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Selenium Supplementation in Pregnancy (Serena)

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ClinicalTrials.gov Identifier: NCT01465867
Recruitment Status : Completed
First Posted : November 7, 2011
Last Update Posted : January 30, 2018
Sponsor:
Information provided by (Responsible Party):
Andrea M. Isidori, University of Roma La Sapienza

Tracking Information
First Submitted Date  ICMJE November 2, 2011
First Posted Date  ICMJE November 7, 2011
Last Update Posted Date January 30, 2018
Study Start Date  ICMJE April 2012
Actual Primary Completion Date June 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 25, 2013)
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 ]
TPOab and Tgab titers will be measured using a ECLIA kit. Plasma selenium concentration will also be measured
Original Primary Outcome Measures  ICMJE
 (submitted: November 4, 2011)
Changes in TPOab and/or Tgab [ Time Frame: 0 and 12 ± 2, 20 ± 2, 32± 2, 36± 2 weeks; and 3 and 6 months after labour ]
TPOab and Tgab titers will be measured using a ECLIA kit. Plasma selenium concentration will also be measured
Change History Complete list of historical versions of study NCT01465867 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: February 25, 2013)
  • 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 ]
    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 ]
  • Evaluation of Maternal risks [ Time Frame: From the date of randomization until the date of first documented event ]
    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 ]
    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 ]
    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 ]
    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 ]
    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 ]
    Clinical implantation rate (IR) and pregnancy rate (PR)
Original Secondary Outcome Measures  ICMJE
 (submitted: November 4, 2011)
  • Changes in thyroid volume and echogenicity [ Time Frame: 0 and 12 ± 2, 20 ± 2, 32± 2, 36± 2 weeks; and 3 and 6 months after labour ]
    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 12 ± 2, 20 ± 2, 32± 2, 36± 2 weeks; and 3 and 6 months after labour ]
  • Evaluation of Maternal risks [ Time Frame: before and after labour ]
    Pre-eclampsia (gestational hypertension: systolic pressure ≥140 mmHg or diastolic blood pressure ≥ 90 mmHg [Korotkoff V] on ≥ 2 occasions after 20 weeks gestation), Miascarriage, 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: labour ]
    Small for gestational age, Admission to special care, Cretinism, Jaundice requiring phototherapy, Poor feeding, Constipation, Hoarse cry, Lethargy, Hypotonia, Macroglossia, Umbilical hernia, Patent fontanelles
  • Changes in of quality of life [ Time Frame: 0 and 12 ± 2, 20 ± 2, 32± 2, 36± 2 weeks; and 3 and 6 months after labour ]
    Quality of life will be measured by questionnaire SF12
  • Evaluation of Health Services: [ Time Frame: at labour ]
    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, 20 ± 2, 36± 2 weeks; and 6 months after labour ]
    Glucose, Vitamin B-12, folate, methionine, albumin and cytokines will be also measured in serum
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Selenium Supplementation in Pregnancy
Official Title  ICMJE Selenium Supplementation Treatment in Euthyroid Pregnant Women With Autoimmune Thyroid Disease: Effects on Obstetrical Complications
Brief Summary

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.

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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Prevention
Condition  ICMJE
  • Pregnancy
  • Infertility
  • Auto-immune Thyroiditis
Intervention  ICMJE
  • 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)
  • 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)
  • 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)
  • 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)
Study Arms  ICMJE
  • Experimental: Selenium
    Intervention: Dietary Supplement: Selenium
  • Placebo Comparator: Sugar Pill Placebo
    Intervention: Other: Sugar Pill Placebo
  • Experimental: Selenium + L-Thyroxine (LT4)
    Intervention: Other: Selenium + L-Thyroxine (LT4)
  • Experimental: Sugar Pill Placebo + L-Thyroxine (LT4)
    Intervention: Other: Sugar Pill Placebo + L-Thyroxine (LT4)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 27, 2018)
56
Original Estimated Enrollment  ICMJE
 (submitted: November 4, 2011)
240
Actual Study Completion Date  ICMJE January 2018
Actual Primary Completion Date June 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years to 38 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Italy
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01465867
Other Study ID Numbers  ICMJE Sel-01
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Andrea M. Isidori, University of Roma La Sapienza
Study Sponsor  ICMJE University of Roma La Sapienza
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Andrea M Isidori, MD, PhD Department of Experimental Medicine, Section of Clinical Pathophysiology and Endocrinology, "Sapienza" University of Rome
PRS Account University of Roma La Sapienza
Verification Date January 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP