The GINGER-BLEED study is a randomized, double-blind, placebo-controlled clinical trial evaluating the effect of ginger powder on heavy menstrual bleeding in women with coagulopathies. This type of bleeding, defined as a loss of more than 80 ml per cycle, significantly affects women's quality of life, causing anemia, pain, and social limitations. Although conventional treatments exist, they can cause adverse effects, especially in women with coagulation disorders.

The hypothesis is that administering 750 mg of ginger daily for six months can reduce menstrual bleeding. The main objective is to analyze this effect, while specific objectives include evaluating changes in coagulation parameters and prostaglandin levels.

The study will be conducted between March 2028 and January 2029 at the University of Valladolid. Seventy-four women with coagulopathies, selected after a gynecological evaluation, ultrasound, and blood tests, will participate. They will be divided into two groups: one will receive ginger capsules and the other a placebo (Stevia) during the first three days of each menstrual cycle for six consecutive cycles.

The PBAT tool will be used to estimate bleeding, and statistical analyses will be performed using SPSS v29. Variables such as adverse effects, treatment adherence, and clinical parameters will be considered. The study complies with current ethical standards, including the Declaration of Helsinki and Spanish data protection legislation. The results will be disseminated in scientific journals and patient associations, proposing improvements in public health policies.

INTRODUCTION: CURRENT STATUS AND JUSTIFICATION FOR RESEARCH Heavy menstrual bleeding is one of the common causes of gynecological health problems in women of childbearing age who suffer from coagulation disorders.

Heavy menstrual bleeding is bleeding of endometrial origin that occurs in the first phase of the female hormonal cycle during menstruation. It is considered heavy when it exceeds 80 ml in a menstrual cycle.

Up to 25% of gynecological consultations in hospitals are due to heavy menstrual bleeding in both women with and without coagulation problems. It is known that despite this, there is underdiagnosis, as women often do not seek medical advice for this problem.

The quality of life of women with heavy menstrual bleeding is clearly impaired, as it can interfere with their lifestyles, work performance, daily activities, and even social commitments. It is not uncommon for these women to develop anemia due to excessive blood loss and iron deficiency.

The factors involved in heavy menstrual bleeding are known to be higher levels of fibrinolysis, or the dissolution of clots that prevent bleeding from stopping, and an imbalance in prostaglandin levels, as the uterus tends to contain higher levels of prostaglandin receptors.

The usual treatments for heavy bleeding are: combined or progesterone-only contraceptives, tranexamic acid, and nonsteroidal anti-inflammatory drugs. The problem is that this therapeutic approach is often associated with unwanted side effects that are more serious in women with coagulation problems.

For some time now, numerous studies have been conducted on the use of plants in gynecological disorders, from irregular menstrual cycles to infertility, but heavy menstrual bleeding has not been studied as extensively.

Ginger, whose scientific name is Zingiber officinale, is a rhizomatous plant that grows in the tropical rainforests of India. It grows to a height of 2 m and has linear leaves 5-25 cm long and 1-3 cm wide. But without a doubt, what is most interesting are its rhizomes, which are the horizontal stems from which the roots grow and the main part of ginger that is consumed for its nutritional importance. Its spicy aroma is mainly due to the presence of ketones, particularly gingerols, which appear to be the main component of ginger.

This spice was used by the ancient Greeks and Romans around 750 BC. In the 2nd century, ginger appears in a list of imports made in Alexandria (Egypt) from the Red Sea, subject to customs duties by Rome. After pepper, ginger was the second most popular spice among the Romans, and it remained a highly sought-after product in Europe even after the fall of the Roman Empire. Its trade was then controlled by Arab merchants.

Galen, a Greek physician, surgeon, and philosopher, considered one of the most accomplished medical researchers of ancient times, used it as a medicine to treat tumors, physical defects, and paralysis caused by excess phlegm.

Avicenna, a renowned Muslim physician, recommended it as an aphrodisiac, highly beneficial in the treatment of "sexual weakness." The Portuguese introduced it to Africa, and during the 15th century, the Spanish brought it to the Antilles. It is known that Francisco de Mendoza planted pepper, cloves, and ginger in New Spain (now Mexico), with ginger yielding the best results, as it was considered good for stews and as a digestive aid.

Ginger was not only tasty, but also had properties that helped preserve bread. According to French legend, gingerbread was brought to Europe in 992 by the Armenian monk Gregory of Nicopolis, who lived for seven years in Bondaroy, France, near the village of Pithiviers, where he taught priests and other Christians how to bake it.

Another medieval legend links it to the birth of Jesus, which is attested to in an 8th-century Greek document of presumed Irish origin and translated into Latin with the title "Collectanea et Flores," which states that in addition to gold, frankincense, and myrrh given by three "wise men from the East" (magicians), ginger was the gift of a wise man (magus) who was unable to complete the journey to Bethlehem. While recovering in his final days in a city in Syria, the magician gave his chest of ginger roots to the rabbi who had kindly cared for him during his illness. The rabbi was accustomed to having his young students make houses out of bread to eat. The magician suggested adding ground ginger to the bread for flavor.

