Evaluation of the Effect of Jawarish Amla Concoction on Controlling Stress in Women Candidate Intracytoplasmic Sperm Injection or In Vitro Fertilization: A Randomized Clinical Trial

Abstract

Background:

Infertility diagnostic investigations and treatment through assisted reproductive technology (ART) predispose infertile women to stress, while stress itself can severely affect the results of infertility treatment. This research aimed to investigate the effect of Jawarish Amla Concoction on controlling stress in female candidate intracytoplasmic sperm injection (ICSI) or in vitro fertilization (IVF).

Materials and Methods:

This randomized clinical trial was conducted between December 2022 and June 2023 at Shahid Akbarabadi Hospital, affiliated with the Iran University of Medical Sciences (IRCT20230411057883N1). A sample of 100 infertile female candidates for ICSI/IVF was randomly divided into two groups. Patients in the intervention group received one tablespoon of the Jawarish Amla Concoction (Phyllanthus emblica, Rosa damascene, and honey). The control group was only followed up on without any intervention. The stress level of the patients was measured based on Newton’s Fertility Problem Inventory (FPI) at the beginning and end of the study, and its changes were compared in both groups.

Results:

Ninety women completed the study, and their data were analyzed. The mean FPI score in the intervention group was 160.76 ± 28.2 before the intervention and 153.39 ± 28.5 after the intervention, while it was respectively 141.07 ± 25.58 and 142.8 ± 31.05 in the control group. After four weeks, the percentage of changes in the FPI score was 16.67 ± 3.32% in the intervention group and 11.28 ± 1.18% in the control group (P = 0.045). No complications were observed.

Conclusion:

Consuming the Jawarish Amla Concoction for four weeks significantly reduced stress in female candidates for ICSI/IVF.

INTRODUCTION

Infertility is defined as the inability to conceive after 12 months of regular and unprotected intercourse in women under 35 years of age. In women over 35 years of age or in couples who have a history of diseases that reduce their fertility, this duration reduces to 6 months.[1] Infertility is a crisis with a substantial prevalence worldwide.[2] Infertility affects all aspects of a couple’s life, the most important of which is mental health. Couples who seek fertility treatment are more anxious than the general population and suffer more mental problems.[3] Infertility stress involves a group of symptoms that emerge after the diagnosis of infertility, are similar to Post-Traumatic Stress Disorder (PTSD), and specifically appear in beliefs and affects related to infertility and their avoidance.[4]

For many people, infertility causes stress and can lead to many negative psychological reactions, including depression, anxiety, worry, anger, shame, envy, loneliness, despair, low self-esteem, a sense of sexual inadequacy, sexual dysfunction, and reduced sexual satisfaction.[5]

Overall, the prevalence of major depressive disorder (clinical depression), generalized anxiety, stress, and depression in infertile female patients was found to be 22.9%, 13.3%, 78.8%, and 31.6%, respectively.[6]

Considering the prevalence of mental disorders among infertile women, the physical treatments for infertility alone are not enough, and the psychological needs of infertile couples need to be addressed for successful treatment of infertility.[5] So far, various methods have been designed and implemented to help improve the mental health of infertile people, including counseling and educational programs, cognitive-behavioral therapy, psychotherapy, and medication therapy, some of which are effective in reducing anxiety and stress and increasing the probability of success in infertility treatment.[7] Selective Serotonin Reuptake Inhibitors (SSRIs) are among the medications used to control stress in infertile individuals. However, their use has been proven to have a negative effect on the results of IVF and reduce the chance of pregnancy and live births.[8] Therefore, it appears necessary to use alternative therapies for this purpose. In Persian medicine (PM), there are many plants with anti-anxiety properties. Jawarish Amla Concoction is a mixture of Phyllanthus emblica fruit, Rosa damascene, and honey, all three of which are effective in controlling anxiety and stress.[9,10,11] This study aimed to investigate the effect of Jawarish Amla Concoction on controlling stress in women candidate assisted reproductive technology (ICSI/IVF).

MATERIALS AND METHODS

This was a randomized clinical trial conducted in the sub-specialty infertility clinic of Shahid Akbarabadi Hospital, affiliated with the Iran University of Medical Sciences, between December 2022 and June 2023. According to similar papers and considering 10% attrition, the sample size was estimated to be 96 (48 people per group).[12,13] But during the study, it was increased to 100 people.

