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Thyroid Therapy for Mild Thyroid Deficiency in Pregnancy (TSH)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT00388297
Recruitment Status : Completed
First Posted : October 16, 2006
Results First Posted : January 30, 2019
Last Update Posted : February 21, 2019
Sponsor:
Collaborators:
National Institute of Neurological Disorders and Stroke (NINDS)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):
The George Washington University Biostatistics Center

Brief Summary:
The purpose of this study is to determine whether treating women, who are diagnosed with a mild imbalance of thyroid hormones during pregnancy, with thyroid hormone replacement affects their children's intellectual development at 5 years of age.

Condition or disease Intervention/treatment Phase
Subclinical Hypothyroidism Hypothyroxinemia Pregnancy Drug: Levothyroxine Drug: Placebo for Levothyroxine Phase 3

Detailed Description:

Published research reports have stimulated national and international controversy regarding the value of maternal thyroxine therapy given to improve neurodevelopment of the fetus in women with variously defined hypothyroidism. These reports have led to conflicting and confusing recommendations as to whether or not all pregnant women in the U.S. should be screened for subclinical hypothyroidism or hypothyroxinemia.

Pregnant women less than 20 weeks gestation will have a blood test to screen for subclinical hypothyroidism or hypothyroxinemia. If eligible for the trial, patients will receive levothyroxine or placebo until delivery. Blood draws will be done at monthly study visits and the dosage will be adjusted based on test results. The children of these patients will have developmental testing done annually until they are 5 years of age.

Comparison(s): thyroxine supplementation versus placebo given during pregnancy to determine whether therapy is effective in improving intellectual ability at 5 years of age.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 1203 participants
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: A Randomized Trial of Thyroxine Therapy for Subclinical Hypothyroidism or Hypothyroxinemia Diagnosed During Pregnancy
Study Start Date : October 2006
Actual Primary Completion Date : August 2015
Actual Study Completion Date : October 2015

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Hypothyroidism

Arm Intervention/treatment
Experimental: Levothyroxine for Subclinical Hypothyroidism
100 µg of Levothryoxine for participants with subclinical hypothyroidism
Drug: Levothyroxine
Coded study drug is thyroxine encapsulated in a gel capsule; matching placebo contains only cellulose. Color of capsule corresponds to mcg dose level (100mcg or 25 mcg). Subjects in subclinical hypothyroidism stratum are started on 1 capsule of 100 mcg per day; subjects in hypothyroxinemia stratum are started on 2 capsules of 25 mcg per day. Thyroxine dosing adjustments for both strata are determined centrally, using an algorithm, based on results of monthly TSH or free-T4 assays. Subjects take study medication until delivery.

Placebo Comparator: Placebo for Levothyroxine - Subclinincal Hypothyroidism
Placebo for Levothyroxine for participants with subclinical hypothyroidism
Drug: Placebo for Levothyroxine
Experimental: Levothyroxine for Hypothyroxinemia - Hypothyroxinemia
50 µg of Levothyroxine for participants with hypothyroxinemia
Drug: Levothyroxine
Coded study drug is thyroxine encapsulated in a gel capsule; matching placebo contains only cellulose. Color of capsule corresponds to mcg dose level (100mcg or 25 mcg). Subjects in subclinical hypothyroidism stratum are started on 1 capsule of 100 mcg per day; subjects in hypothyroxinemia stratum are started on 2 capsules of 25 mcg per day. Thyroxine dosing adjustments for both strata are determined centrally, using an algorithm, based on results of monthly TSH or free-T4 assays. Subjects take study medication until delivery.

Placebo Comparator: Placebo for Levothyroxine
Placebo for Levothyroxine for participants with hypothyroxinemia
Drug: Placebo for Levothyroxine



Primary Outcome Measures :
  1. Intellectual Function of Children at 5 Years of Age in Women Diagnosed With a) Subclinical Hypothyroidism or b) Hypothyroxinemia During the First Half of Pregnancy, or Death. [ Time Frame: 60 months of age ]

    The primary outcome was death or IQ score at 5 years of age (or at 3 years of age if the 5-year examination was missing). The full-scale IQ was assessed with the use of the Wechsler Preschool and Primary Scale of Intelligence III (WPPSI-III) at 5 years of age or the overall (general conceptual ability) score from the Differential Ability Scales-II at 3 years of age if the WPPSI-III score was not available. Results are expressed as an age-standardized score, with an expected population mean of 100 and a standard deviation of 15. Death before 3 years of age was assigned a score of 0 (lowest possible rank) and was included in the estimation of the median.

