See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/327332754

Double-blind randomized placebo-controlled trial on efficacy and safety of

Lactuca sativa L. seeds on pregnancy-related insomnia

Article in Journal of Ethnopharmacology · August 2018

DOI: 10.1016/j.jep.2018.08.001

CITATIONS READS

10 422

8 authors, including:

Ayda Hosseinkhani Nasrin Asadi

Shiraz University of Medical Sciences Shiraz University of Medical Sciences
30 PUBLICATIONS 142 CITATIONS 68 PUBLICATIONS 732 CITATIONS

SEE PROFILE SEE PROFILE

Hadi Raeisi Homeira Vafaei

Shahrekord University of Medical Sciences Shiraz University of Medical Sciences
84 PUBLICATIONS 260 CITATIONS 60 PUBLICATIONS 375 CITATIONS

SEE PROFILE SEE PROFILE

Some of the authors of this publication are also working on these related projects:

Formulation and clinical trial of a traditional Iranian based preparation in oligomenorrhea caused by polycystic ovary syndrome (PCOS) in comparison with
Dydrogesterone View project

EXPERIMENTAL MODELS View project

All content following this page was uploaded by Hadi Raeisi on 16 September 2019.

The user has requested enhancement of the downloaded file.

Author’s Accepted Manuscript

Double-blind randomized placebo-controlled trial

on efficacy and safety of Lactuca sativa L. seeds
on pregnancy-related insomnia

Zohreh Safari pour, Ayda Hosseinkhani, Nasrin

Asadi, Hadi Raeisi Shahraki, Homeira Vafaei,
Maryam Kasraeian, Khadije Bazrafshan, Azam
Faraji www.elsevier.com/locate/jep

PII: S0378-8741(17)34204-6
DOI: https://doi.org/10.1016/j.jep.2018.08.001
Reference: JEP11459
To appear in: Journal of Ethnopharmacology
Received date: 21 November 2017
Revised date: 20 July 2018
Accepted date: 1 August 2018
Cite this article as: Zohreh Safari pour, Ayda Hosseinkhani, Nasrin Asadi, Hadi
Raeisi Shahraki, Homeira Vafaei, Maryam Kasraeian, Khadije Bazrafshan and
Azam Faraji, Double-blind randomized placebo-controlled trial on efficacy and
safety of Lactuca sativa L. seeds on pregnancy-related insomnia, Journal of
Ethnopharmacology, https://doi.org/10.1016/j.jep.2018.08.001
This is a PDF file of an unedited manuscript that has been accepted for
publication. As a service to our customers we are providing this early version of
the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting galley proof before it is published in its final citable form.
Please note that during the production process errors may be discovered which
could affect the content, and all legal disclaimers that apply to the journal pertain.
Double-blind randomized placebo-controlled trial on efficacy and safety of La
ctuca sativa L. seeds on pregnancy-related insomnia
Zohreh Safari poura1, Ayda Hosseinkhanib2, NasrinAsadic*, Hadi Raeisi Shahrakid3,
Homeira Vafaeie4, Maryam Kasraeiane5, Khadije Bazrafshane6, Azam Farajie7
a
Resident of Obstetrics & Gynecology, Dept of Obstetrics &Gynecology, Maternal-Fetal
Medicine Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
b
Research center for traditional medicine and history of medicine, Shiraz University of medical
sciences, Shiraz, Iran
c
Maternal-Fetal Medicine Research Center, Perinatology Ward, Shiraz University of Medical
Sciences, Shiraz, Iran
d
Department of biostatistics school of medicine Shiraz University of Medical Science, Shiraz,
Iran
e
Maternal-Fetal Medicine Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

[email protected]

[email protected]

[email protected]

[email protected]

[email protected]

[email protected]

[email protected]

[email protected]

*Corresponding author. Mobile: +989173137810; fax: +98-7136128257

1
Mobile: +989173323197; fax: +98-7132332365.
2
Mobile: +989173153745; fax: +98-7136128257
3
Mobile: +989133857830
4
Mobile: +989173430210; fax +98-7136281591
5
Mobile: +989173138847; fax: +98-7136281591
6
Mobile: +989179130032; fax: +98-7132332365
7
Mobile: +989173185433; fax +98-7132332365
Abstract
Ethnopharmacological relevance

There is limited evidence about the role of herbal and traditional medicine in pregnancy-related
insomnia. Extant documents on traditional Persian medicine refer to many plants which could
induce sleep and which were used by pregnant women. In Iran, local herbal shops continue to
provide these herbs to pregnant women to treat insomnia. One such herb is Lactuca sativa L. The
aim of this study was to evaluate the effects of lettuce seed on pregnant women for the treatment
of insomnia.

