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PI4: ensayo que evalúa la metformina para prolongar la gestación en la preeclampsia prematura (PI4)

23 de septiembre de 2026 actualizado por: Lina Bergman

Intervención 4 para la preeclampsia: ensayo controlado aleatorio de fase III triple ciego que evalúa la metformina para prolongar la gestación en la preeclampsia prematura

Preterm preeclampsia is a severe condition for both the mother and the fetus. Currently, the only treatment available to stop disease progression is termination/delivery of the fetus and placenta. Therefore, preterm preeclampsia carries the highest rates of neonatal morbidity and mortality due to iatrogenic preterm birth. There is evidence suggesting metformin, a drug commonly used to treat diabetes in and outside pregnancy, may be able to counter the pathophysiology of preeclampsia, raising the possibility that it could be used to treat the condition. This multi centre double blind randomised controlled trial aims to investigate if metformin can prolong gestation, lower neonatal length of stay and increase birthweight in a Nordic setting.

Descripción general del estudio

Estado

Reclutamiento

Condiciones

Intervención / Tratamiento

Descripción detallada

Preeclampsia is globally responsible for 60,000 maternal deaths per year, and far greater numbers of fetal losses. Preterm preeclampsia is a severe variant with the highest rates of neonatal morbidity and mortality due to iatrogenic preterm birth (clinicians are forced to deliver the baby preterm for maternal or fetal health reasons).

There is preclinical evidence suggesting metformin, a drug commonly used to treat diabetes in and outside pregnancy, may be able to counter the pathophysiology of preeclampsia, raising the possibility that it could be used to treat the condition.

Previous research from the Preeclampsia Intervention 2 trial (PI2) show that metformin was able to delay delivery in early preterm preeclampsia. Metformin extended release (ER) was associated with a median 7.6-day prolongation of pregnancy (geometric mean ratio (GMR) 1.39 (95% CI 0.99 to 1.96) P=0.057).Trends towards increased birthweight (mean difference 110gm (95%CI -80 to 300), a decreased length of stay at the neonatal intensive care unit (median difference 5.0 days less; GMR 0.86, 95% CI 0.62 to 1.2) and a shorter period of admission in any neonatal ward (median difference 12.0 days less; GMR 0.82, 95% CI 0.57 to 1.18) in the metformin ER group were found. Importantly, while gastrointestinal side effects were common, no serious adverse events related to trial medications were observed.

The PI 2 trial has shown that metformin may be a disease modifying treatment for preterm preeclampsia. The trial is being repeated in a larger scale in the PI3 trial in South Africa to also assess neonatal outcomes. In the Nordic countries, the demographics of the population are different and expectant management of preeclampsia allows for the women to reach 37 weeks of gestation as opposed to 34 weeks of gestation in the PI2 trial. This trial aims to investigate if metformin can prolong gestation, lower neonatal length of stay and increase birthweight in a Nordic setting. Follow up of mothers and children will be carried out two years post partum.

Tipo de estudio

Intervencionista

Inscripción (Estimado)

294

Fase

  • Fase 3

Contactos y Ubicaciones

Esta sección proporciona los datos de contacto de quienes realizan el estudio e información sobre dónde se lleva a cabo este estudio.

Estudio Contacto

Copia de seguridad de contactos de estudio

  • Nombre: Lina Bergman, Associate Professor
  • Número de teléfono: 0046-3134307
  • Correo electrónico: lina.bergman@obgyn.gu.se

Ubicaciones de estudio

  • Finlandia
      • Helsinki, Finlandia, 00290
        • Reclutamiento
        • Helsinki University Hospital
        • Contacto:
          • Pia Villa, Associate Professor
          • Número de teléfono: 00358-405389779
          • Correo electrónico: pia.villa@helsinki.fi
        • Investigador principal:
          • Pia Villa, Associate Professor
      • Tampere, Finlandia, 33520
        • Reclutamiento
        • Tampere University Hospital
        • Contacto:
        • Investigador principal:
          • Hannele Laivuori, Professor
  • Noruega
      • Lørenskog, Noruega, N-1474
        • Reclutamiento
        • Akershus University Hospital
        • Contacto:
        • Investigador principal:
          • Camilla Haavaldsen, PhD
      • Oslo, Noruega, 0372
        • Reclutamiento
        • Oslo University Hospital
        • Contacto:
          • Trond Michelsen, Professor
          • Número de teléfono: 0047-23072619
          • Correo electrónico: trmi1@ous-hf.no
        • Investigador principal:
          • Ingvil Krarup Sørbye, Professor
  • Suecia
      • Borås, Suecia, 50455
        • Reclutamiento
        • Södra Älvsborgs Hospital
        • Contacto:
        • Investigador principal:
          • Lina Bergman, Associate Professor
      • Falun, Suecia, 79129
      • Gothenburg, Suecia, 416 85
      • Linköping, Suecia, 581 85
      • Lund, Suecia, 221 85
        • Reclutamiento
        • Skåne University Hospital
        • Contacto:
        • Contacto:
          • Simon Timpka, Associate professor
          • Número de teléfono: 0046-46171000
          • Correo electrónico: simon.timpka@med.lu.se
      • Malmö, Suecia, 205 02
        • Reclutamiento
        • Skåne University Hospital
        • Contacto:
      • Skövde, Suecia, 549 49
        • Reclutamiento
        • Skaraborg Hospital
        • Contacto:
      • Stockholm, Suecia, 17176
        • Reclutamiento
        • Karolinska University Hospital Solna
        • Contacto:
          • Anna Sandström, Associate Professor
          • Número de teléfono: 0046-739829820
          • Correo electrónico: anna.sandstrom@ki.se
        • Contacto:
      • Stockholm, Suecia, 182 88
        • Reclutamiento
        • Danderyd Hospital
        • Contacto:
      • Stockholm, Suecia, 14157
        • Reclutamiento
        • Karolinska University Hospital Huddinge
        • Contacto:
          • Anna Sandström, Associate Professor
          • Número de teléfono: 0046-739829820
          • Correo electrónico: anna.sandstrom@ki.se
        • Contacto:
      • Trollhättan, Suecia, 461 74
        • Reclutamiento
        • Norra Älvsborgs County Hospital
        • Investigador principal:
          • Lina Bergman, Associate Professor
        • Contacto:
      • Umeå, Suecia, 901 85
        • Reclutamiento
        • Norrland´s University Hospital
        • Contacto:
        • Investigador principal:
          • Marie-Therese Vinnars, PhD
      • Uppsala, Suecia, 75237
        • Reclutamiento
        • Uppsala University Hospital
        • Contacto:
      • Västerås, Suecia, 72335
        • Reclutamiento
        • Västmanlands Hospital Västerås
        • Contacto:
        • Investigador principal:
          • Linda Lindström, PhD

Criterios de participación

Los investigadores buscan personas que se ajusten a una determinada descripción, denominada criterio de elegibilidad. Algunos ejemplos de estos criterios son el estado de salud general de una persona o tratamientos previos.

Criterio de elegibilidad

Edades elegibles para estudiar

18 años y mayores (Adulto, Adulto Mayor)

Acepta Voluntarios Saludables

No

Géneros elegibles para el estudio

Femenino

Descripción

Inclusion Criteria:

  • A diagnosis of preeclampsia (defined as hypertension in combination with significant proteinuria (albumin/creatinine ratio >8 mg/mmol, protein/creatinine ratio>30 mg/mmol or >2+ protein on a urinary dipstick) has been made by the attending clinician
  • The managing clinicians have made the assessment to proceed with expectant management.
  • The subject has given written consent to participate in the study.
  • The woman must be 18 years of age or older
  • The gestational age is between 22+0 weeks to 33+6 weeks with a viable fetus
  • The woman carries a singleton pregnancy

Exclusion Criteria:

  • Contraindications to treatment with metformin as outlined in SmPC
  • Contraindications for expectant management of preeclampsia such as an immediate indication for delivery according to SFOG guidelines for preeclampsia (https://www.sfog.se/media/338533/pe-riktlinje-230214.pdf).
  • Type 1 Diabetes Mellitus
  • Current use of metformin
  • Known or suspected allergies against metformin
  • Reluctance or language difficulties that result in difficulty understanding the meaning of study participation
  • Unable to understand the informed consent process
  • Previous participation in the study
  • Established fetal compromise that necessitates imminent delivery (including planned delivery after 48 hours of corticosteroid treatment). This will be decided by the clinical team before expectant management is offered to the patient.
  • Suspicion of a major known fetal anomaly or malformation.
  • Renal disease or dysfunction, suggested by a creatinine level greater than or equal to 125 µmol/L or rapidly declining renal function
  • Known acute or chronic metabolic acidosis, including diabetic ketoacidosis
  • Not suitable for inclusion by the opinion of the investigator

Plan de estudios

Esta sección proporciona detalles del plan de estudio, incluido cómo está diseñado el estudio y qué mide el estudio.

¿Cómo está diseñado el estudio?

Detalles de diseño

  • Propósito principal: Tratamiento
  • Asignación: Aleatorizado
  • Modelo Intervencionista: Asignación paralela
  • Enmascaramiento: Triple

Armas e Intervenciones

Grupo de participantes/brazo
Intervención / Tratamiento
Comparador activo: Metformin ER

Metformin ER oral tablet 500 mg three times daily and increased to one gram (two tablets) three times daily as tolerated.
Droga: Metformin ER

Metformin ER, one gram three times daily taken orally. Once the participants have been recruited, they will start by taking one 500 mg tablet three times a day. If well tolerated it will be increased day two to a maximum of two tablets three times a day. Treatment will continue until delivery. If there are side effects that are not tolerable, the dose will be decreased and the participant will remain blinded. Each participant will keep a treatment diary and number of tablets taken will be documented by the participant or hospital staff. The study will not alter or interfere with treatment or care routinely given for preterm preeclampsia.

Otros nombres:
  • Glucophage SR 500 mg comprimidos de liberación prolongada
Comparador de placebos: Placebo

1 placebo tablet three times daily and increased to 2 placebo tablets three times daily as tolerated.
Droga: Placebo

Placebo, two tablets three times daily taken orally. Once the participants have been recruited, they will start by taking one tablet three times a day. If well tolerated it will be increased day two to a maximum of two tablets three times a day. Treatment will continue until delivery. If there are side effects that are not tolerable, the dose will be decreased and the participant will remain blinded. Each participant will keep a treatment diary and number of tablets taken will be documented by the participant or hospital staff. The study will not alter or interfere with treatment or care routinely given for preterm preeclampsia.

¿Qué mide el estudio?

Medidas de resultado primarias

Medida de resultado
Medida Descripción
Periodo de tiempo
Pregnancy prolongation
Periodo de tiempo: From randomisation to delivery, measured in days and hours, up to 105 days

Length of pregnancy from diagnosis of preeclampsia to delivery
From randomisation to delivery, measured in days and hours, up to 105 days

Medidas de resultado secundarias

Medida de resultado
Medida Descripción
Periodo de tiempo
Time for neonatal care
Periodo de tiempo: From birth to discharge from neonatal care, measured in days and hours, up to 126 days

Time for neonatal care from birth to discharge
From birth to discharge from neonatal care, measured in days and hours, up to 126 days
Neonatal birth weight
Periodo de tiempo: At birth

Birth wight measured in grams
At birth

Otras medidas de resultado

Medida de resultado
Medida Descripción
Periodo de tiempo
Occurrence of maternal death
Periodo de tiempo: Registered from inclusion to two month post partum

Occurrence of maternal death
Registered from inclusion to two month post partum
Occurrence of Eclampsia
Periodo de tiempo: Registered from inclusion to two month post partum

Occurrence of Eclampsia
Registered from inclusion to two month post partum
Occurrence of Cerebral vascular event
Periodo de tiempo: Registered from inclusion to two month post partum

Occurrence of Cerebral vascular event
Registered from inclusion to two month post partum
Occurrence of posterior reversible encephalopathy syndrome
Periodo de tiempo: Registered from inclusion to two month post partum

Occurrence of posterior reversible encephalopathy syndrome
Registered from inclusion to two month post partum
Occurrence of pulmonary edema
Periodo de tiempo: Registered from inclusion to two month post partum

Occurrence of pulmonary edema
Registered from inclusion to two month post partum
Occurrence of left ventricular failure
Periodo de tiempo: Registered from inclusion to two month post partum

Occurrence of left ventricular failure
Registered from inclusion to two month post partum
Occurrence of renal dialysis
Periodo de tiempo: Registered from inclusion to two month post partum

Occurrence of renal dialysis
Registered from inclusion to two month post partum
Occurrence of renal failure
Periodo de tiempo: Registered from inclusion to two month post partum