    For Quotient and Composite score:

    below 70 is Extremely Low, 70-79 is Borderline, 80-89 is Low Average, 90-109 is Average, 110-119 is High Average, 120-129 is Superior, 130+



Secondary Outcome Measures :
  1. Week of Gestation at Delivery [ Time Frame: Delivery ]
    Gestational age at delivery and preterm birth < 37 weeks' gestation or < 34 weeks' gestation

  2. Number of Participants With Preterm Delivery [ Time Frame: Delivery ]
    Preterm delivery at less than 37 weeks or less than 34 weeks gestation

  3. Selected Cognitive Abilities From the Subscales of the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III) [ Time Frame: 60 months ]

    Standardized full-scale IQ scores from the Wechsler Preschool and Primary Scale of Intelligence III (WPPSI-III) at 5 years of age. Quotient and Composite scores have a mean of 100 and a standard deviation of 15. Subtest scaled scores have a mean of 10 and a standard deviation of 3.

    For Quotient and Composite score:

    below 70 is Extremely Low, 70-79 is Borderline, 80-89 is Low Average, 90-109 is Average, 110-119 is High Average, 120-129 is Superior, 130+ is Very Superior.


  4. Cognitive and Achievement Levels From the Differential Ability Scales (DAS II) [ Time Frame: 36 months ]

    Overall general conceptual ability score as measured by the DAS-II at 36 months of age.

    GCA General Conceptual Ability Classification ≥ 130 Very high 120-129 High 110-119 Above average 90-109 Average 80-89 Below average 70-79 Low

    ≤ 69 Very low


  5. Cognitive and Achievement Levels From Two DAS-II Subtests (Recall of Digits Forward and Recognition of Pictures) [ Time Frame: 48 months of age ]

    Cognitive and achievement levels from two DAS-II subtests (Recall of Digits Forward and Recognition of Pictures)

    GCA General Conceptual Ability Classification ≥ 130 Very high 120-129 High 110-119 Above average 90-109 Average 80-89 Below average 70-79 Low

    ≤ 69 Very low


  6. Cognitive, Motor and Language Scale Scores From the Bayley Certified Scales of Infant Development III Edition [ Time Frame: 12 and 24 months of age ]
    Composite scores are derived for cognitive, language, and motor development and scaled to a metric, with a mean of 100, standard deviation of 15, and range of 40 to 160. Results can also be expressed as percentile ranks relative to the standardization sample, with a mean and median of 50 and range from 1 to 99

  7. Behavioral Problems and Social Competencies at 36 and 60 Months of Age, as Measured by the Child Behavior Checklist (CBCL) [ Time Frame: 36 and 60 months of age ]
    Behavioral problems and social competencies at 36 and 60 months of age, as measured by the Child Behavior Checklist (CBCL). The CBCL is filled out by the caregiver. Each of the 100 questions indicates a behavior for which the caregiver scores as Not True (0), Sometimes True (1), or Often True (2). The scores for all the questions are then summed and evaluated against the normative data/T-scores. A Tscore of less than 60 is considered to be in the normal range. A T score of 60-63 is a borderline, and a T score of more than 63 is in the clinical range. Lower scores represent better outcomes.

  8. Attention Deficit Hyperactivity Disorder (ADHD) Index Score From the Connors' Rating Scales (Parent-S) - Revised [ Time Frame: 48 months of age ]
    The Conners' Rating Scales-Revised were used to assess attention deficit-hyperactivity disorder (ADHD). A T score of 45 to 55 is considered to be typical or average; a T score of 44 or less is not a concern, a T score of 56 to 60 is considered to be a borderline score, and a T score of 61 or higher indicates a possible or clinically significant problem.

  9. Participants With Placental Abruption [ Time Frame: Duration of pregnancy, delivery ]
    Clinically significant placental abruption will be determined by centralized (blinded) chart review

  10. Participants With Gestational Hypertension [ Time Frame: During pregnancy and until delivery ]
    Gestational hypertension defined as patient having a diastolic ≥ 90 during pregnancy without proteinuria

  11. Participants With Preeclampsia [ Time Frame: Duration of pregnancy, Delivery ]
    Preeclampsia defined as patient having a diastolic ≥ 90 during pregnancy with at least 1 + proteinuria. Preeclampsia will also include HELLP syndrome or eclampsia.

  12. Gestational Diabetes Mellitus [ Time Frame: During pregnancy until delivery ]
    A patient is considered to have gestational diabetes if clinically diagnosed with class A1 or A2

  13. Participants With Composite Neonatal Outcome [ Time Frame: Within 72 hours of delivery. ]
    The composite neonatal outcome was defined as periventricular leukomalacia, intraventricular hemorrhage of grade III or IV, necrotizing enterocolitis (stage ≥II), severe retinopathy of prematurity (stage ≥III), the severe respiratory distress syndrome, bronchopulmonary dysplasia, neonatal death, stillbirth, or serious infectious complication.

  14. Participants Who Experienced a Stillbirth or Miscarriage [ Time Frame: Delivery ]
    Stillbirth or miscarriage.

  15. Number of Neonatal Deaths [ Time Frame: Through 72 hours post delivery ]
    Fetal and neonatal death

  16. Number of Infants With Apgar Score 4 at 1 Minute and < 7 at 5 Minutes [ Time Frame: 1 minute and 5 minutes post delivery ]
    Apgar score < 4 at 1 minute and < 7 at 5 minutes

  17. Number of Infants Admitted to NICU [ Time Frame: Delivery ]
    Admission to NICU

  18. Infants With Birth Weight < 10th Percentile (Gestational Age z Score) [ Time Frame: Delivery ]
    Birth weight < 10th percentile (gestational age z score)

  19. Neonatal Head Circumference (Centimeters) [ Time Frame: Within 24 hours of birth ]
    Neonatal head circumference measured within 24 hours of birth. This measurement is included based on a report showing that maternal treatment with thyroxine for overt hypothyroidism was associated with reduced head circumference in the newborn infant

  20. Number of Infants With Respiratory Distress Syndrome [ Time Frame: Delivery and greater than or equal to 24 hours ]
    Respiratory distress syndrome (RDS) will be defined based on a clinical diagnosis of RDS Type I and oxygen therapy (FiO2 ≥ 0.40) for greater than or equal to 24 hours. For infants dying before 24 hours of age, a clinical diagnosis of RDS Type I and oxygen therapy (FiO2 ≥ 0.40) are sufficient.

  21. Number of Infants With Retinopathy or Prematurity [ Time Frame: Through 72 hours of birth ]
    This diagnosis will be reached when an ophthalmologic examination of the retina has been performed and ROP is diagnosed at Stage I (demarcation line in the retina) or greater

  22. Number of Infants With Necrotizing Enterocolitis [ Time Frame: Delivery within 2 weeks of birth ]
    Necrotizing enterocolitis (NEC) is defined by the following: the unequivocal presence of intramural air on abdominal x-ray, perforation seen on abdominal x-ray, clinical evidence as suggested by erythema and induration of the abdominal wall, or intra-abdominal abscess formation, or stricture formation observed at surgery or autopsy following an episode of suspected NEC. The condition is classified based on the Bell staging system

  23. Number of Infants With Bronchopulmonary Dysplasia [ Time Frame: Through 72 hours post delivery ]
    Bronchopulmonary dysplasia (BPD) is defined as the need for supplemental oxygen at 36 weeks corrected age, for babies born <34 weeks by project gestational age only

  24. Number of Infants With Respiratory Therapy Greater Than or Equal to 1 Day [ Time Frame: 72 hours post delivery ]
    oxygen therapy (FiO2 ≥ 0.40) for greater than or equal to 24 hours

  25. Number of Days in the Hospital Nursery [ Time Frame: Through hospital discharge ]
    Median number of days in the hospital nursery



Information from the National Library of Medicine

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, Learn About Clinical Studies.


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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Subclinical Hypothyroidism as defined by an elevated TSH (≥ 3.00 mU/L) and a free-T4 in the normal range (i.e. 0.86 to 1.90 ng/dL) or Hypothyroxinemia as defined by a TSH in the normal range (0.08 to 2.99 micrometers (mU)/L) and a low free-T4 (<0.86 ng/dL)
  • Singleton Pregnancy
  • Gestational age at randomization between 8 weeks 0 days and 20 weeks 6 days

Exclusion Criteria:

