The Effectiveness of Aloe Vera on Relief of Irritation and Nipple Pain in Lactating Women: Systematic Review and Meta-Analysis

Background Aloe vera is one of the herbal products with anti-inflammatory, antioxidant, moisturizing, bactericidal, anti-viral, and anti-fungal effects that were used to relieve pain and irritation. The aim of the current systematic review and meta-analysis is to determine the effect of Aloe vera on the relief of irritation and nipple pain in lactating women. Methods A search was carried out in four English electronic databases including Scopus, Embase, PubMed, and Web of Science until November 2021. All clinical trials that assessed the effect of Aloe vera on the relief of irritation and nipple pain in lactating women were included. The study's risk of bias was assessed using the Cochrane risk of bias checklist. Study heterogeneity was determined using the I2 statistic and publication bias using Begg's and Egger's tests. Results of the random-effects meta-analysis were presented using standard mean difference (SMD) with 95% confidence intervals (CIs). Data were analyzed using STATA software version 16 MP. Results In total, 7 articles with 1670 subjects were included in the meta-analysis. Overall, we found a positive impact of Aloe vera on reducing breast pain (pooled SMD= −0.45; CI= −0.83, −0.07, P value <0.02) and irritation (pooled SMD= −0.48; CI= −0.64, −0.32, P value<0.001) in lactating women. There is a high heterogeneity among pain studies (I2= 86%) but was low within irritation studies (I2= 26%). Conclusion Our result showed that Aloe vera can be considered a choice for relieving breast pain or irritation in lactating women compared with routine care or another treatment. Considering the limited number of studies conducted on this topic and the low sample size, future studies with a larger sample will be required to draw better conclusions.


Introduction
Breastfeeding is considered the most important factor in reducing the infant mortality rate, as well as has many benefts for maternal health. Accordingly, the World Health Organization and UNICEF recommend that every infant should have exclusive breastfeeding for at least six months after birth and it should continue for 2 years [1,2]. Despite their recommendation, only 37% of infants aged less than six months are exclusively breastfed in low-income and middleincome countries [3].
Treating breastfeeding is an art that requires many skills and knowledge, especially for new mothers. Improper attachment of the infant to the breast, along with the growth factor of mucus present in infant saliva and breast milk, can be associated with nipple damage [4,5]. Nipple pain is a protective response of damaged tissue following vasospasm of the nipple tissue, reduction of capillary blood supply, swelling, and oedema [6]. Nipple pain, with a prevalence of 34 and 97%, is one of the most common complaints among breastfeeding mothers and the second reason for premature discontinuation of breastfeeding after feeling insufcient milk secretion [7,8]. Breast and nipple pain can reduce oxytocin and milk secretion by increasing catecholamine secretion, as well as increasing cytokines and proinfammatory factors [9].
Various methods have been proposed for the prevention and treatment of nipple fssures, such as correcting breastfeeding techniques, rubbing milk on the nipple, glycerin pads, using topical and collagenase ointments, hydrogel, honey, and herbal medicine, neither of which is superior to the other [5].
Te natural products in the diet play an important role in the prevention and treatment of many chronic conditions such as diabetes, cancer, cardiovascular disease, and hypertension [8,10,11]. Some studies support the importance of food-derived natural compounds such as favonoids, terpenes, alkaloids, phenols, carotenoids, palmitoylethanolamide, zerumbone, dehydrocorybulbine, β-caryophyllene, berberine, chlorogenic acid, and isofavones in the relief of neuropathic pain through multiple mechanisms such as regulating the estrogen receptor, antioxidant, and anti-infammatory activities [10,12].
Today, herbal medicine is widely used in the felds of obstetrics and gynaecology. Aloe vera is one of the herbal products with anti-infammatory, antioxidant, moisturizing, bactericidal, anti-viral, and anti-fungal efects that was used to relieve pain and irritation [2,13,14]. Tere are high amounts of molecular material, water, polysaccharides, sugars, minerals, proteins, lipids, phenolic compounds, as well as many vitamins such as A, C, E, B1, B2, and B9 in Aloe vera [15]. In addition, there are many enzymes such as bradykinase, carboxypeptidase, cellulase, amylase, catalase, and oxidase in this plant. Tese enzymes by blocking the synthesis of bradykinin, cyclooxygenase-2, and thromboxane synthase can reduce the pain intensity [16]. Carboxypeptidase inactivates bradykinase at the wound site and exerts anti-infammatory and pain-relieving efects. Te anti-infammatory efects of this plant are attributed to the presence of salicylic acid (efective in inhibiting the formation of bradykinin and histamine) and the arachidonic acid oxidation pathway through cyclooxygenase [17]. Magnesium lactate in the Aloe vera plant prevents the histamine reaction, therefore relieving itching and skin irritation [18]. Te previous study reveals that anthraquinones, allantoin, and other polysaccharide compounds in Aloe vera inhibit histamine and bradykinin synthesis, thereby reducing wound pain severity [19]. Also, the phenolic compound of aloe-vera can be reduced edema by a reduction in the level of prostaglandins [20]. Moreover, Aloe vera increases the number of fbroblasts and collagen, which can accelerate wound healing [21].
Many studies show a positive impact of Aloe vera on the relief of irritation and pain in the nipple, but there is a controversy in their results. Terefore, this study as a frst systematic review and meta-analysis was conducted to determine the efect of Aloe vera on the relief of irritation and nipple pain in lactating women.