Methods and materials

In a prospective randomized clinical trial, 100 pregnant women with insomnia aged 20-45 years
were assigned to receive capsules containing 1000 mg of lettuce seed or a placebo daily for two
weeks. The main outcome was the quality of sleep, which was measured using the Pittsburgh
Sleep Quality Index (PSQI).

Results

Each group contained 50 participants. An improvement in the PSQI score was significantly
greater in patients receiving lettuce seed than those receiving the placebo. Linear regression
analysis showed that, after controlling for the other variables, the average sleep score of the
experimental group was significantly lower than for the placebo group (p = 0.03).

Conclusions

The findings of this study suggest that lettuce seed decreased insomnia during pregnancy and
could be recommended as a safe natural remedy for treatment of pregnancy-related insomnia.

Keywords: Insomnia; Pregnancy; Herbal medicine; Hypnotic.

1. Introduction

One of the most important physiological needs for human health is sleep. Insomnia can affect the
quality of life and cause physical and psychological health problems. Sleep is affected by
different factors during different periods of life. Research has endorsed the view that sleep in
women differs in many respects from that in men. Pregnancy effects the duration and quality of
sleep among women (Moline, Broch et al. 2003, Kızılırmak, Timur et al. 2012). Reports show
that 13% to 20% of women complain about altered sleep in the first trimester of pregnancy and
this number increases to 66% to 90% by the third trimester (Moline, Broch et al. 2003). Almost
two-thirds of pregnant woman report sleep abnormalities during pregnancy mainly owing to an
increase in overall size, back pain and physiological changes (da Silva, Nakamura et al. 2005,
Çoban and Yanıkkerem 2010). Sleep patterns in the pregnant woman are affected by hormonal,
emotional, mental and physical factors (Marques, Bos et al. 2011). Insomnia is an important
problem both for maternal and fetal health during pregnancy. Changes in sleep patterns alters the
quality of life and leads to daily dysfunction and fatigue (Kızılırmak, Timur et al. 2012).

One way to measure the quality and disturbances of sleep in adults is the Pittsburgh Sleep
Quality Index (PSQI) which is a self-rated questionnaire. It has seven components: subjective
sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of
sleeping medications and daytime dysfunction over the last month (Buysse, Reynolds et al.
1989). A PSQI global score of greater than 5 indicates a sensitivity of 98.7 and specificity of
84.4 as a marker for sleep disturbances in insomnia. It has a high test–retest reliability and good
validity to distinguish patients with primary insomnia (Backhaus, Junghanns et al. 2002).
Studies on sleep problems during pregnancy indicate an increased risk of preterm birth (Steer,
Scholl et al. 1992). In general, fear of the adverse effects of medication on pregnant patients
suffering from insomnia prevent its use, despite the fact that the lack of sleep can decrease their
quality of life (da Silva, Nakamura et al. 2005). The treatment of sleep disorders during
pregnancy is complicated. Zolpidem is frequently recommended by physicians to pregnant
women suffering from insomnia; however, this medicine crosses the human placenta rapidly and
is categorized under drugs to avoid during pregnancy. It does not have a proven teratogenic
effect, but is associated with an increased risk of low birth weight and preterm delivery (Wang,
Lin et al. 2010).

Historically, women have used medicinal herbs and herbal medicine for pregnancy-related
problems (Nordeng and Havnen 2005). Research has shown that pregnant women today have
increased interest in treatments with herbal and traditional medicine and are seeking help for
their insomnia from natural medicine and traditional methods (da Silva, Nakamura et al. 2005,
Beddoe, Lee et al. 2010, Hollenbach, Broker et al. 2013). Although evidence-based data is
limited, complementary medicine is being integrated into maternity care (Tiran 2006). Studies
report different statistics on the use of herbs during pregnancy and indicate that between 7% and
45% of pregnant women in Western countries seek out such options (Nordeng and Havnen
2005). Traditional systems of medicine contain thousands of formulations and remedies which
have helped human beings throughout history. These remedies are often natural and scientists
and researchers are now showing interest in studying them to find new medicinal compounds
(Hosseinkhani, Falahatzadeh et al. 2017).