The volunteers were examined by a practitioner to qualify for the study. The inclusion criteria included having infertility confirmed by a gynecologist, being candidates for ICSI/IVF, moderate or higher stress (Newton’s Fertility Problem Inventory (FPI) score), and consenting to participate in the study. The attrition criteria included intending to have a surrogate, chronic physical diseases, taking psychiatric medications, receiving therapy from a psychologist or psychiatrist during the study, using relaxation and psychotherapy techniques, adverse life events such as the death of relatives or family quarrels in the month before the study, the last embryo transfer, infertility due to male causes only, smoking, or alcohol consumption. The exclusion criteria included failure to complete the ICSI/IVF treatment period, becoming pregnant, severe family quarrels, or an adverse event, such as the death of a loved one during the treatment.

According to the consort diagram, through interviews with more than 200 infertile female candidates for ICSI/IVF, 100 eligible women were selected after explaining the research objectives and receiving their consent to participate [Figure 1]. A random list was generated using random allocation software and random blocks, and the women were assigned to the control and intervention groups. The random allocation sequence was generated by an investigator who was not involved in eliciting data or conducting the study.

Figure 1.

The CONSORT diagram of the studied sample

Patients in the intervention group took one tablespoon of the Jawarish Amla Concoction (Tala-ye Sabz-e Tooba Company; license number: S-92-0185 from the Food and Drug Administration of Iran) twice a day (in the morning before breakfast and at night before sleep) for four weeks (5 potion packs in total). The control group did not receive any intervention. At the end of the study (end of week 4), the stress level of the patients was evaluated based on Newton’s FPI, and the patients were followed up until the pregnancy outcome was determined. Finally, the pregnancy outcome was evaluated in both groups. The primary outcome of this study was determining the effectiveness of Jawarish Amla Concoction on stress control based on the total score of Newton’s FPI, and the secondary outcome was the subscales scores of FPI included social concern, sexual concern, relationship concern, need for parenthood, and a negative view of a child-free lifestyle, the success rate of ICSI/IVF, the incidence of pregnancy in the two groups, and determining the possible side effects after the intervention in the Jawarish Amla Concoction group.

The data collection instruments were a demographic information questionnaire, a medical and infertility information questionnaire, and the FPI. The demographic information section examined age and education level. The medical information questionnaire checked information related to infertility and its treatment, including awareness of infertility, treatment period, menstrual status, cause of infertility, type of infertility, attempting treatment, the number of IUIs and IVFs, and history of failure and success of the treatment.

The FPI was developed by Newton et al. (1999). It was used to assess infertility stress and problems. FPI has five subscales: social concern, sexual concern, relationship concern, need for parenthood, and a negative view of child-free lifestyle. Answers are assigned from 1 (strongly disagree) to 6 (strongly agree). The FPI scores are organized into five subscales, and the total score composed of all the previous factors. The total score range is from 46 to 276. A score between 92 and 184 indicates a moderate level of infertility stress. The higher scores showed higher levels of stress. The overall integrity was 0.87. Cronbach’s alpha for all sub-scales was more than 0.7.[14] In Iran, Samani et al. (2017)[15] investigated the validity and reliability of this instrument.

Finally, the obtained information was statistically analyzed in SPSS version 27. The distribution of quantitative variables in the two groups was checked by the Kolmogorov-Smirnov test. Quantitative variables were described using mean and standard deviation (SD), and qualitative variables were described with frequency percentages. Quantitative variables were compared between the two groups using a t-test or Mann-Whitney U test. A Wilcoxon signed-rank test was used for comparing the quantitative variables within groups. Qualitative variables were compared between the two groups using a Chi-square test or Fisher’s exact test. A significance level of 0.05 was considered for the main outcome variable.

This study was approved by the Ethics Committee of the Iran University of Medical Sciences (approval code: IR.IUMS.REC.1401.297) and registered at the Iranian Registry of Clinical Trials; https://irct.ir under the code number of; IRCT20230411057883N1.

RESULTS

Clinical trial

First, the patients were examined in terms of inclusion/exclusion criteria; 100 eligible patients were included in the study and participated in the randomization process. Fifty women were assigned to the control group and 50 to the intervention group. During the study, four women from the intervention group and six from the control group withdrew from the study at different stages. Reasons for withdrawal included unwillingness to continue participation and personal reasons. Finally, 90 women were examined, including 46 women in the intervention group and 44 women in the control group. After removing the excluded cases, a per-protocol analysis was performed. The process of recruitment, treatment, and follow-up is detailed in Figure 1.