Search Strategy, Data Sources, and Data Extraction.
Tis systematic review and meta-analysis were conducted based on the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement. A comprehensive and systematic search was performed in English and Persian electronic databases including Medline, PubMed, Web of Science, Scopus, Embase, Cochrane Database of Systematic Reviews (CDSR), CINAHL, Sid, IRANDOC, and Mag-Iran for the period up to November 20, 2020, using the following search strategies following the Mesh browser keywords and free-text words: ("Aloe" [mh] OR "Aloe vera gel" [mh] OR "Aloe" [tiab] OR "Aloe vera gel" [tiab] OR "Herbal Medicine" [mh] OR "herbal medicine" [tiab] OR "herb" [tiab]) AND ("Nipples" [mh] OR "nipple trauma" [tiab] OR "nipple injuries" [tiab] OR "nipple wound" [tiab] OR "nipple fssure" [tiab] OR " nipple sore" OR "nipple pain" Or "irritation" OR "Nipples" [tiab] OR "breast pain" [tiab] OR "Breast Feeding" [mh] OR "Breast Feeding" [tiab] "Breastfeeding" [tiab] OR "Breast Fed" [tiab] OR "Breastfed" [tiab]). Moreover, the manual approaches, in particular, hand-searching and perusing the bibliographies of retrieved articles were performed to fnd additional articles. Also, various grey literature databases (such as Google Scholar, Open Grey SIGLE, Global Index Medicus (GIM), NTIS, World Cat, and UW Libraries Search), theses and dissertations, as well as conference proceedings were scanned for collecting unpublished data.
Using Endnote software ver.X9 duplicate, studies in diferent databases were eliminated by following the PRISMA Systematic Review Flowchart. Te titles and abstracts of all articles were scanned. In the next step, we checked the full text of the studies to identify the articles that met the inclusion criteria. Also, to reduce the potential risk of bias, two reviewers performed the literature review, data selection, and quality assessment of data independently. Disagreements of the investigator were resolved through discussion or consultation with the third reviewer to reach a consensus [22].
After fnding the full texts, data of each article were extracted using a structured form that included the author's name, publication date, location of study, setting, the sample size of each group, type of intervention in each group, measurement tool, results, and P value. Te quantitative data were entered into STATA version 15.

Inclusion and Exclusion Criteria.
Clinical trial studies using Aloe vera that have a control group with placebo or comparison with other treatments in the prevention and treatment of irritation and nipple pain were included in the systematic review.
Studies were excluded if they were at least one of the following criteria: (1) lack of access to full text, (2) unexplained methods, (3) systematic reviews and meta-analysis, animal experiment, cross-sectional, and observational study design, (4) letters, editorials, case reports, review articles, and conference abstracts, and (5) inability to extract the outcome measures.

Outcome.
Te main outcome of this study was nipple pain and irritation.

