of use and inexpensive nature. In most cases, a secondary
 4
TABLE 1 Medicinal plants/herbal drugs with primary emmenagogue and/or abortifacient effectsa
Species and dose range
Common name Latin name Effects on uterus Traditional/clinical use for effects on uterus Studies for effects on uterus

Angelica Angelica Emmenagogue effects and uterine contractions Dyspepsia and premature Isolated rat uterus, (Du et al., 2006)
ejaculation ligustilide 2‐8 μg/ml
Asafoetida Ferula asafoetida Emmenagogue effects Bronchitis and asthma (Tiwari, Majumder, &
Bhattacharjee, 1982)
Ashwagandha Withamia somnifera Abortifacient properties and uterine relaxation Stress (Mir, Khazir, Mir, Hasan, &
Koul, 2012)
Basil Ocimum basilicum Emmenagogue and contraceptive effects Acne and stomach spasms Rats, 364 and 624 mg/kg (Bilal, Jahan, Ahmed, Bilal, &
Habib, 2013)
Bitter melon Momordica Emmenagogue and abortifacient effects Diabetes (Grover & Yadav, 2004)
charantia
Black cohosh Cimicifuga Estrogenic activity, suppresses endogenous luteinizing hormone secretion (in rats) Menopausal symptoms (hot (Dugoua, Seely, et al., 2006)
racemosa and binds to uterine estrogen receptors, reduces circulating luteinizing hormone flashes, vasomotor
levels. Emmenagogue effects symptoms, and anxiety)
Bloodroot Sanguinaria Emmenagogue and uterine stimulant Dental plaque and gingivitis (Croaker, King, Pyne,
canadensis Anoopkumar‐Dukie, & Liu,
2016)
Blue cohosh Caulophyllum Stimulates contraction of uterine muscle, inhibits embryo implantation (in rats), Laxative, antispasmodic, and (Dugoua, Perri, et al., 2008;
thalictroides alleged to induce menstruation, and promote abortion induction of labor Rao & Hoffman, 2002)
Boneset Eupatorium Abortifacient effects (contains pyrrolizidine alkaloids) Common cold (Roeder, Wiedenfeld, & Edgar,
perfoliatum 2015)
Borage Borago officinalis Mutagenic effects (contains pyrrolizidine alkaloids) Rheumatoid arthritis and (Roeder et al., 2015)
acute respiratory distress
syndrome
Buckthorn Rhamnus Abortifacient, mutagenic and genotoxic effects Constipation (Kumar, Kumar, & Prakash,
catharticus 2012)
Bugleweed Lycopus virginicus Antigonadotropic and antithyrotropic activities Hyperthyroidism, breast pain, Rats (Winterhoff, Gumbinger, &
and nervousness Sourgens, 1988)
Butterbur Petasites hybridus Emmenagogue, hepatotoxic, genotoxic, and carcinogenic effects Allergic rhinitis and migraine (Roeder et al., 2015)
headache
Calamus Acorus calamus Emmenagogue and genotoxic activities Digestive disorders (Rajput, Tonge, & Karuppayil,
2014)
Calendula Calendula officinalis Emmenagogue and abortifacient effects Anal fissures and diaper rash (Basch et al., 2006)
Cascara sagrada Rhamnus Abortifacient, mutagenic, and genotoxic actions Constipation (Johns & Sibeko, 2003)
purshinana
Cassia Cinnamomum Emmenagogue and abortifacient effects Diabetes (Ulbricht et al., 2011)
cinnamon aromaticum
Castor bean Ricinus communis Emmenagogue and abortifacient effects Bowel preparation, Guinea pig, R. communis (Makonnen, Zerihun, Assefa,
constipation, and seed extract & Rostom, 1999)
contraception

BRUNO
Catnip Nepeta cataria Emmenagogue and abortifacient effects Insomnia, migraine headache, (Sarkar, Rashmi, Vikramaditya,
and mosquito repellant & Varma, 1995)

ET AL.
(Continues)
TABLE 1 (Continued)