Baseline demographics and other variables

The baseline characteristics of the subjects are described in Table 1. There was no statistically significant difference in the baseline characteristics between the two groups.

Table 1.

Comparison of baseline characteristics between intervention and control groups

		Intervention		Control		P
Age		6.13±35.13		4.78±35.56		0.708
Primary infertility		82.60%		70.46%		0.173
Regular menstruation		74%		72.3%		0.711

There was no significant difference between the intervention and control groups in terms of the frequency distribution of infertility causes (P = 0.407). Husbands of six patients in the control group (13.63%) and six patients in the intervention group (13.06%) had sperm problems (P = 0.934). Table 2 presents the median and interquartile range (IQR) of the number of IUIs, the number of IVFs, the number of treatment failures, and the number of spontaneous pregnancies ending in abortion separately in the intervention and control groups.

Table 2.

Median and interquartile range (IQR) of the number of IUIS, number of IVFS, number of treatment failures, and number of spontaneous pregnancies ending in miscarriage in the intervention and control groups

Group		Median		IQR
Number if IUIs
Control		1		0-1.75
Intervention		1		0-2
Number of IVFs
Control		0		0-1
Intervention		1		0-2
Number of treatment failures
Control		1		0-2
Intervention		2		1-3
Number of spontaneous pregnancies ending in miscarriage
Control		0		0-1
Intervention		0		0-1

Newton’s Fertility Problem Inventory scores

The mean FPI score in the intervention group was 160.76 ± 28.2 before the intervention and 153.39 ± 28.5 after the intervention; while it was respectively 141.07 ± 25.58 and 142.8 ± 31.05 in the control group. After four weeks, the percentage of changes in the FPI score was 16.67 ± 3.32% in the intervention group and 11.28 ± 1.18% in the control group (P = 0.045). Table 3 presents the mean score of FPI and its subscales before and after the intervention.

Table 3.

Mean and standard deviation of Newton's Fertility Problem Inventory and its subscales scores before and after the intervention in each group

Newton score		Group		Mean (SD) pre-treatment		Mean (SD) post-treatment		P		% of changes in median (IQR)		P, Wilcoxon signed-rank test
Social concern		Intervention		33.93 (9.25)		32.47 (8.24)		0.266		4.38 (-15.06-16.91		0.628
		Control		29.18 (7.35)		28.02 (8.42)		0.367		0 (-6.66-12.03)
Sexual concern		Intervention		24.19 (8.08)		22.04 (6.42)		0.53		9.72 (-11.33-20.98)		0.031
		Control		20.09 (7.08)		21.06 (7.50)		0.21		0 (-15.83-5.49)
Relationship concern		Intervention		29.08 (9.41)		28.76 (10.12)		0.652		3.7 (-13.22-15.14)		0.037
		Control		24.63 (9.29)		26.40 (10.40)		0.03		-6.47 (-24.18-2.27)
negative view of child-free lifestyle		Intervention		30.43 (7.14)		27.90 (7.05)		0.01		5.27 (-4.24-18.2)		0.859
		Control		27.38 (6.64)		27.90 (6.41)		0.803		0 (-10.92-8.79)
Need for parenthood		Intervention		43.10 (6.86)		42.17 (6.36)		0.475		0 (-10.97-11.27)		0.032
		Control		39.77 (6.33)		39.38 (7.92)		0.566		0 (-6.28-8.6)
Total score		Intervention		160.76 (28.2)		153.39 (28.5)		0.03		3.25 (-2.89-10.89)		0.045
		Control		141.07 (25.58)		142.8 (31.05)		0.576		0 (-9.72-5.43

IVF/ICSI pregnancy outcome

Table 4 presents the frequency of pregnancy after embryo transfer in both groups. Evidently, 4.5% of women in the control group and 17.4% of the women in the intervention group became pregnant after embryo transfer (one woman in the intervention group had a twin pregnancy). Although the frequency of pregnancy was higher in the intervention group than that in the control group, there was no significant difference between the two groups in terms of embryo transfer outcome (P = 0.113).

Table 4.