Traditional Persian medicine (TPM) is still practiced in Iran and has a rich history. Local herbal
shops continue to provide medicinal herbs and herbal medicine. Ancient tests contain thousands
of pharmaceutical formulations and herbs for treatment of different conditions (Aghili 2007,
Hosseinkhani, Asadi et al. 2017). In this system of medicine, sedatives and hypnotic drugs are
described by the term monavem (sedative) and mosabet (hypnotic), respectively (Salehi,
Alembizar et al. 2016). One such herbs is khas or lettuce. In TPM, a hypnotic effect has been
mentioned for lettuce and the seeds of this plant (Ghorbani, Rakhshandeh et al. 2013). It is used
in traditional systems of countries such as India for its hypnotic properties. The seed oil is used
in the folk medicine of many countries for its sleep induction properties as well as for pain relief
and as an anti-inflammatory(Sayyah, Hadidi et al. 2004). The seeds are used by pregnant women
to treat pregnancy-related insomnia.

Despite its well-known safety as evidenced by thousands of years of use, Lactuca sativa L. seed
oil has only recently been subjected to extensive pharmacological and toxicological
investigation. It has been found to have significant sedative, analgesic and anti-inflammatory
activity using a murine model after a locomotor activity test (Said, Kashef et al. 1996). Its
sedative dose was reported to be 500 mg to 1.25 g. Previous L. sativa seed analysis has shown
that it is rich in unsaturated fatty acids. It contains oleic acid 61.5%, stearic acid 20.4%, palmitic
acid 9.7%, myristic acid 2.8%, cis-palmitoleic acid 1.2%, behenic acid 0.5%, lignoseric acids
0.3%, α-linolenic acid 8.5% and palmitoleic acid 0.2%. It also contains saturated fatty acids,
including palmitic acid 13.6% and stearic acid 1.3% (Ghorbani, Rakhshandeh et al. 2013).

A recent clinical pilot study evaluated the sedative and hypnotic effects of L. sativa seed oil in
patients complaining of sleeping difficulties with or without anxiety (Yakoot, Helmy et al. 2011).
The results of that study showed that L. sativa seed oil was useful as a sleeping aid and may be a
hazard-free line of treatment of sleeping difficulties. In addition, no side effects were found to be
attributable to L. sativa seed oil at the given dose. The current study aimed to evaluate the
efficacy and safety of this traditionally used seed in pregnant women for the treatment of
insomnia.

2. Materials and Methods

2.1.Trial design

The present study was designed as a prospective randomized clinical trial which was conducted
to assess the efficacy, safety and effect of lettuce seed in pregnant women with insomnia. The
research followed the guidelines of Helsinki Declaration and IAHAIO Tokyo Declaration. The
Medical Ethics Committee of Shiraz University of Medical Sciences approved the protocol of
the study and a signed informed consent form was obtained from each participant. The trial was
registered at the Iranian registry of clinical trials (WWW.IRCT.IR) under the registration number
of IRCT2017042017827N2.

2.2.Patients

The study was performed on 100 outpatient pregnant women who complained of insomnia and
referred to Hafez and Hazrat Zeinab hospitals affiliated with the Shiraz University of Medical
Sciences. The women aged 20-45 years with singleton pregnancies at a gestational age of 12 to
36 weeks were included in the study. Their PSQI scores should have been greater than 5. Patients
with gestational diabetes mellitus, hypertension, preeclampsia or a history of chronic somatic
disease, fetal disorder or drug abuse were excluded from the study. Patients with history of sleep
or mood disorders prior to pregnancy were also excluded from the study. Women with BMI
more than 30 were excluded from the study due to the likelihood of sleep apnea.

2.3.Study design and interventions

The study population were randomized into two groups. Individuals in one group (n = 50)
received capsules containing 1000 mg of lettuce seed daily. They took one capsule every night
for two weeks (lettuce seed group). The other group (n = 50) received placebo capsules
containing starch. They took 1 capsule every night for two weeks. Both capsules were made by
our research pharmacist. The patients were blinded to the type of drug allocated to them.