BRUNO
Species and dose range
Common name Latin name Effects on uterus Traditional/clinical use for effects on uterus Studies for effects on uterus

ET AL.
Chamomile Chamaemelum Emmenagogue and abortifacient effects Indigestion, nausea, and (Farnsworth, Bingel, Cordell,
(Roman) nobile vomiting Crane, & Fong, 1975)
Chaste tree Vitex agnus‐castus Emmenagogue effects Premenstrual (Dugoua, Seely, et al., 2008)
dysphoricdisorder and
premenstrual syndrome
Chicory Cichorium intybus Emmenagogue and abortifacient effects Tonic, diuretic, and laxative (Balbaa, Zaki, Abdel‐Wahab,
El‐Denshary, & Motazz‐
Bellah, 1973)
Cinchona Cinchona Abortifacient, uterine stimulant, oxytoxic, and teratogenic effects Appetite stimulant, Mice, 1–4.5 ml/kg (do Amaral et al., 2014)
gastrointestinal stimulant,
and leg cramps
Cola nut Cola nitida, caffeine Low birthweight, birth defects, and premature birth Obesity and fatigue Linear increase above (Rhee et al., 2015)
100 mg caffeine/day
Coltsfoot Tussilago farara Contains hepatotoxic pyrrolizidine alkaloids, risk of fatal hepatic veno‐occlusive Bronchitis, asthma, and (Roeder et al., 2015)
disease, and abortifacient effects pertussis
Comfrey Symphytum Contains hepatotoxic pyrrolizidine alkaloids, risk of fetal hepatic veno‐occlusive Osteoarthritis, back pain, and (Roeder et al., 2015)
officinale disease, and hepatotoxic and carcinogenic in animals sprains
Fennel Foeniculum vulgare Emmenagogue effects Colic and lactation (Albert‐Puleo, 1980)
Feverfew Tanacetum Emmenagogue effects Migraine headache (Pareek, Suthar, Rathore, &
parthenium Bansal, 2011)
Flaxseed Linum usitatissimum Estrogenic effects Diabetes, hypertension, and Hen ovaries (Dikshit, Gao, Small, Hales, &
hypercholesteremia Hales, 2016)
Garlic Allium sativum Abortifacient effects Atherosclerosis, colorectal (Farnsworth et al., 1975)
cancer, and hyperlipidemia
Guarana Paullinia cupana, Low birthweight, birth defects, and premature birth Obesity, fatigue, and anxiety Linear increase above (Rhee et al., 2015)
caffeine 100 mg caffeine/day
Hemp agrimony Eupatorium Contains hepatotoxic pyrrolizidine alkaloids and emmenagogue and abortifacient Colds and fever (Roeder et al., 2015)
cannabinum effects
Hibiscus Hibiscus rosa‐ Emmenagogue effects Hypertension Rats, 100 mg/kg water (Nivsarkar, Patel, Padh, Bapu,
sinensis extract & Shrivastava, 2005)
Horehound Marrubium vulgare Emmenagogue and abortifacient effects Diabetes Rats, 1 g/kg subchronic (Aouni, Ben, Jaafoura, Bibi‐
for 19 days Derbel, & Haouari, 2017)
Joe‐pye weed Eupatorium Contains hepatotoxic pyrrolizidine alkaloids and abortifacient effects (Roeder et al., 2015)
purpureum
Juniper Juniperus communis Increase uterine tone; possible anti‐implantation, and abortifacient and Cathartic in large doses, Mice, 15–135 ml/kg, (Pages et al., 1989)
emmenagogue effects diuretic subchronic for 15 days
Khella Ammi visnaga, Emmenagogue and uterine stimulant Colic and abdominal cramps (Al‐Snafi, 2013)
khelline
Knotweed Polygonum Abortifacient effects Bronchitis, cough, and (Daniyal & Akram, 2015)
aviculare gingivitis

(Continues)