Frequency distribution of pregnancy after embryo transfer in the two groups

Group		No Pregnancy, Number (Frequency %)		Delay in Transfer, Number (Frequency %)		Pregnancy, Number (% Percentage)		Sig. Level (Two-Tailed)
Control group		32 (72.8%)		10 (22.7%)		2 (4.5%)		0.113
Intervention group		26 (56.6%)		12 (26.1%)		8 (17.4%)

Other symptoms

The frequency distribution of gastrointestinal symptoms (bloating, heartburn, and constipation) was evaluated after the intervention compared to before the intervention in both groups. In the intervention group, bloating, heartburn, and constipation decreased after the intervention compared to before the intervention, and this decrease was statistically significant for bloating and constipation (bloating improved in 76% of cases, constipation in 61% of cases, and heartburn in 40% of cases); meanwhile, in the control group, all the symptoms increased after the study compared to before. Moreover, Jawarish Amla Concoction increased appetite in two patients.

DISCUSSION

The findings revealed that one tablespoon of Jawarish Amla Concoction twice a day significantly reduced the level of stress, demonstrating the superiority of Jawarish Amla Concoction over the control group. We did not find any clinical trials on the effect of Jawarish Amla Concoction on stress, but many studies have been conducted on the constituents of this product.

The studies conducted on P. emblica fruit show that this plant has anti-depressant and anti-stress properties, and that it improves neurological and behavioral functions in mice by preventing the increase in glucose and cortisol induced by stress. It appears that these effects are due to its antioxidant activity and MAO-A and GABA inhibition.[9,16,17]

Studies conducted on R. damascene also show that this plant has anti-depressant effects and can reduce anxiety by lowering corticosterone levels, which is probably due to its antioxidant properties.[10,18] Also, Akram et al.[19] declared in their research that it has antistress activity and is used in nervous tension.

So far, several studies have examined the anti-anxiety effects of honey. The results of these studies show that polyphenol compounds in honey can reduce anxiety and improve memory functioning. In fact, with its antioxidant effects against oxidative stress in the brain, honey can decrease dementia, reduce anxiety, and be a suitable alternative to anti-anxiety drugs.[11,20]

Therefore, it can be concluded that Jawarish Amla Concoction has anti-depressant and anti-stress properties due to the inhibition of MAO-A and GABA, polyphenol compounds, and the antioxidant activity of its contents.

Several studies have reported that stress, anxiety, and depression in women can be associated with reduced odds of pregnancy and live birth.[21,22] As a result, ICSI/IVF candidate patients experience more stress than those who are in the early stages of infertility treatment. These levels of stress and anxiety remain high during repeated IVF cycles, indicating the need to pay more attention to stress management methods during the IVF cycle.[23] Several studies have also shown that treatment-induced psychological burden and stress are two of the most important factors causing couples to stop treatment due to unsuccessful IVF treatment.[24,25]

The PM point of view clearly mentions the influence of mental states on the development or exacerbation of diseases. These states are not only considered a cause of a couple’s infertility, but they are also viewed as an outcome of infertility.[26]

A 2009 study by Serafini et al.[27] compared levels of anxiety experienced during four stressful times of ICSI/IVF and treatment outcomes between women taking fluoxetine and placebo. In this randomized, double-blind, placebo-controlled trial, the intervention group was given fluoxetine, and the control group was given folic acid. The State-Trait Anxiety Inventory (STAI) was used to assess the state of anxiety at the beginning of ovarian stimulation, ovum pick-up, embryo transfer, and on the day of the pregnancy test. The results of this study showed that the level of anxiety increased from the day of ovarian stimulation to the day of the pregnancy test in both groups. However, the IVF outcome was not affected by the treatment in the two groups. Finally, it was recommended that fluoxetine be administered to reduce anxiety in patients undergoing IVF with caution and that more studies be conducted to investigate the impacts of higher doses of fluoxetine on IVF outcomes. In our study, as mentioned, the mean stress and anxiety scores of the patients increased in the control group from the beginning of the study to the day of embryo transfer.

