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Selenium Supplementation in Pregnancy (Serena)

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2014 by University of Roma La Sapienza
Sponsor:
Information provided by (Responsible Party):
Andrea M. Isidori, University of Roma La Sapienza
ClinicalTrials.gov Identifier:
NCT01465867
First received: November 2, 2011
Last updated: October 25, 2014
Last verified: October 2014
  Purpose

Serum levels of isolated anti-thyroperoxidase (TPOab) and anti-thyreoglobulin (Tgab) autoantibodies are strongly associated with an increased risk of miscarriage and premature deliveries in euthyroid pregnant women. Replacement of thyroxine (LT4) or other supplementations in euthyroid-Ab positivity during pregnancy has not been established. The development of a safe and effective intervention that modulates inappropriate inflammatory responses could be a very important component of prevention against adverse health outcomes during pregnancy.

The anti-oxidant Selenium (Se) suppresses autoimmune destruction of thyrocytes and at daily dose of 200 mcg and 100 mcg decreases titers of serum TPOAb and TgAb also in Se-non-deficient patients with autoimmune thyroiditis (AIT).

The use of Se in AIT has been shown to reduce the incidence of postpartum thyroiditis and hypothyroidism.

Women with recurrent pregnancy loss had lower Se levels and Se deficiency has been implicated in the pathogenesis of AIT and in the impairment of T/B cell-mediated immunity.

The purpose of the present study is performed to establish the effect of Se supplementation in euthyroid women with AIT (pregnant and in whom embryo transfer is expected within 60 days) on Ab trend, thyroid function and structure, implantation rates, pregnancy rates, pregnancy outcome and number of obstetrical, fetal and neonatal complications.


Condition Intervention Phase
Pregnancy
Infertility
Auto-immune Thyroiditis
Dietary Supplement: Selenium
Other: Sugar Pill Placebo
Other: Selenium + L-Thyroxine (LT4)
Other: Sugar Pill Placebo + L-Thyroxine (LT4)
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Prevention
Official Title: Selenium Supplementation Treatment in Euthyroid Pregnant Women With Autoimmune Thyroid Disease: Effects on Obstetrical Complications

Resource links provided by NLM:


Further study details as provided by University of Roma La Sapienza:

Primary Outcome Measures:
  • Changes in TPOab and/or Tgab [ Time Frame: 0 and 14 ± 2, 24 ± 2, 32± 2, 36± 2 weeks; and between 3° and 6° month after labour; and optionally 12° after labour ] [ Designated as safety issue: No ]
    TPOab and Tgab titers will be measured using a ECLIA kit. Plasma selenium concentration will also be measured


Secondary Outcome Measures:
  • Changes in thyroid volume and echogenicity [ Time Frame: 0 and 14 ± 2, 24 ± 2, 32± 2, 36± 2 weeks; and between 3° and 6° month after labour; and optionally 12° after labour ] [ Designated as safety issue: No ]
    Also changes in thyroid nodules diameters and/or nodules formation will be measured by Ultrasonographic (US) imaging

  • Changes in thyroid hormones (TSH, FT4, FT3) [ Time Frame: 0 and 14 ± 2, 24 ± 2, 32± 2, 36± 2 weeks; and between 3° and 6° month after labour; and optionally 12° after labour ] [ Designated as safety issue: No ]
  • Evaluation of Maternal risks [ Time Frame: From the date of randomization until the date of first documented event ] [ Designated as safety issue: Yes ]
    Pre-eclampsia (gestational hypertension: systolic pressure ≥140 mmHg or diastolic blood pressure ≥ 90 mmHg [Korotkoff V] on ≥ 2 occasions after 20 weeks gestation), Miscarriage, Placental Abruption, Abruption, Gestational hypertension, Breech presentation at birth, Preterm birth (< 37 weeks gestation), Symptomatic hypothyroidism, Preterm labour, Postpartum haemorrhage, Postpartum depression, Postpartum Thyroiditis, Maternal death

  • Evaluation of Infant risks [ Time Frame: From the date of labour until the date of the first documented event ] [ Designated as safety issue: Yes ]
    Small for gestational age, Admission to special care, Cretinism, Jaundice requiring phototherapy, Poor feeding, Constipation, Hoarse cry, Lethargy, Hypotonia, Macroglossia, Umbilical hernia

  • Changes in of quality of life [ Time Frame: 0 and 14 ± 2, 24 ± 2, 32± 2, 36± 2 weeks; and between 3° and 6° month after labour; and optionally 12° after labour ] [ Designated as safety issue: No ]
    Quality of life will be measured by questionnaire SF12

  • Evaluation of Health Services: [ Time Frame: from the date of admission until the date of discharge ] [ Designated as safety issue: No ]
    Maternal length of hospital stay (days), Neonatal length of hospital stay (in days), Cost of services