5
TABLE 1 (Continued)

6
Species and dose range
Common name Latin name Effects on uterus Traditional/clinical use for effects on uterus Studies for effects on uterus
Licorice Glycyrrhiza glabra Emmenagogue effects Dyspepsia and atopic (Parvaiz et al., 2014)
dermatitis
Golden ragwort Senecio aureus Contains hepatotoxic pyrrolizidine alkaloids and emmenagogue and teratogenic Diabetes and hypertension (Roeder et al., 2015)
effects
Lovage Levisticum officinale Emmenagogue effects Diuretic and urinary tract Brine shrimp (Hogg, Svoboda, Hampson, &
infections Brocklehurst, 2001)
Madagascar Vinca rosea Teratogenic effects Diabetes and cancer Mice, 0.767 mg/kg for (Cohlan & Kitay, 1965)
periwinkle 6 days
Madder Rubia tinctorum, Genotoxic and emmenagogue effects Kidney stones and urinary Ames test, 5–100 μg/ml (Blomeke, Poginsky,
lucidin disorders Schmutte, Marquardt, &
Westendorf 1992)
Male fern Dryopteris filix‐mas Abortifacient effects Nose bleeds and heavy (Srivastava, 2007)
menstrual bleeding
Marjoram Origanum Emmenagogue effects Asthma, rhinitis, and colds (Bina & Rahimi, 2017)
marjorana
Marsh tea Rhododendron Abortifacient effects Whooping cough, bronchitis, (Popescu & Kopp, 2013)
tomentosum and cold
Masterwort Heracleum lanatum Emmenagogue effects Muscle cramps and stomach (Kuhnlein & Turner, 1986)
disorders
Yerba mate Ilex paraguariensis, Low birthweight, birth defects, and premature birth Cognitive function, diabetes, Linear increase above (Rhee et al., 2015)
caffeine and fatigue 100 mg caffeine/day
Motherwort Leonurus cardiaca Emmenagogue effects Sleep, arrhythmias, and Human, 165 assigned to (Liu, Ma, Pan, & Tan, 2016)
amenorrhea oxytocin or oxytocin
plus motherwort group
(40 mg injected
solution)
Mugwort Artemisia vulgaris Emmenagogue and abortifacient effects Colic, diarrhea, and cramps Rats, 300–600 mg/kg (Shaik et al., 2014)
Myrrh Commiphora Emmenagogue and abortifacient effects Indigestion, ulcers, and cold Case study (Al‐Jaroudi, Kaddour, & Al‐
myrrha Amin, 2017)
Nutmeg Myristica fragrans Abortifacient and mutagenic effects Diarrhea, nausea, and gastric (Carstairs & Cantrell, 2011)
spasms
Parsley Petroselinium Emmenagogue and abortifacient effects Urinary tract infections and (Farzaei, Abbasabadi,
sativum kidney stones Ardekani, Rahimi, & Farzaei,
2013)
Pennyroyal Mentha pulegium Abortifacient effects Antispasmodic, antiflatulent, (Gordon & Khojasteh, 2015)
and diaphoretic
Peony Paeonia officinalis Emmenagogue effects Aging skin and muscle cramps Mice, 0.54 and 1.08 g/kg (Sun et al., 2016)
in combination extract
Peppermint Mentha piperita Emmenagogue effects Irritable bowel syndrome, Rats, 20 g/L (Guney, Oral, Karahanli,
common cold, and Mungan, & Akdogan, 2006)

BRUNO
bronchitis

(Continues)

ET AL.
 BRUNO
ET AL.
TABLE 1 (Continued)