Quality Assessment.
Te risk of bias for each selected study was assessed independently by two investigators (AM and SY) based on seven criteria that are required by Cochrane guidelines for quality assessment of randomized controlled trials [22]. Tis tool examines the following issues: random sequence generation (selection bias), allocation concealment (selection bias), blinding of the participants and personnel (performance bias), incomplete outcome data (attrition bias), blinding of outcome assessors (detection bias), selective outcome reporting (reporting bias), and other risks of bias. Each item was evaluated using three evaluation options, including low, unclear, and high risk options. Any disagreements in the risk of bias/quality appraisal assessments were discussed by the two authors until a consensus was reached.

2.3.2.
Analysis. STATA software version 16 was used for data analysis. Te standardized mean diference or SMD was used to fnd the efect for quantitative data. Te I 2 , Tau2, and χ 2 statistics were used to evaluate the heterogeneity of the included studies. To identify the degree of heterogeneity, the following classifcations of the I 2 statistic were used: unimportant (0-40%), moderate heterogeneity (30-60%), substantial heterogeneity (50-90%), and high heterogeneity (75-100%) [20]. Due to the high level of heterogeneity, the random efect was applied instead of the fxed efect. Sensitivity analyses were done, when we observe a high level of heterogeneity. Publication bias was evaluated by the funnel plot, as well as Egger's and Begg's tests (Figure 1).

Description of Included
Studies. We identifed 296 articles by search in the English and Persian major databases including Scopus (105), ISI [5], PubMed (75), Sid [5], Mag-Iran [12], and other sources (88) based on the Mesh browser keywords and free-text words adapted for other databases with no publication year or language limitations. Among the identifed articles, we excluded 17 duplicate articles, 271 in the title and abstract review, and fnally, one article in the full-text review due to the one-group pretest-posttest design. In total, 7 articles with 1670 subjects were included in the meta-analysis. Te selection procedure of the articles is presented in Figure 2. Te description of the 7 studies is summarized in Table 1. Of these, 4 studies were conducted in Iran. Two studies were conducted in Indonesia and one study in China. Four articles were published in the English language, one article in the Persian language, and the rest in the Indonesian language. Regarding the type of study, 5 articles were randomized control trials (RCTs) study design, and two articles were in a quasi-experimental design. Te source of pain and irritation in four articles was breast soreness, and the rest were milk stasis and breast engorgement in lactating women. Te topical gel/extract of Aloe vera is applied on breast sores by massage or cold compress. In one study, Aloe vera was combined with cactus, and in all studies, the efect of Aloe vera was compared with the no treatment/breast milk or lanolin group. Te follow-up period for assessing pain and irritation outcomes ranged from immediately after treatment to 14 days after the intervention. In all studies, the pain level was recorded using the Visual Analogue Scale (VAS) for pain and the store scale for breast irritation intensity (Table 1).
Te results reported that no signifcant publication bias was observed according to Begg's and Eggerʼs tests (P � 0.8417and P � 0.938), respectively. In Figure 1, the funnel plot showed symmetrical distribution among studies.   Obstetrics and Gynecology International

Quality of the Included Studies.
We used the Cochrane Collaboration recommend tools for assessing the methodological quality of clinical trials. In our study, the quality of the 5 studies was high [4,14,[25][26][27] and that of the two studies were low [23,24] (Figure 5).

Sensitivity Analysis.
We explored the impact of Aloe vera combined with cactus by using a sensitivity analysis and excluding that result. Te pool estimates of the sensitive analysis demonstrated that pooled SMD was −0.56; CI= −0.87, −0.26, P value<0.001, and I 2 = 75% ( Figure 6).