Gingerbread is believed to have been first baked in Europe in the late 11th century, and as we know it today, it descends from medieval European culinary traditions. In the 13th and 14th centuries, the value of a pound of ginger was equivalent to the cost of a sheep.

Its current name comes from the Middle English gingivere, but this spice dates back more than 3,000 years to the Sanskrit word srngaveram, which means "horn root," based on its appearance. In Greek it was called ziggiberis and in Latin zinziberi. It is not related to the wild ginger of the northern hemisphere, whose roots have similar aromatic properties but should not be consumed as they contain aristolochic acid, a compound associated with permanent kidney damage.

In addition to its culinary value, it is used medicinally for various ailments. Because ginger and its metabolites appear to accumulate in the gastrointestinal tract, consistent observations of its effects in this area are not surprising. It has been said to exert a variety of powerful therapeutic and preventive effects, and for thousands of years it was used to treat ailments such as colds, nausea, arthritis, migraines, and hypertension.

Like many medicinal herbs, much of the information has been passed down by word of mouth with little controlled scientific evidence. However, in recent years, more organized scientific research has focused on the mechanisms and targets of ginger and its various effective components as an anti-inflammatory agent and antioxidants.

Caution has been suggested when taking ginger due to an apparent association of ginger with reported incidents of increased risk of bleeding after surgery, or if taken with anticoagulant medications.

Ginger products are made from fresh or dried ginger root, or from steam distillation of the root oil. You can find ginger extracts, tinctures, capsules, and oils. You can also buy the fresh root and make tea. Ginger is a common cooking spice and is found in a variety of foods and beverages, including gingerbread, ginger cookies, ginger sticks, and ginger beer.

Ginger has therapeutic properties for dysmenorrhea, morning sickness during pregnancy, and inflammatory processes in general. In terms of its physiological effect, it appears to modulate prostaglandin synthesis and increase the activity of the uterine smooth muscle in the endometrium. A reduction in prostaglandin synthesis inhibits contractions and therefore prevents the clot formed by the shedding of the endometrium from breaking up, while an increase in myometrial muscle tone generates an effect similar to that of the formation of Pinard's living ligatures in placental detachment during childbirth, which facilitates the vascular closure of those vessels that have ruptured with the expulsion of the endometrium during menstruation.

HYPOTHESIS AND OBJECTIVES:

Hypothesis:

Taking 750 mg of powdered ginger daily for 6 months reduces heavy menstrual bleeding in women with coagulopathies.

Main objective:

To analyze the effect of using 750 mg of ginger powder daily for 6 months on heavy menstrual bleeding in women with coagulopathies.

Specific objectives:

• To analyze the effect of taking 750 mg of ginger powder daily for 6 months on analytical parameters related to blood coagulation in women with coagulopathies.
• Analyze the effect of using 750 mg of ginger powder daily for 6 months on the level of prostaglandins in the blood on the third day of the menstrual cycle in women with coagulopathies.

RESEARCH METHODOLOGY:

Design This is a randomized, double-blind, placebo-controlled clinical trial consisting of two parallel groups.

This study will be conducted within the Nursing Care Research Groups (GICE) at the University of Valladolid.

The study period will run from March 2028 to January 2029. The clinical trial will be registered on clinicaltrials.gov, which belongs to the US National Library of Medicine, once approval has been obtained from the Ethics Committee of the Valladolid Areas.

Participants Women with coagulopathy who meet the inclusion criteria and who voluntarily wish to take part in the study and give their signed informed consent after being informed of the purpose of the study and the intervention that will be carried out on them.

Inclusion criteria Women of childbearing age with coagulopathies, regular menstrual cycles, and heavy menstrual bleeding (demonstrated by recording 3 menstrual cycles), who voluntarily wish to participate in the study.

Exclusion criteria Women with coagulopathy who have a gynecological disease such as endometriosis, who are taking any type of hormonal treatment including contraception, who take nonsteroidal anti-inflammatory drugs during their menstruation, who have active vaginal infections or pelvic inflammatory disease, who are overweight (BMI>25) or underweight (BMI<25), or who lack the cognitive ability to understand the menstrual cycle and the instructions to follow, and who are allergic to ginger and/or Stevia.

Selection of participants Before beginning the study, women who were contacted through Fedhemo and who met the inclusion criteria underwent an evaluation of their next three menstrual cycles to determine their menstrual pattern. A gynecological medical history, vaginal ultrasound, and blood test will be performed to determine the status of parameters related to blood clotting.

Sample size Accepting an alpha risk of 0.05, a beta risk of 0.20 in a two-tailed test, and a standard deviation of 2.1, and estimating sample losses of 10%, 74 participants will be needed, 37 for each group. To determine the eligibility of women, since not all of them will have a regular hormonal cycle, it is estimated that 10% of the women needed to reach the required sample size will be available, i.e., 82 women of childbearing age with coagulopathies. If more women than necessary are recruited, those exceeding 74 will be randomly excluded. If the sample size is not sufficient, a new selection of participants will be used until the required 74 women are reached. The sampling process can be consulted in the diagram below.