  • Changes in the selenium-dependent antioxidant enzyme glutathione peroxidase [ Time Frame: 0, 24 ± 2, 36± 2 weeks; and 6 months after labour ] [ Designated as safety issue: No ]
    Glucose, Vitamin B-12, folate, methionine, albumin and cytokines will be also measured in serum

  • Changes in implantation and pregnancy rates [ Time Frame: From the date of embryo transfer until the date of documented progression ] [ Designated as safety issue: No ]
    Clinical implantation rate (IR) and pregnancy rate (PR)


Estimated Enrollment: 150
Study Start Date: April 2012
Estimated Study Completion Date: May 2015
Estimated Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Selenium Dietary Supplement: Selenium
83 micrograms of selenium (in the form of selenium methionine) in tablet form taken orally daily for all the length of pregnancy and for 3-6th month after labour
Other Name: Intervention I (Se)
Placebo Comparator: Sugar Pill Placebo Other: Sugar Pill Placebo
Placebo supplements in the same capsule as selenium. 1 tablet daily for all the length of pregnancy and for 3-6th month after labour.
Other Name: Intervention II (Plb)
Experimental: Selenium + L-Thyroxine (LT4) Other: Selenium + L-Thyroxine (LT4)

83 micrograms of selenium (in the form of selenium methionine) in tablet form taken orally daily for all the length of pregnancy and for 3-6th month after labour

+ LT4 taken orally daily according to the dose required(in women already receiving it or needing of start it)

Other Name: Intervention III (Se+LT4)
Experimental: Sugar Pill Placebo + L-Thyroxine (LT4) Other: Sugar Pill Placebo + L-Thyroxine (LT4)

Placebo supplements in the same capsule as selenium. 1 tablet daily for all the length of pregnancy and for 3-6th month after labour

+ LT4 taken orally daily according to the dose required(in women already receiving it or needing of start it)

Other Name: Intervention IV (Plb + LT4)

Detailed Description:

Adverse outcomes, postpartum thyroid dysfunction and permanent hypothyroidism have been associated with isolated TPOab positivity in euthyroid pregnant women.

In areas with severe selenium deficiency there is a higher incidence of thyroiditis due to a decreased activity of selenium-dependent glutathione peroxidase activity within thyroid cells. Selenium-dependent enzymes also have several modifying effects on the immune system. Therefore, even mild selenium deficiency may contribute to the development and maintenance of autoimmune thyroid diseases.

Selenium substitution exerts anti-inflammatory and anti-oxidant activities. Se could represents an important supplementation in euthyroid women with AIT in order to improve thyroid function and structure and to prevent obstetrical adverse events related to autoimmune diseases and reactive oxygen species, such as recurrent miscarriage and pre-eclampsia.

The aim of this study is to document the effects of Selenium Supplementation with and without L-thyroxine (LT4) in euthyroid women with AIT, during pregnancy.

This protocol will evaluate the trend of TPOab and Tgab, selenium concentration, thyroid volume and echogenicity, nodule formation and number of adverse effects that affect the mother (during and after pregnancy), the fetus, the infant and the heath service, needing to elucidate the nature of the emerging associations.

The study also aims to assess the impact of Selenium Supplementation on implantation rate and pregnancy rate in women with transfer planned within the next 60 days.

This is designed as a phase IV study on treatment with a cohort size of pregnant women and women in whom embryo transfer is expected within 60 days with TSH value into the normal range (0.4-2.5 mUI/mL) and Tgab and/or TPOab positivity. We have performed two randomizations arms: Randomization arm A will include women LT4 replacement-free that will take Selenium or Placebo and Randomization arm B will include women already under LT4 replacement that will take Selenium or Placebo. Patients included in Randomization A will move into Randomization B, if TSH increases above 2.5 mUI/mL during pregnancy.

Pregnant women with TSH > 2.5 mU/mL at time 0 will begin (or will adjust) LT4 replacement and will be included in Randomization arm B.

Accounting for a 30% drop off, a total enrolment of 150 patients is planned. Patients will be randomized at time 0 (10°± 2 weeks of gestation). Follow-up visits will take place at weeks 14 ± 2, 24 ± 2, 32 ± 2, 36 ± 2 weeks, and between months 3° and 6° after labour. An optional visit could be done 12 months after labor. Plasma and serum monitoring of thyroid hormones, Tgab, TPOab, Se concentration, Selenoproteins and cytokines, thyroid US, SF12 questionnaire will be made at all the follow-up visits. At visit 3 (24 ± 2 weeks) patients will optionally do the OGTT). Gestational, obstetrical, maternal, fetal, and infant anamnestic data will be taken, during the follow up visits and at labour.

The long-term objective is to identify a safe and easily administered supplementation that improves:

  1. implantation and pregnancy rates in infertile women Tgab and/or TPOab positives
  2. maternal and fetal complication in pregnant euthyroid women Tgab and/or TPOab positives.
  Eligibility

Ages Eligible for Study:   18 Years to 38 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • pregnant women with 10°± 2 weeks of gestation
  • women in whom embryo transfer is expected within 60 days
  • euthyroid women (0.4 μIU/ml < TSH < 2.5 μIU/ml), positive for TPOab and/or TgAb, not assuming LT4 replacement
  • euthyroid women (0.4 μIU/ml < TSH < 2.5 μIU/ml), positive for TPOab and/or TgAb under LT4 replacement (to maintain TSH within the control range).
  • women with TSH > 2.5 μIU/ml positive for TPOab and/or TgAb, not assuming LT4 replacement (requiring the beginning of LT4 replacement)
  • women with TSH > 2.5 μIU/ml positive for TPOab and/or TgAb, under LT4 replacement (requiring an adjustment of LT4 replacement)

Exclusion Criteria:

  • use of dietary supplements containing selenium in the previous 4 months;
  • use of antidepressive/psychotic drugs, amiodarone, propanolol, lithium, cytokines;
  • history of hyperthyroidism positive anti-thyrotropin ab;
  • previous partial or total thyroidectomy;
  • known fetal anomaly;
  • known infections (PID, HIV, HCV) and mola hydatidoses;
  • chronic renal failure;
  • uncontrolled hypertension;
  • uterine malformation;
  • history of medical and metabolic complication such as heart disease or diabetes;
  • previous embryo transfer failed within last 3 months;
  • miscarriage within last 3 months;
  • gestational diabetes in previous pregnancies.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01465867

Contacts
Contact: Andrea M Isidori, MD, PhD 0039-06-49970540 andrea.isidori@uniroma1.it
Contact: Elisa Giannetta, MD, PhD 0039-06-49970540 elisa.giannetta@uniroma1.it

Locations
Italy
Azienda ospedaliero-universitaria Careggi Active, not recruiting
Florence, Italy, 50134
Istituto Auxologico Italiano Active, not recruiting
Milan, Italy, 20095
Ospedale Maggiore Policlinico Recruiting
Milan, Italy, 20122
Contact: Giovanna Mantovani, MD       giovanna.mantovani@unimi.it   
University Federico II Recruiting
Naples, Italy, 80131
Contact: Anna Maria Colao, Prof       annamaria.colao@unina.it   
University "Piemonte Orientale, A. Avogadro" Active, not recruiting
Novara, Italy, 28100
Department of Experimental Medicine, "Sapienza" University of Rome Not yet recruiting
Rome, Italy, 00161
Contact: Andrea M Isidori, MD, PhD    0039-06-49970540    andrea.isidori@uniroma1.it   
Contact: Elisa Giannetta, MD, PhD    0039-06-49970540    elisa.giannetta@uniroma1.it   
Department of Gynecological/Obstetric/Urological Sciences, "Sapienza" University of Rome Active, not recruiting
Rome, Italy, 00161
Dpt of Experimental Medicine Recruiting
Rome, Italy, 00161
Contact: Angela Fumarola, Prof.       angela.fumarola@uniroma1.it   
European Hospital Active, not recruiting
Rome, Italy, 00148
Ospedale S. Giovanni Calibita Fatebenefratelli Active, not recruiting
Rome, Italy, 00153
Torvergata University of Rome - Ospedale S. Eugenio Active, not recruiting
Rome, Italy, 00145
Sponsors and Collaborators
University of Roma La Sapienza
Investigators
Principal Investigator: Andrea M Isidori, MD, PhD Department of Experimental Medicine, Section of Clinical Pathophysiology and Endocrinology, "Sapienza" University of Rome
  More Information

No publications provided

Responsible Party: Andrea M. Isidori, Principal Investigator, Clinical Professor, University of Roma La Sapienza
ClinicalTrials.gov Identifier: NCT01465867     History of Changes
Other Study ID Numbers: Sel-01
Study First Received: November 2, 2011
Last Updated: October 25, 2014
Health Authority: Italy: National Institute of Health

Keywords provided by University of Roma La Sapienza:
Selenium
Pregnancy
Auto-immune thyroiditis
Post-partum thyroiditis
Miscarriage
Pre-eclampsia
Implantation and Pregnancy rate
Infertility

Additional relevant MeSH terms:
Hashimoto Disease
Infertility
Thyroiditis
Thyroiditis, Autoimmune
Autoimmune Diseases
Endocrine System Diseases
Genital Diseases, Female
Genital Diseases, Male
Immune System Diseases
Thyroid Diseases
Contraceptives, Oral
Selenium
Antioxidants
Contraceptive Agents
Contraceptive Agents, Female
Growth Substances
Micronutrients
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Protective Agents
Reproductive Control Agents
Therapeutic Uses
Trace Elements

ClinicalTrials.gov processed this record on November 25, 2014