Species and dose range

Common name Latin name Effects on uterus Traditional/clinical use for effects on uterus Studies for effects on uterus
Pomegranate Punica granatum Emmenagogue and uterine stimulant effects Atherosclerosis and chronic Rat, 250 mg/ml (Promprom, Kupittayanant,
obstructive pulmonary Indrapichate, Wray, &
disorder Kupittayanant, 2010)
Prickly ash Zanthoxylum Emmenagogue effects Cramps and intermittent (Patiño, Prieto, & Cuca, 2012)
americanum claudication
Rosemary Rosmarinus Decreased uterotropic effects of estrogens Dyspepsia, flatulence, and Mice, 2% rosemary diet (Zhu et al., 1998)
officinalis inducing abortion
Rue Ruta graveolus Emmenagogue and abortifacient effects Menstrual disorders and Mice, 1,000 mg/kg on (de Freitas, Augusto, &
abortifacient pregnancy Days 1–9 Montanari, 2005)
Safflower Carthamus Altered endometrium lining, altered fertility, and possible emmenagogue and Hypercholesteremia Cows, 95.3% lineolate (Scholljegerdes et al., 2007)
tinctorius abortifacient effects. safflower
Saffron Crocus sativus, Emmenagogue, teratogenic, and abortifacient effects Alzheimer's disease, Mice, 200 or 600 mg/kg (Moallem, Afshar, Etemad,
safranal and depression, and crocin, 0.075 or Razavi, & Hosseinzadeh,
crocin dysmenorrhea 0.225 ml/kg safranal 2016)
Sage Salvia officinalis, Emmenagogue and abortifacient effects Alzheimer's disease, cognitive (Raal, Orav, & Arak, 2007)
thujone performance, and herpes
labialis
Savin Juniperus sabina Abortifacient effects Abortion (Schiebinger, 2000)
Scotch broom Cytisus scoparius Abortifacient effects Edema and improving (Belew, 1999)
circulation
Shepherd's Capsella bursa‐ Emmenagogue and abortifacient effects Headache and mild cardiac (Al‐Snafi, 2015)
purse pastoris insufficiency
St. John's wort Hypericum Emmenagogue, teratogenic, and abortifacient effects Depressive disorders, (Dugoua, Mills, et al., 2006)
perforatum menopausal symptoms, and
somatization disorders
Watercress Nasturtium Emmenagogue and abortifacient effects Respiratory tract infections, (Shaik, Yalavarthi, & Bannoth,
officinale cough, and bronchitis 2017)
Wild cherry Prunus serotina Teratogenic effects Cold, whooping cough, and (Selby et al., 1971)
bronchitis
Wormseed Chenopodium Emmenagogue and abortifacient effects (Dembitsky, Shkrob, & Hanus,
ambrosioides 2008)
Wormwood Artemesia Emmenagogue and abortifacient effects Fever, anthelmintic, and (Raal et al., 2007)
absinthium, digestive disorders
thujone
Yellow cedar Thuja occidentalis Emmenagogue and abortifacient effects Common cold, herpes labialis, Rats, 500 mg/kg extract, (Akkol et al., 2015)
and sinusitis 5 mg/kg thujone
a
The information contained in this table has been collated from Ernst (2002).

7
8 BRUNO ET AL.

TABLE 2 Medicinal plants/herbal drugs with primary uterine stimulant or relaxing effectsa
Common Species and dose range Studies for
name Latin name Effects on uterus Traditional/clinical use for effects on uterus effects on uterus