Procedure and randomization All participants attended a baseline consultation where they were informed of the purpose of the study, asked to sign an informed consent form, underwent initial tests, and were instructed to record their menstrual cycle for three consecutive months. After three months, those who met the requirement of having a regular menstrual cycle were included in the study and assigned to one of the groups (ginger or placebo). All participants attended a visit after their first menstruation, after their second, after their third, and after their sixth. At these visits, they reported their menstrual bleeding records and were given the tablets to take in the next cycle or cycles. In addition, any questions that arose were answered.

At the end of the intervention, all the records kept by the women were collected and blood coagulation tests were performed.

The participants were randomly assigned to one of the two groups: the intervention group (ginger), consisting of 37 participants, and the control group (placebo), consisting of 37 participants. The allocation sequence was generated using the Epidat® program by a researcher from the group who was not directly involved in the study. The number each participant obtained depended on when they attended the baseline consultation.

Intervention The services of a pharmaceutical laboratory will be contracted to prepare capsules containing 250 mg of dried, crushed, and powdered ginger. Placebo capsules will be prepared with powdered Stevia. The appearance of the capsules must be identical. The capsules will be packaged in identical containers, indicating the participant number from 1 to 74 and generating six packages reflecting the first, second, third, fourth, fifth, and sixth cycles for each participant number.

Both the intervention and control groups will take three capsules per day in the morning and store them in a dry place. In each cycle, they will begin taking the capsules on the first day of the cycle and continue until the third day of the cycle.

They will be given a record sheet on which they will indicate the date of intake, the number of capsules taken each day, and the estimated amount of bleeding according to the PBAT Tool. They will also be allowed to indicate any incidents or possible adverse effects that may have arisen.

Variables

• Independent variable: treatment (ginger vs. placebo).
• Primary dependent variable: amount of menstrual bleeding (PBAT).
• Secondary dependent variables: coagulation parameters, adverse effects, and treatment adherence.
• Control variables: age, type of coagulopathy, menstrual cycle characteristics, and baseline clinical variables.

Statistical analysis of data Absolute frequencies and percentages will be used to characterize the sample if the variables are categorical, while the mean and standard deviation will be used in the case of quantitative variables. The Kolmogorov-Smirnov test will be used to verify compliance with the normality criteria for quantitative variables. To determine the existence of an association between variables, parametric or non-parametric tests will be used according to the assumption of normality. For the PBAT score, Student's t-test will be used for related samples or Wilcoxon for paired samples, depending on normality. To compare the effect of ginger versus placebo, ANOVA or Friedman's non-parametric test will be used. For coagulation parameters, the pre-post intervention intragroup comparison will be performed using the paired t-test or Wilcoxon test; and for intergroup (pre-post change), the independent t-test or Mann-Whitney test will be used. For adverse effects, the χ² or Fisher's exact test will be used, and for treatment adherence, the Student's t-test or Mann-Whitney test will be used. In all cases, effect sizes will be included using Cohen's d or partial η². Where possible, ANCOVA analyses will be performed with analysis of variance between both groups. Statistical significance will be considered if p<0.05, with a 95% confidence interval. Statistical analysis will be performed using SPSS version 29 software (IBM-Inc, Chicago-IL-USA).

Ethical aspects The study has been submitted for evaluation and approval by the Drug Research Ethics Committee of the Valladolid Health Areas.

Participants will be informed prior to completing the survey of the voluntary and disinterested nature of their participation, as well as the anonymity of their responses.

An email address will also be provided to resolve any issues. This address will be created exclusively for the project: eximco@gmail.com Compliance with Organic Law 3/2018, of December 5, on the Protection of Personal Data and Guarantee of Digital Rights, and Regulation 2016/679 of the European Parliament and of the Council of April 27, 2016, on the protection of natural persons with regard to the processing of personal data and on the free movement of such data, will be ensured. The World Medical Association (WMA) Declaration of Helsinki and its subsequent updates were followed at all times.

The quality of the study is guaranteed by following the CONSORT quality assessment guidelines for randomized clinical trials.

Inclusion Criteria:

• Women of childbearing age with coagulopathies, -Regular menstrual cycles, -heavy menstrual bleeding (demonstrated by recording 3 menstrual cycles), -who voluntarily wish to participate in the study.

Exclusion Criteria:

• Women with coagulopathy who have a gynecological disease such as endometriosis, -who are taking any type of hormonal treatment including contraception, -who take nonsteroidal anti-inflammatory drugs during their menstruation, -who have active vaginal infections or pelvic inflammatory disease, -who are overweight (BMI>25) or underweight (BMI<25), -who lack the cognitive ability to understand the menstrual cycle and the instructions to follow, -who are allergic to ginger and/or Stevia.

Women

Given that the disease is not very common in the Spanish population, participants could be identified.