2.4.Outcomes

The effects of lettuce seed and placebo capsules on the quality and patterns of sleep were
assessed at the end of two weeks of treatment using the PSQI. The adverse effects of treatment
also were recorded. The baseline characteristics of the participants of age, parity, gravidity,
gestational age, height, weight and BMI was obtained using a data gathering questionnaire. The
PSQI scores ranged from 0 to 21 and global scores higher than 5 yielded a sensitivity and
specificity of 89.6 and 86.5, respectively, in the general population (Buysse, Reynolds et al.
1989).

2.5.Herbal drug

Plant samples were purchased from the local market in the city of Shiraz. The samples were
authenticated in the herbarium of the Faculty of Pharmacy at Shiraz University of Medical
Sciences. When confirmed as Lactuca sativa L. seeds, voucher specimens (PM 1082) were
deposited in the herbarium. The seeds were then crushed and the capsules were prepared. Each
capsule contained 1000 mg of lettuce seed.

Because the sedative effect of lettuce seed is attributed its oil, the oil yield of the seeds was
calculated. To evaluate the oil yield of the seeds, the cold press method was applied. The seeds
recorded at 33.33% oil yield.

2.6.Randomization

Randomization was done using a randomization table based on the registration number of the
patients (in order of referral).

2.7.Statistical analysis

To obtain 90% power to detect significant differences between changes in PSQI, 30 participants
were required in each study group (p < 0.05; two-sided). To compensate for possible invalid
samples and those who might exit the study early, the total sample size was set at 100.
Descriptive statistics were reported as mean (±SD) and univariate analysis was performed by
independent t-test and analysis of covariance (ANCOVA). Multivariate linear regression analysis
was performed to assess effect of intervention on the sleep score after adjustment for all
confounders. SPSS 18.0 was used for statistical analysis and p < 0.05 was considered statistically
significant.

3. Results

Of the 100 patients who were assessed for eligibility, all underwent randomization. Five patients
from the lettuce seed group and 1 patient from the placebo group were lost to follow up and 10
patients from the intervention group and 14 from the placebo group discontinued intervention. A
total of 35 patients in each group ultimately were assessed and the results between these two
groups were compared (Figure 1).
Fig. 1 CONSORT 2010 flow diagram for this randomized clinical trial of effects of a Lactuca
sativa L. seed on insomnia in pregnant women.

3.1.Demographic and clinical factors:

The mean age of participants in the experimental group was 30.2 (4.9) and in the placebo group
was 28.6 (5.6), which were not significantly different (p = 0.21). The t-test indicated that there
was no difference between the experimental and placebo groups in term of gestational age (GA;
31.2 (4.7) versus 30.1 (5.7), p = 0.39) and gravidity (2.2 for both groups).

3.2.Intervention:

ANCOVA was used to control effect of sleep score before intervention to investigate effect of
intervention on sleep score. The sleep scores of both groups before and after intervention are
shown in Table 1.

Table 1: Sleep scores of the study groups before and after the intervention

Time Group Mean SD

Before the intervention Placebo 12.34 2.68

Experimental 12.51 1.98

After the intervention Placebo 8.54 3.87

Experimental 6.86 4.03

ANCOVA revealed that the intervention had a significant effect (p = 0.021) on sleep score
(Table 2).

Table 2: Results of ANCOVA test to control effect of sleep score before the intervention.

Source Mean square F P-value

Sleep score before the 346.1 32.44 <0.001
intervention

Intervention 59.8 5.61 0.021

Error 10.7

Although demographic factors were not significantly different between groups, to confirm that
effect of intervention is not due to other variables, linear regression analysis was carried out and
the results are presented in Table 3. Linear regression analysis showed that, after controlling for
other variables, average sleep score of experimental group was 1.83 lower than for the placebo
group, which was statistically significant (p = 0.03).

Table 3: Linear regression analysis for confirming the effect of intervention

Variable coefficient SE P-value

Constant -5.52 4.14 0.19

Sleep score of before the intervention 0.94 0.17 <0.001

Intervention -1.83 0.80 0.03

Age -0.02 0.08 0.83

GA 0.01 0.08 0.92

Gravidity -0.46 0.34 0.19

It was noticed that sleep latency and sleep quality had the highest scores in patients before they
took the medication which shows that their main complaint was in this domain.

3.3.Adverse outcomes

No mother reported any side effects that could be attributable to the use of lettuce seed at the
given dose. Intervention was stopped three weeks before delivery. Adverse neonatal outcomes
were also assessed. Two neonates were admitted to the neonatal intensive care unit (NICU) in
the lettuce seed group due to sepsis and transient tachypnea of the newborn and one neonate was
admitted to NICU from the placebo group due to sepsis. One fetal death at 29 weeks of GA was
reported in the lettuce seed group due to previa accreta and bleeding. Thereafter, adverse
neonatal outcomes in both groups were similar normal population and these adverse outcomes
appeared not to be attributable to the use of lettuce seed.