Alfalfa Medicago sativa May cause uterine Hyperlipidemia Rodents, doses in regular (Naciff et al., 2004)
stimulation feed
Barberry Berberis vulgaris Uterine stimulant Diabetes and gingivitis Mice, 5.46 mg/d equivalent (Liu et al., 2011)
mediated by to 42 g/d for humans
alkaloid berberine
Broom Cytisus scoparius Contains sparteine, Induction of labor (isolated 711 female patients, various (Schulman &
a powerful sparteine) and no clinical doses of sparteine for Ledger, 1965)
oxytocic compound, use for extracts induction of labor
traditionally used
to induce labor
Buttercup Ranunculus acris Uterine stimulant No clinical use for extracts Isolated rat uterus, doses (Bhargava, Kishor, Pant,
and traditional use for not mentioned, tryptamine & Saxena, 1965)
migraine derivatives likely
responsible
Celandine Chelidonium majus Uterine stimulant Dyspepsia Isolated swine uterus, (Kuenzel et al., 2013)
dose range from
0.5–2.5 mg/ml with
effects between 1
and 2 mg/ml
Ephedra Ephedra sinica, Contains ephedrine Obesity, banned by Food Rats, chronic administration (Arbo et al., 2009)
(Ma Huang) Ephedra equisetina and related alkaloids, and Drug Administration of ephedra extract 85.5
(and others) increases blood in 2004 and 855 mg/kg and
pressure, heart rate, ephedrine5 mg/kg,
causes central nervous antiestrogenic
system activity, effect through increased
and stimulates uterine uterine weight
muscle.
Goldenseal Hydrastis canadensis Uterine stimulant No clinical use for extracts, Mice, 5.46 mg/d equivalent (Liu et al., 2011)
mediated by traditional use for upper to 42 g/d for humans
alkaloid berberine respiratory tract
infections and allergic
rhinitis
Ipecac Cephalis ipecacuanha Uterine stimulant No clinical use for extracts, Humans, no dose mentioned (Nussey, Hawthorn,
past use as emetic in toxic Page, Ang, & Jenkins,
ingestions, and rarely 1988)
used today
Kava Piper methysticum Loss of uterine tone Anxiety disorders Case reports (Meyer &
(likely due to pyrone Dierstein, 1965)
constituents)
Passionflower Passiflora incarnata Uterine stimulant Anxiety disorders Isolated guinea pig uterus (Pilcher, Delzell, &
Burman, 1916)
Raspberry Rubus idaeus Stimulates contraction Labor facilitation Isolated rat uterus (Zheng, Pistilli,
in strips of pregnant Holloway, &
human uterus, Crankshaw, 2010)
antigonadotrophic
and estrogenic
activities
Rhubarb Rheum palmatum Uterine stimulant Herpes labialis Ovariectomized rats, (Keiler, Papke,
and mutagenic and renal failure 1 mg and 1 g rhubarb Kretzschmar,
and genotoxic extract Zierau, &
effects Vollmer, 2012)
Valerian Valeriana officinalis Causes uterine Anxiety and sleep Isolated human uterus (Occhiuto et al., 2009)
relaxation disorders muscles, extracts
10–80 μg/ml, single
compounds
0.5–4 μg/ml
a
The information contained in this table has been collated from Ernst (2002).

test has to be conducted which may be in whole animals and then has
to consider general testing. This has confirmed the genotoxic and ter-
atogenic effects of Scutellaria baicalensis and Epimedium sp. Even if
such findings are not confirmed in clinical studies, there may at times
be case reports from traditional uses that support them and hence lead
to the recommendation not to use such herbal medicines during preg-
nancy (Costa, Bezerra, Norte, Nunes, & Olinda, 2012).
Because toxicological testing with animals is time‐consuming,
expensive, and raises serious ethical issues, there is an urgent need
to develop alternative or complementary models to support the 3Rs
principle (replace, reduce, and refine) in animal testing (Bhogal,
Grindon, Combes, & Balls, 2005; National Centre for Replacement
Refinement & Reduction of Animals in Research, 2017). Reproductive
medicine is now entering the exciting era of the omics approach
BRUNO ET AL. 9

TABLE 3 Comparison of in vitro and in vivo methods for teratogenicity assessmenta

Example of tested herbs or natural
Test Principle Specificity/sensitivity compounds