  1. Major fetal anomaly or demise
  2. Planned termination of the pregnancy
  3. History of thyroid cancer or current thyroid disease requiring medication
  4. Diabetes, on medication (insulin, glyburide)
  5. Collagen vascular disease (autoimmune disease), such as lupus, scleroderma and polymyalgia rheumatica, on medication
  6. Receiving anticoagulant therapy
  7. Depression, currently on treatment with tricyclics or selective serotonin reuptake inhibitors (SSRIs)
  8. Other known serious maternal medical complications including:

    1. Chronic hypertension requiring antihypertensive medication (including diuretics)
    2. Epilepsy or other seizure disorder, on medication
    3. Active or chronic liver disease (acute hepatitis, chronic active hepatitis) with persistently abnormal liver enzymes
    4. Cancer (including melanoma but excluding other skin cancers)
    5. Heart disease (tachyrhythmia, class II or greater heart disease or on heart medication). Mitral valve prolapse without arrhythmia is not an exclusion.
    6. Asthma, on oral corticosteroids
  9. Known illicit drug or alcohol abuse during current pregnancy
  10. Delivery at a non-network hospital
  11. Participation in another intervention study that influences maternal and fetal morbidity and mortality, or participation in this trial in a previous pregnancy
  12. Unwilling or unable to commit to 5 year follow-up of the infant

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00388297


Locations
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United States, Alabama
University of Alabama - Birmingham
Birmingham, Alabama, United States, 35249
United States, Illinois
Northwestern University
Chicago, Illinois, United States, 60611
United States, Michigan
Wayne State University
Detroit, Michigan, United States, 48201
United States, New York
Columbia University
New York, New York, United States, 10032
United States, North Carolina
University of North Carolina - Chapel Hill
Chapel Hill, North Carolina, United States, 27599
United States, Ohio
Case Western University
Cleveland, Ohio, United States, 44109
Ohio State University
Columbus, Ohio, United States, 43210
United States, Oregon
Oregon Health & Sciences University
Portland, Oregon, United States, 97239
United States, Pennsylvania
University of Pittsburgh Magee Womens Hospital
Pittsburgh, Pennsylvania, United States, 15213
United States, Rhode Island
Brown University
Providence, Rhode Island, United States, 02905
United States, Texas
University of Texas - Southwest
Dallas, Texas, United States, 75235
University of Texas Medical Branch - Galveston
Galveston, Texas, United States, 77555
University of Texas-Houston
Houston, Texas, United States, 77030
United States, Utah
University of Utah Medical Center
Salt Lake City, Utah, United States, 84132
Sponsors and Collaborators
The George Washington University Biostatistics Center
National Institute of Neurological Disorders and Stroke (NINDS)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Investigators
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Study Chair: Brian Casey, MD University of Texas Southwestern Medical Center
Study Director: Menachem Miodovnik, MD NICHD Project Scientist

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: The George Washington University Biostatistics Center
ClinicalTrials.gov Identifier: NCT00388297     History of Changes
Other Study ID Numbers: HD36801-TSH
U10HD021410 ( U.S. NIH Grant/Contract )
U10HD027869 ( U.S. NIH Grant/Contract )
U10HD027917 ( U.S. NIH Grant/Contract )
U10HD027860 ( U.S. NIH Grant/Contract )
U10HD027915 ( U.S. NIH Grant/Contract )
U10HD034116 ( U.S. NIH Grant/Contract )
U10HD034208 ( U.S. NIH Grant/Contract )
U10HD034136 ( U.S. NIH Grant/Contract )
U10HD040500 ( U.S. NIH Grant/Contract )
U10HD040485 ( U.S. NIH Grant/Contract )
U10HD040544 ( U.S. NIH Grant/Contract )
U10HD040545 ( U.S. NIH Grant/Contract )
U10HD040560 ( U.S. NIH Grant/Contract )
U10HD040512 ( U.S. NIH Grant/Contract )
U10HD036801 ( U.S. NIH Grant/Contract )
U10HD053118 ( U.S. NIH Grant/Contract )
First Posted: October 16, 2006    Key Record Dates
Results First Posted: January 30, 2019
Last Update Posted: February 21, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: The data will be shared after the completion of the trial and publication of the main analyses per NIH policy. When made available, requests for the dataset(s) can be sent to mfmudatasets@bsc.gwu.edu.

Keywords provided by The George Washington University Biostatistics Center:
Subclinical Hypothyroidism
Hypothyroxinemia
Thyroid
Pregnancy
Intellectual Development

Additional relevant MeSH terms:
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Hypothyroidism
Thyroid Diseases
Endocrine System Diseases