4. Discussion

Sedative and hypnotic medicines can have adverse effects and endanger the fetus as well as the
mother (Wang, Lin et al. 2010). The use of benzodiazepine in early pregnancy increases the risk
of preterm delivery, caesarian delivery and is related to a small increase in limb anomalies
(Czeizel, Erös et al. 2003, Kjær, Horvath‐Puhó et al. 2007). Another study has shown that the use
of benzodiazepine in early pregnancy increase congenital anomalies (Wikner, Stiller et al. 2007).
In recent decades, interest has increased in research based on traditional medicines worldwide.
Researchers are hoping to find new drugs hidden in the formulations of traditional systems of
medicine (Czeizel, Erös et al. 2003, Yakoot, Helmy et al. 2011). Pregnant women also are
increasingly turning to non-pharmacological health care for treatment of insomnia (Hollenbach,
Broker et al. 2013).

A limited number of studies have investigated the effect of herbal and traditional medicine on
insomnia in pregnancy. In this regard, da Silva et al. designed a study with the aim of testing the
effects on pregnant women of acupuncture on insomnia in pregnant women and comparing it
with the results of undergoing sleep hygiene treatment(da Silva, Nakamura et al. 2005). Their
results demonstrate that the acupuncture group showed a greater decrease in insomnia (5.1) than
the control group (0.0) (p = 0.0028). Moreover, the average insomnia scores decreased by at least
50% over time in nine (75%) patients in the acupuncture group and three (30%) in the control
group.

An important aspect of the current study is its originality. To the best of our knowledge, the
present study is the first study to investigate the effect of lettuce seeds on insomnia during
pregnancy. A pilot study confirmed the positive hypnotic effect of lettuce seed oil on insomnia.
The findings of the current study showed that lettuce seed can significantly improve the sleep
score of pregnant women in the second and third trimesters. Its effect on insomnia was
concordant with the results of a previous pilot study (Yakoot, Helmy et al. 2011). Yakoot M. et
al reported improvement in sleep rating scale scores was significantly greater in patients
receiving L. sativa seed oil compared with those on the placebo. Similar to the current results,
they reported no apparent side effects related to L. sativa seed preparation.

Conclusion

The current investigation was a subjective-self reported study that showed that lettuce seed could
be used as a safe hypnotic treatment for pregnant women with no side effects and seems to be att
ributable to lettuce seed at the given dose. Many patients were lost to follow up because many of
the patients, after consulting with their families, chose not to participate in the study. We suggest
that this study could be performed with a larger sample size. It was concluded that lettuce seed is
a good natural remedy in treatment of insomnia during pregnancy.

Acknowledgements

This article was extracted from the thesis written by Zohreh Safaripour for a degree of Obstetrics
and Gynecology and was financed and supported by the Research Vice-chancellor of Shiraz
University of Medical Sciences (grant No. 9386).

Disclosure

The authors declare no conflicts of interest.

References:

Aghili, S. (2007). Qarabadin Kabir, Iran University of Medical Sciences.