Mammalian micromass Cells from the rat limb bud (Day 14 of Overall accuracy of 70% Foeniculum vulgare L. (no
assay gestation) tested for differentiation into teratogenicity)
chondrocytes. Evaluation with a
chondrocyte‐specific dye
Fish embryo toxicity test Zebrafish embryos are observed for 48 hr 75% success rate in identifying Flavonoids, delta‐9‐
for lethal and sublethal endpoints nonteratogenic compounds; 100% tetrahydrocannabinol, arecoline
success rate in identifying teratogenic
compounds, international
standardization (ISO 15088)
Methods based on Determination and evaluation of three Good reproducibility; overall accuracy of Epimedium sp. (the flavonol icariin
mammalian stem cells endpoints (cytotoxicity assays on both 78%, validation data published stimulates ESC differentiation in
and embryos, ESCs and 3T3 fibroblasts; ESC cariomyocytes); Boehmeria nivea
embryonic stem cell differentiation inhibition assay) L. (nonembryotoxic)
(ESC) tests
Methods based on During the first 96 hr, Xenopus embryo Overall accuracy in predicting teratogenic Solanum tuberosum (glycoalkaloid
embryos of lower order development parallels many of the major potential has been in the range of 79– chaconine shows teratogenicity),
species. Frog embryo processes of human organogenesis 83%. The test is considered not artemisinin (teratogenic effects)
teratogenesis assay— (measurement of mortality, sufficiently validated or optimized for
Xenopus malformation, and growth inhibition) regulatory applications.
Mammalian whole Embryos are isolated on Day 10 of Overall accuracy of 80% Dihydroartemisinin primarily
embryo culture test gestation and cultured for 48 hr; affects primitive red blood cells,
morphological, developmental, causing subsequent tissue
functional, and growth parameters are damage and dysmorphogenesis
measured
Mice and rats Prenatal development toxicity, two Correct classification of 83% of tested Fetal and maternal adverse effects:
generation reproduction toxicity, chemicals, Organization for Economic Psoralea crylifolia L., Ligusticum
reproductive/developmental toxicity Cooperation and Development test chuanxiong Hurt., Scutellaria
screening, repeated dose toxicity guidelines baicalensis Georgi
combined with reproductive/ No adverse effect: Boehmeria nivea L.
developmental toxicity screening, and (test of combinations indicate
postnatal growth and viability protective interactions)
a
The information contained in this table has been collated from Ouedraogo et al. (2012).