A 2019 study by Romano et al.[12] investigated prophylactic treatment with SSRI on female candidates for IVF who suffered from anxiety and mood disorders. In this randomized, double-blind, parallel study, 41 patients were randomly divided into two groups. Twenty-two individuals in the intervention group received 10 mg/day of citalopram for 8 weeks, and 19 individuals in the control group received placebo. Patients were evaluated at the beginning of the intervention and on the day of embryo transfer. The results revealed that the short-term use of prophylactic treatment with SSRI in female IVF candidates could significantly prevent the aggravation and continuation of depression and anxiety symptoms. This study did not assess the effect of prophylactic SSRI treatment on fertility and IVF outcomes. In a 2015 study, Casilla-Lennon et al.[28] investigated the effect of antidepressants on natural fertility. In this retrospective study, out of 957 women examined, 92 took antidepressants while trying to get pregnant. The results of this study showed that antidepressants in a specific cycle were associated with a decrease in the probability of pregnancy in that cycle. A 2012 review by Domar et al.[29] showed that the use of common antidepressants, including SSRIs, can increase the risk of miscarriage, preterm birth, birth defects, behavioral disorders, and pulmonary hypertension in the newborn; there was no evidence for improvement in pregnancy outcomes when taking antidepressants.

Cesta et al. (2016)[30] investigated the effect of depression, anxiety, and the use of antidepressants on the outcome of IVF. This study evaluated nulliparous women who visited the infertility center from January 2007 to December 2012 and underwent their first IVF cycle (n = 23557). The results showed that the diagnosis of anxiety or depression, as well as antidepressant medications before IVF, can reduce the probability of pregnancy and live birth. Another review study in 2021 by Jovana Z Milosavljević et al.[8] investigated the effects of SSRIs on fertility. The results of this study revealed that some SSRIs, such as paroxetine and citalopram, can have a negative effect on female pregnancy by changing the movement of the fallopian tubes. The findings of these studies are not consistent with those of our study, in which the fertility rate after embryo transfer in the intervention group was four times that of the control group.

Several studies have investigated the effect of Jawarish Amla Concoction components on fertility. Various studies have examined the impacts of P. emblica on fertility. The results of these studies show that P. emblica has a very strong estrogenic and gonadotropic activity, can improve sexual activity, and can clearly increase fertility and the number of oocytes.[31,32] Mohebitabar et al. (2017)[33] conducted a review study on the therapeutic effects of R. damascene oil. This review examined 13 clinical trials. In these studies, R. damascene oil was used by inhalation or topically. The results showed that R. damascene oil has anti-anxiety, anti-depressant, sedative, and soothing effects and can improve sexual function. Studies show that honey increases progesterone levels, limits body weight gain, prevents uterine and vaginal atrophy, has antioxidant and antifungal effects, and can improve fertility. Finally, it has been stated that honey can be used as a practical food product in treating disorders of the female reproductive system.[34,35] The findings of these studies are consistent with our study; in the present study, eight women from the intervention group and two women from the control group got pregnant after embryo transfer, and one woman in the intervention group had a twin pregnancy.

Gastrointestinal symptoms are very common during pregnancy. During this period, the increased level of female sex hormones alters the movements of the digestive system, causing or aggravating digestive symptoms such as heartburn, nausea, vomiting, and constipation.[36] In the current study, Jawarish Amla Concoction reduced stress and anxiety, helped improve fertility, and mitigated the patients’ digestive problems, such as bloating, eartburn, and constipation; therefore, by improving these digestive symptoms before pregnancy, it can prevent aggravation of symptoms during pregnancy and help women pass this period more easily with fewer problems.

This was the first study to evaluate the effect of a completely herbal medicine on stress in women candidates for ICSI/IVF. It is suggested that other studies with a larger sample size and a longer treatment period be conducted. The patients should be followed up after the treatment period in order to measure the persistence of the medication effects. The most important limitation of this study was the placebo effect. Since the medicinal form studied was a potion, and it was difficult to prepare a similar placebo, the control group did not receive any treatment.

CONCLUSION

This randomized clinical trial showed that Jawarish Amla Concoction, used for four weeks, significantly reduced stress in women candidates for ICSI/IVF. Given the patients’ acceptance of complementary medicine, such as Persian medicine, and considering the findings of this research, the use of Jawarish Amla Concoction is suggested to women of reproductive age who wish to become pregnant as a completely herbal and cheap treatment, without specific side effects, and effective in controlling stress, improving fertility, and mitigating digestive symptoms.

Ethics approval and consent to participate

This study was approved by the Ethics Committee of the Iran University of Medical Sciences (approval code: IR.IUMS.REC.1401.297), and registered at the Iranian Registry of Clinical Trials; https://irct.ir under the code number of IRCT20230411057883N1.

Consent for publication

An informed consent form was obtained from all participants in the study.

Availability of data and materials

All the information collected from the participants, including the demographic information questionnaire, medical and infertility information questionnaire, and Newton’s infertility stress questionnaire, and the data Excel file, are available.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.