Occurrence of renal failure:≥ 90 µmol/L or no urinary output for 6 hours
Registered from inclusion to two month post partum
Occurrence of elevated liver transaminases
Periodo de tiempo: Registered from inclusion to two month post partum

Occurrence of elevated liver transaminases: ALT or AST ≥ 2 times highest normal value (ALAT >1.5 µkat/L and ASAT > 1.2 µkat/L)
Registered from inclusion to two month post partum
Occurrence of HELLP syndrome
Periodo de tiempo: Registered from inclusion to two month post partum

Occurrence of HELLP (Haemolysis, elevated liver enzymes and low platelets) syndrome
Registered from inclusion to two month post partum
Occurrence of thrombocytopenia
Periodo de tiempo: Registered from inclusion to two month post partum

Occurrence of thrombocytopenia (platelets <100 X 109/L)
Registered from inclusion to two month post partum
Occurrence of liver haematoma or rupture
Periodo de tiempo: Registered from inclusion to two month post partum

Occurrence of liver haematoma or rupture
Registered from inclusion to two month post partum
Occurrence of admission to an intensive care unit
Periodo de tiempo: Registered from inclusion to two month post partum

Occurrence of admission to an intensive care unit
Registered from inclusion to two month post partum
Occurrence of severe hypertension
Periodo de tiempo: Registered from inclusion to two month post partum

Occurrence of severe hypertension (BP>160/110 mm Hg)
Registered from inclusion to two month post partum
Occurrence of disseminated intravascular coagulation
Periodo de tiempo: Registered from inclusion to two month post partum

Occurrence of disseminated intravascular coagulation
Registered from inclusion to two month post partum
Occurrence of caesarean section
Periodo de tiempo: At birth

Occurrence of caesarean section
At birth
Occurrence of major postpartum hemorrhage
Periodo de tiempo: At birth

Occurrence of major postpartum hemorrhage (>1000 ml)
At birth
Occurrence of thromboembolic disease
Periodo de tiempo: Registered from inclusion to two month post partum

Occurrence of thromboembolic disease: deep venous thrombosis or pulmonary embolism
Registered from inclusion to two month post partum
Duration of maternal postpartum hospital stay
Periodo de tiempo: Registered from birth to hospital discharge

Duration of maternal postpartum hospital stay (days)
Registered from birth to hospital discharge
Number of antihypertensive drugs
Periodo de tiempo: At discharge

Number of antihypertensive drugs at discharge after delivery
At discharge
Duration of antihypertensive medication
Periodo de tiempo: From inclusion to two month postpartum

Duration of antihypertensive medication (days)
From inclusion to two month postpartum
Occurrence of intrauterine fetal demise
Periodo de tiempo: From inclusion to birth

Occurrence of intrauterine fetal demise
From inclusion to birth
Occurrence of neonatal death
Periodo de tiempo: From inclusion to two month post partum

Occurrence of neonatal death
From inclusion to two month post partum
Occurrence of growth restriction at birth
Periodo de tiempo: At birth

Occurrence of growth restriction at birth (less than 2 standard deviations from median weight from Swedish birth weight growth curves).
At birth
Occurrence of grade 3 or 4 intraventricular hemorrhage
Periodo de tiempo: Registered from birth to two month post partum

Occurrence of grade 3 or 4 intraventricular hemorrhage
Registered from birth to two month post partum
Occurrence of necrotizing enterocolitis
Periodo de tiempo: Registered from birth to two month post partum

Occurrence of necrotizing enterocolitis
Registered from birth to two month post partum
Occurrence of reversed a-wave in the ductus venosus
Periodo de tiempo: Registered from birth to two month post partum

Occurrence of reversed a-wave in the ductus venosus
Registered from birth to two month post partum
Occurrence of persistent reversed flow in the umbilical artery
Periodo de tiempo: Registered from inclusion to birth

Occurrence of persistent reversed flow in the umbilical artery
Registered from inclusion to birth
Occurrence of redistribution in the middle cerebral artery
Periodo de tiempo: Registered from birth to two month post partum

Occurrence of redistribution in the middle cerebral artery
Registered from birth to two month post partum
Occurrence of low APGAR score
Periodo de tiempo: At birth

Occurrence of low APGAR score, defined as less than 4 at 5 minutes
At birth
Occurrence of umbilical artery pH below 7.1
Periodo de tiempo: At birth