Discussion
To our knowledge, this study is the frst meta-analysis to assess the efect of Aloe vera on breast pain and irritation in lactating women. Based on the available evidence, the meta-analysis showed that Aloe vera can be relieved 0.45-       Obstetrics and Gynecology International unit pain and 0.48-unit irritation than the no treatment/ breast milk lanolin group, and it was statistically signifcant.
Several systematic reviews were performed regarding the efectiveness of herbal medicine, especially Aloe vera, on wound healing and breast issues (eg., fssures, soreness, and irritation) in the postpartum period. In this regard, in 2017, Niazi et al. conducted a systematic review of 17 clinical trials (2 articles for herbal treatment, 2 articles for drug treatment, and 7 articles for nondrug treatment) to evaluate the effectiveness of various methods (such as silver cup, polyethylene protector, tea bag, phototherapy, laser therapy, marigold, Z. jujube, and Aloe vera) on the prevention and treatment of nipple pain and fssures. For assessing the efectiveness of Aloe vera, only one study was included in the review process and reported that Aloe vera is more efective than lanolin for treating nipple fssures [5]. Te systematic search in this article has not been conducted accurately, many articles related to Aloe vera have not been included, and no meta-analysis has been performed. Terefore, a general conclusion cannot be reached by the results of one study.
Similar to a previous study, Asadi et al. conducted a systematic review to assess the efect of herbal medicine (eg., menthol, Aloe vera, cotton soaked, lanolin cream, peppermint cream, Ziziphus jujuba fruit, and saqez ointment) on the prevention and treatment of nipple trauma and pain of Iranian women. Authors searched the Iranian indexed publications in English and Persian until December 2017, and 11 articles were included in the systematic review. Among included articles, only 2 articles assessed the efect of Aloe vera on nipple pain, which shows a positive efect. Also, this article has not performed meta-analysis [28].
Also, in 2016, Hekmatpou et al. conducted a systematic review of 23 randomized control trials to evaluate the effectiveness of Aloe vera on the prevention of skin ulcers and treating burn wounds, psoriasis, postoperative wounds, genital herpes, chronic wounds, and cracked nipples. Teir study's search period was from 1990 to 2016 with Persian and English language limitations. Tey were reported that Aloe vera has a positive efect on the prevention and healing of skin wounds and cracked nipple. In their study, only two articles include the review process regarding the efect of Aloe vera on the cracked nipple, and we are not doing a meta-analysis. On the other hand, the quality of the included study has not been assessed. Lack of assessing all resources and gray literature for systematic search has led to some relevant articles not being included in the systematic review [29].
Also, Pezeshki et al. in 2020 performed a systematic review of 6 interventional studies. Teir study examined the efect of Aloe vera extract, breast milk, calendit-E, curcumin, lanolin, olive oil, and purslane on the healing of breast fssures in lactating women. Teir results show that Aloe vera is more efective than olive oil and rubbing milk on the nipple fssures. But they don't perform any meta-analysis, and only 2 studies have assessed the efect of Aloe vera [30]. Moreover, in another systematic review that was conducted by Niazi et al. in 2021, the efects of topical treatment for the prevention and relief of nipple fssures and pain in lactating mothers were assessed. Tey have included 3 articles related to Aloe vera, and they show the positive efect of Aloe vera on nipple fssures, but they also did not perform a meta-analysis [31].

Strengths
(1) Reviewing previous systematic review studies revealed that an accurate systematic search was not conducted in some studies, as well as none of them performed a meta-analysis and had only qualitative reports. Tis study is the frst meta-analysis regarding the efect of Aloe vera on irritation and nipple pain in lactating women. (2) Searching in a large number of electronic databases, as well as hand-searching to yield maximum relevant articles in this feld. (3) Te homogeneity of studies that included the irritation outcome and their high quality. (4) High heterogeneity was seen among the included studies; therefore, a sensitivity analysis was performed to reduce the level of heterogeneity. After sensitive analysis, the level of heterogeneity in nipple pain was decreased.
Despite the study's strengths, the results have inherent limitations. Te quasi-experimental studies were included in the systematic review. Furthermore, a meta-analysis of only seven articles was too small to prove our hypothesis. Terefore, these results need to be interpreted with caution.

Conclusion
Our result showed that Aloe vera can be considered a choice for relieving breast pain or irritation in lactating women compared with routine care or another treatment. Considering the limited number of studies conducted on this topic and the low sample size, future studies with a larger sample will be required to draw better conclusions. Future studies with large sample sizes will be required to draw better conclusions.

Data Availability
Te data used to support the fndings of this study are available upon request.

Conflicts of Interest
Te authors declare no conficts of interest.