(Scott Jr & Treff, 2010; Ouedraogo et al., 2012); the current omics
approaches for predicting teratogenicity are applied in teratology but
are still in its infancy. However, their advent has added further impetus
to the development of alternatives to in vivo preclinical toxicity testing
(Araújo et al., 2016; Bhogal et al., 2005; Costa et al., 2012; Luijten
et al., 2010; March of Dimes Birth Defects Foundation, 2006;
Ouedraogo et al., 2012; Scott Jr & Treff, 2010).
At least 17 signaling pathways have been described during fetal
development with specific periods of activity; six of these are
known to be crucial for early development in most animals,
whereas four are more active in late development (Lather et al.,
2011; Ton et al., 2006). Studies of these pathways have been
explored by omics methods in animal or cell models that may give
important clues about teratogenic agents and allow the develop-
ment of high‐throughput tests for teratogenicity biomarker assays
(Ouedraogo et al., 2012).
3 P O T E N T I A L TO X I C I T Y OF
| Recent experimental studies have shown that nanoparticles can inter-
NANOTECHNOLOGY FORMULATIONS OF
H E RB A L M E D I C I N E S D U R I N G P RE G N A N C Y
The application of nanotechnology methods for the treatment, identi-
fication, monitoring, and management of biological systems in recent
studies has been referred to as nanomedicine. As this relates to herbal
formulation research, incorporating nano‐based formulations have a
number of advantages for phytomedicine including improvement of
solubility and bioavailability, safeguard from toxicity, enhancement of
pharmacological activity, improvement of stability, increase in tissue
macrophage distribution, sustained delivery, and protection from phys-
ical and chemical degradation (Amorim & Scott‐Fordsmand, 2012;
Ansari, Islam, & Sameem, 2012; Blum, Xiong, Hoffman, & Zelikoff,
2012; Gunasekaran, Haile, Nigusse, & Dhanaraju, 2014; Ton et al.,
2006). Thus, nano‐phytomedicine has a prospective future for improv-
ing the activity and overcoming problems associated with herbal drugs
(Ansari et al., 2012; Gunasekaran et al., 2014; Hu et al., 2008). Despite
these encouraging findings, nanoparticles decomposed gradually after
insertion into the body and can pose risks to the biological system par-
ticularly throughout its early development (Amorim & Scott‐
Fordsmand, 2012; Ansari et al., 2012; Gunasekaran et al., 2014; Hu
et al., 2008).
With the introduction of new technologies in the delivery of
phytomedicines comes the need to test such formulations and the
respective chemicals for the possibility of functional teratogenicity.
fere with development processes that can affect important reproduc-
tive functions among other physiological parameters. The evaluation
of reproductive function and of health risks through the development
and implementation of these technologies will be topics of great
importance in the near future (National Centre for Replacement
Refinement & Reduction of Animals in Research, 2017; Ouedraogo
et al., 2012).
10
4 | RESULTS A ND DIS CUS SION
Out of 151 included articles, the conclusion is that a lack of knowledge
and clinical data to properly inform both women and their healthcare
provider's remains. These findings should be considered in the formu-
lation of public policies for promoting the rational use of herbal medi-
cines during pregnancy and maintaining the quality of women's health.
The inclusion of herbal medicine within the definition of CAM
can give the false impression that they are harmless and can be used
without caution (Baum, 2007; Buehler, 2003; Hall, McKenna, &
Griffiths, 2012; Kennedy et al., 2016; Ramawat, Dass, & Mathur,
2009). Nevertheless, herbal medicines have the potential to cause
the same types of adverse reactions than conventional drugs because
they consist of whole extracts or, more commonly, of defined parts of
the plant used for each preparation (e.g., roots, rhizomes, leaves, and
flowers) that may contain numerous active constituents in varying
concentrations (Baum, 2007; British National Formulary [BNF],
2016; Buehler, 2003; Ramawat et al., 2009). The BNF advises that
the prescription of drugs should only be done if the expected benefit
to the mother is thought to be better than the risk to the fetus. And if
prescribed, there is little evidence of drug avoidance in the first tri-
mester of pregnancy (BNF, 2016).
Moreover, in most countries, medicinal plants are sold as dietary
supplements, even as herbal drugs (use with pharmaceutical/nutraceu-
tical purpose; Andrew & Izzo, 2017), without a license and are available
to consumers as items that do not require prescription. In many cases,
dietary supplements are not sufficiently regulated and do not require
the same thorough research in regard to effectiveness and safety as
conventional medicines with the risk of contamination or tampering
with the addition of toxic metals, undeclared plants, or synthetic drugs
(Buehler, 2003; Hall et al., 2011; Nordeng, Bayne, Havnen, & Paulsen,
2011; Ramawat et al., 2009).
A recent study from North East Scotland indicated that a wide
variety of CAM therapies (including herbal medicines) was actually rec-
ommended to pregnant women by approximately a third of healthcare
professionals (BNF, 2016; Hall et al., 2011, 2013; Kennedy et al., 2016;
Stewart, Pallivalappila, Shetty, Pande, & McLay, 2014). However, in
one multinational study, most women (80%) used herbal medicine in
pregnancy on their own initiative rather than as the result of a recom-
mendation by a healthcare professional (physicians, naturopaths, mid-
wives, etc.; Kennedy et al., 2016; Stewart et al., 2014). Thus, the
main reason for the use of medicinal plants by consumers and patients