Backhaus, J., K. Junghanns, A. Broocks, D. Riemann and F. Hohagen (2002). "Test–retest
reliability and validity of the Pittsburgh Sleep Quality Index in primary insomnia." Journal of
Psychosomatic Research 53(3): 737-740.
Beddoe, A. E., K. A. Lee, S. J. Weiss, H. Powell Kennedy and C.-P. P. Yang (2010). "Effects of
mindful yoga on sleep in pregnant women: a pilot study." Biological research for nursing 11(4):
363-370.
Buysse, D. J., C. F. Reynolds, T. H. Monk, S. R. Berman and D. J. Kupfer (1989). "The
Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research."
Psychiatry research 28(2): 193-213.
Çoban, A. and U. Yanıkkerem (2010). "Sleep quality and fatigue in pregnant women." Ege
Journal of Medicine 49(2): 87-94.
Czeizel, A. E., E. Erös, M. Rockenbauer, H. T. Sørensen and J. Olsen (2003). "Short-term oral
diazepam treatment during pregnancy." Clinical drug investigation 23(7): 451-462.
da Silva, J. B. G., M. U. Nakamura, J. A. Cordeiro and L. Kulay (2005). "Acupuncture for
insomnia in pregnancy–a prospective, quasi-randomised, controlled study." Acupuncture in
Medicine 23(2): 47-51.
Ghorbani, A., H. Rakhshandeh and H. R. Sadeghnia (2013). "Potentiating effects of Lactuca
sativa on pentobarbital-induced sleep." Iranian journal of pharmaceutical research: IJPR 12(2):
401.
Hollenbach, D., R. Broker, S. Herlehy and K. Stuber (2013). "Non-pharmacological
interventions for sleep quality and insomnia during pregnancy: A systematic review." The
Journal of the Canadian Chiropractic Association 57(3): 260.
Hosseinkhani, A., N. Asadi, M. Pasalar and M. M. Zarshenas (2017). "Traditional Persian
Medicine and management of metabolic dysfunction in polycystic ovary syndrome." Journal of
Traditional and Complementary Medicine.
Hosseinkhani, A., M. Falahatzadeh, E. Raoofi and M. M. Zarshenas (2017). "An evidence-based
review on wound healing herbal remedies from reports of traditional Persian medicine." Journal
of evidence-based complementary & alternative medicine 22(2): 334-343.
Kızılırmak, A., S. Timur and B. Kartal (2012). "Insomnia in pregnancy and factors related to
insomnia." The Scientific World Journal 2012.
Kjær, D., E. Horvath‐ Puhó, J. Christensen, M. Vestergaard, A. E. Czeizel, H. T. Sørensen and J.
Olsen (2007). "Use of phenytoin, phenobarbital, or diazepam during pregnancy and risk of
congenital abnormalities: a case‐ time‐ control study." Pharmacoepidemiology and drug safety
16(2): 181-188.
Marques, M., S. Bos, M. J. Soares, B. Maia, A. T. Pereira, J. Valente, A. A. Gomes, A. Macedo
and M. H. Azevedo (2011). "Is insomnia in late pregnancy a risk factor for postpartum
depression/depressive symptomatology?" Psychiatry research 186(2): 272-280.
Moline, M. L., L. Broch, R. Zak and V. Gross (2003). "Sleep in women across the life cycle
from adulthood through menopause." Sleep medicine reviews 7(2): 155-177.
Nordeng, H. and G. C. Havnen (2005). "Impact of socio‐ demographic factors, knowledge and
attitude on the use of herbal drugs in pregnancy." Acta obstetricia et gynecologica Scandinavica
84(1): 26-33.
Said, S., H. E. Kashef, M. E. Mazar and O. Salama (1996). "Phytochemical and pharmacological
studies on Lactuca sativa seed oil." Fitoterapia 67(3): 215-219.
Salehi, A., F. Alembizar and A. Hosseinkhani (2016). "Anesthesia and pain management in
traditional Iranian medicine." Acta Medico-Historica Adriatica 14(2).
Sayyah, M., N. Hadidi and M. Kamalinejad (2004). "Analgesic and anti-inflammatory activity of
Lactuca sativa seed extract in rats." Journal of Ethnopharmacology 92(2–3): 325-329.
Steer, R. A., T. O. Scholl, M. L. Hediger and R. L. Fischer (1992). "Self-reported depression and
negative pregnancy outcomes." Journal of clinical epidemiology 45(10): 1093-1099.
Tiran, D. (2006). "Complementary therapies in pregnancy: Midwives’ and obstetricians’
appreciation of risk." Complementary Therapies in Clinical Practice 12(2): 126-131.
 Wang, L. H., H. C. Lin, C. C. Lin and Y. H. Chen (2010). "Increased risk of adverse pregnancy
outcomes in women receiving zolpidem during pregnancy." Clinical Pharmacology &
Therapeutics 88(3): 369-374.
Wikner, B. N., C. O. Stiller, U. Bergman, C. Asker and B. Källén (2007). "Use of
benzodiazepines and benzodiazepine receptor agonists during pregnancy: neonatal outcome and
congenital malformations." Pharmacoepidemiology and drug safety 16(11): 1203-1210.
Yakoot, M., S. Helmy and K. Fawal (2011). "Pilot study of the efficacy and safety of lettuce seed
oil in patients with sleep disorders." International journal of general medicine 4: 451.

Graphical abstract

View publication stats