Occurrence of umbilical artery pH below 7.1
At birth
Occurrence of invasive ventilation, intubation and mechanical ventilation or non-invasive ventilatione outcome
Periodo de tiempo: Registered from birth to two month post partum

Occurrence of invasive ventilation, intubation and mechanical ventilation or non-invasive ventilation; continuous positive airway pressure (CPAP) support or high flow nasal oxygen
Registered from birth to two month post partum
Occurrence of grade III/IV hyaline membrane disease
Periodo de tiempo: Registered from birth to two month post partum

Occurrence of grade III/IV hyaline membrane disease
Registered from birth to two month post partum
Occurrence of surfactant use
Periodo de tiempo: Registered from birth to two month post partum

Occurrence of surfactant use
Registered from birth to two month post partum
Occurrence of retinopathy of prematurity
Periodo de tiempo: Registered from birth to two month post partum

Occurrence of retinopathy of prematurity
Registered from birth to two month post partum
Occurrence of neonatal sepsis
Periodo de tiempo: Registered from birth to two month post partum

Occurrence of neonatal sepsis
Registered from birth to two month post partum
Tolerability and safety
Periodo de tiempo: From inclusion to birth

Severity of nausea measured by PHASE-20 Severity of vomiting measured by PHASE-20 Severity of diarrhoea measured by PHASE-20 Severity of headache measured by PHASE-20
From inclusion to birth
Tolerability and safety
Periodo de tiempo: From inclusion to birth

Occurrence of lactic acidosis (blood pH< 7.35 or blood lactate> 5 mM)
From inclusion to birth
Tolerability and safety
Periodo de tiempo: From inclusion to birth

Drug adherence (measured by treatment diary)
From inclusion to birth
Pre-eclampsia-related biomarkers
Periodo de tiempo: From inclusion to two years post partum

Concentrations of Soluble Fms-like tyrosine kinase-1 Concentrations of Placental growth factor Concentrations of Soluble endoglin
From inclusion to two years post partum
Gut and vaginal microbiome composition
Periodo de tiempo: From inclusion to two years post partum

Omics-based analysis of the microbiome
From inclusion to two years post partum
Breastfeeding initiation
Periodo de tiempo: From birth to two month postpartum

Breastfeeding initiation (measured by unvalidated breastfeeding questionnaire with no score)
From birth to two month postpartum
Depressive symptoms
Periodo de tiempo: From inclusion to two years post partum

Depressive symptoms (measured by the Edinburgh Postnatal Depression Scale; 0-30, with higher scores indicating higher self-esteem)
From inclusion to two years post partum
Self-esteem
Periodo de tiempo: From inclusion to two years post partum

Self-esteem (measured by The Rosenberg Self-Esteem Scale; 0-30, higher scores indicating higher self-esteem)
From inclusion to two years post partum
Perceived stress
Periodo de tiempo: From inclusion to two years postpartum

Perceived stress (measured by the 10-item Perceived Stress Scale; 0-40, with higher scores indicating greater perceived stress)
From inclusion to two years postpartum
Breastfeeding self-efficacy
Periodo de tiempo: From birth to two month postpartum

Breastfeeding self-efficacy (measured by the Breastfeeding Self-Efficacy Scale-Short Form; 14-70, higher score= greater breastfeeding self-efficacy)
From birth to two month postpartum
Health-related quality of life
Periodo de tiempo: From inclusion to two years post partum

Health-related quality of life (measured using the EQ-5D-5L (the official name) and reported as the EQ-5D-5L index value and the EQ VAS [0-100]). EQ-5D-5L index values will be derived using country-specific value sets where available; higher index values indicate better health-related quality of life. The EQ VAS ranges from 0 to 100, with higher scores indicating better self-rated health)
From inclusion to two years post partum
Parental-infant bonding
Periodo de tiempo: From birth to two month post partum

Parental-infant bonding (measured by the Postpartum Bonding Questionnaire; 0-125, higher score= greater impairment/difficulties in parent-infant bonding)
From birth to two month post partum
Health economic outcomes
Periodo de tiempo: From birth to two years post partum

Cost-effectiveness short-term: direct healthcare costs (based on drug and healthcare use) for mother and child from enrolment until discharge, will be compared to incremental effects measured as prolongation of gestation