seems to be the perception of safety where plant preparations are con-
sidered safer than pharmaceutical drugs. In fact, as pregnant women
recognize the potential risks of pharmaceutical drug use, they often
do not realize that herbal medicines may be taken incorrectly and
can also be associated with adverse effects and drug interactions. This
stems from the implicit belief that basic herbal medicines, being natu-
ral, are necessarily safe (Baum, 2007; Bent, 2008; Buehler, 2003;
Bunchorntavakul & Reddy, 2013; Hall et al., 2011; Herbal Medicine
Advisory Committee, 2014; Kennedy et al., 2016; Ramawat et al.,
2009; J. Zhang et al., 2012; J. Zhang, Onakpoya, Posadzki, & Eddouks,
2015).
The knowledge of the potential side effects of many herbal medi-
cines used during pregnancy is limited, and some of these herbal
BRUNO ET AL.
medicines have been shown to be teratogenic in humans and animal
models (Araújo et al., 2016; Blumenthal et al., 2000; Brinker, 2010;
Buehler, 2003; Dicke, 1989; Ernst, 2002; van Gelder et al., 2010; Goel
et al., 2006; Lather et al., 2011; March of Dimes Birth Defects Founda-
tion, 2006; Tian et al., 2011; Ujházy et al., 2012). Therefore, the Med-
icines and Healthcare Products Regulatory Agency in the United
Kingdom recognizes patients who are pregnant or breastfeeding, chil-
dren, and the elderly as patients at increased risk for adverse effects
when using herbal medicines, because products are usually not tested
in these populations (Alex et al., 2004; Ansari et al., 2012; BNF, 2016;
Ernst, 2000; Herbal Medicine Advisory Committee, 2014; John &
Shantakumari, 2015; Kristanc & Kreft, 2016; National Toxicology
Program, 2008; J. Zhang et al., 2015).
Several factors may be related to a growing demand for herbal
medicines as a therapeutic alternative to conventional medical
approaches. Among these are the disappointments with conventional
treatments, undesirable effects caused by the use and/or misuse of
synthetic drugs, the fact that part of the world population has no
access to manufactured drugs, and the popular belief that what is
“natural” is harmless.
The use of herbal medicines by diverse populations for thousands
of years is considered by some authors and regulators as a safety indica-
tor, but effects such as teratogenicity, drug interactions, or other more
subtle evidence of reproductive toxicity are not always easily associated
with the use of these products by the lay population. The use of any
medication during pregnancy should always be evaluated for its risk‐
to‐benefit ratio. This same caution should be applied to the use of herbal
medicines. Thus, for each specific situation, a proper risk‐to‐benefit
evaluation and ratio should be established. In many cases, this ratio is
not available or has not been determined with sufficient certainty for
medicinal plants to date. In the presence of any evidence that suggests
a risk for either the pregnant woman or the developing fetus, the use of
such plants and their extracts should be avoided.
Based on a widespread lack of sufficient clinical evidence to sup-
port the safety of herbal medicines during pregnancy and
breastfeeding, such extracts should, in general, be avoided with only
a few exceptions as mentioned in this review. Furthermore, the safety
of a wide range of herbal medicines and their extracts has not been
well determined in other populations, specifically children and the
elderly. Patients and healthcare providers who wish to complement
conventional medical approaches with medicinal plants should move
forward with caution and evaluate herbal extracts on a case‐by‐case
basis for benefits, adverse effects, and potential drug interactions. If
such products will be used in these special populations, both the
patient and the healthcare provider should choose products that have
been manufactured according to best practices and under strict quality
control guidelines as well as being associated with sufficient clinical
evidence that support their safe and efficacious use for the intended
application.
5 | CO NC LUSIO N
We concluded that in addition to the lack of adequate knowledge of all
the compounds present in plant extracts and their possible therapeutic
BRUNO ET AL.
and/or harmful effects, the prescription of herbal remedies or even
medicinal herbal teas should be done in a very thoughtful way and cau-
tiously, considering that this may present undesirable effects for both
patients in general, but especially in relation to the class of patients
in the gestational period, especially in the first trimester in which the
embryo is in development, because it is precisely at this stage that
anomalies that are induced by the teratogenic agents (chemical, phys-
ical, or biological) can occur. In the case of medicinal plants, the exact
compounds are often not known which may cause malformations,
and information is often based on case reports. Clinical studies are
often lacking or provide limited information. A majority of current rec-
ommendations are based on animal studies which may not adequately
reflect human conditions and embryo development. Further research
and longitudinal observational studies are necessary to provide
supporting information on the use of herbal medicines during
pregnancy.
ACKNOWLEDGEMEN T
We thank the National Council for Scientific and Technological Devel-
opment (CNPq) for the research grant we received during the develop-
ment of this study.
CONF LICT OF INTE R ES T
All authors have seen and approved the manuscript, and there is no
conflict of interest to declare.
ORCID
Luciana O. Bruno http://orcid.org/0000-0002-1603-3777
Oliver Grundmann http://orcid.org/0000-0003-2302-8949
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