Cost-effectiveness long-term: societal costs (based on drug and healthcare use, and social insurance transactions) for mother and child from enrolment until two years postpartum, will be compared to incremental effects measured as prolongation of gestation and health-related quality of life
From birth to two years post partum
Risk of autism spectrum disorder
Periodo de tiempo: At two years corrected age

Risk of autism spectrum disorder (evaluated by the Modified Checklist for Autism in Toddlers, Revised (M-CHAT/R); 20 questions resulting in score 0-20 where 0-2 indicates no risk, 3-7 moderate risk and 8-20 high risk for autism).
At two years corrected age
Cognitive development of the child
Periodo de tiempo: At two years corrected age

Developmental screening (based on parental questionnaire Ages and Stages Questionnaire, Third Edition 24-months (ASQ-3);questions covering five key developmental domains; communication, gross motor, fine motor, problem-solving and personal-social skills; answers scored from 0-60 with age-specific cut-off levels at -2 and -1SD indicating clear or suspect developmental delay)
At two years corrected age
Cognitive development of the child
Periodo de tiempo: At two years corrected age

Comprehensive developmental assessment (evaluated by the Bayley Scales of Infant Development-4 (BSID-4), with main scores for motor, language and cognitive function. Results expressed as age-corrected developmental scores in each domain with clear developmental delay at scores < 70 (-2SD) and suspect developmental delay at scores < 85 (-1SD).
At two years corrected age

Colaboradores e Investigadores

Aquí es donde encontrará personas y organizaciones involucradas en este estudio.

Patrocinador

Lina Bergman

Colaboradores

The Swedish Research Council

Investigadores

  • Investigador principal: Lina Bergman, Associate professor, Sahlgrenska University Hospital

Publicaciones y enlaces útiles

La persona responsable de ingresar información sobre el estudio proporciona voluntariamente estas publicaciones. Estos pueden ser sobre cualquier cosa relacionada con el estudio.

Publicaciones Generales

Fechas de registro del estudio

Estas fechas rastrean el progreso del registro del estudio y los envíos de resultados resumidos a ClinicalTrials.gov. Los registros del estudio y los resultados informados son revisados ​​por la Biblioteca Nacional de Medicina (NLM) para asegurarse de que cumplan con los estándares de control de calidad específicos antes de publicarlos en el sitio web público.

Fechas importantes del estudio

Inicio del estudio (Actual)

19 de enero de 2024

Finalización primaria (Estimado)

31 de diciembre de 2027

Finalización del estudio (Estimado)

31 de diciembre de 2029

Fechas de registro del estudio

Enviado por primera vez

28 de agosto de 2023

Primero enviado que cumplió con los criterios de control de calidad

10 de septiembre de 2023

Publicado por primera vez (Actual)

13 de septiembre de 2023

Actualizaciones de registros de estudio

Última actualización publicada (Actual)

28 de septiembre de 2026

Última actualización enviada que cumplió con los criterios de control de calidad

23 de septiembre de 2026

Última verificación

1 de agosto de 2026

Más información

Términos relacionados con este estudio

Palabras clave

Términos MeSH relevantes adicionales

Otros números de identificación del estudio

  • EU Trial nr: 2022-502707-2-00

Plan de datos de participantes individuales (IPD)

¿Planea compartir datos de participantes individuales (IPD)?

SÍ

Descripción del plan IPD

Metadata and statistical code will be published in public repositories upon release of the trial's primary results. Deidentified data may be shared upon reasonable request following a written application including a research proposal and ethical approval, in accordance with applicable ethical and legal requirements.

We plan to share data with similar ongoing or planned trials in South Africa and The Netherlands.

Información sobre medicamentos y dispositivos, documentos del estudio

Estudia un producto farmacéutico regulado por la FDA de EE. UU.

No

Estudia un producto de dispositivo regulado por la FDA de EE. UU.

No

producto fabricado y exportado desde los EE. UU.

No

Esta información se obtuvo directamente del sitio web clinicaltrials.gov sin cambios. Si tiene alguna solicitud para cambiar, eliminar o actualizar los detalles de su estudio, comuníquese con register@clinicaltrials.gov. Tan pronto como se implemente un cambio en clinicaltrials.gov, también se actualizará automáticamente en nuestro sitio web. .

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