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. Identifier: NCT00388297
Recruitment Status : Completed
First Posted : October 16, 2006
Last Update Posted : September 13, 2016
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.

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

Arm Intervention/treatment
Experimental: Levothyroxine
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
Drug: Placebo for Levothyroxine

Primary Outcome Measures :
  1. Intellectual function of children at 5 years of age, as measured by the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III), in women diagnosed with a) subclinical hypothyroidism or b) hypothyroxinemia during the first half of pregnancy [ Time Frame: 60 months of age ]

Secondary Outcome Measures :
  1. Cognitive, Motor and Language Scale Scores from the Bayley Certified Scales of Infant Development III Edition [ Time Frame: 12 and 24 months of age ]
  2. Cognitive and achievement levels from two DAS-II subtests (Recall of Digits Forward and Recognition of Pictures) [ Time Frame: 48 months of age ]
  3. 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 ]
  4. Fetal growth [ Time Frame: Delivery ]
  5. Preterm delivery [ Time Frame: Delivery ]
  6. Preeclampsia [ Time Frame: Duration of pregnancy, Delivery ]
  7. Abruption [ Time Frame: Duration of pregnancy, delivery ]
  8. Stillbirth [ Time Frame: Delivery ]
  9. Development of postpartum thyroid dysfunction [ Time Frame: 12 and 60 months postpartum ]
  10. Cognitive and achievement levels from the Differential Ability Scales (DAS II) [ Time Frame: 36 months ]
  11. Selected cognitive abilities from the subscales of the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III) [ Time Frame: 60 months ]
  12. Attention Deficit Hyperactivity Disorder (ADHD) index score from the Connors' Rating Scales (Parent-S) - Revised [ Time Frame: 48 months of age ]

Information from the National Library of Medicine

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

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 identifier (NCT number): NCT00388297

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)
Principal Investigator: Brian Casey, MD University of Texas Southwestern Medical Center

Additional Information:
Publications automatically indexed to this study by Identifier (NCT Number):
Responsible Party: The George Washington University Biostatistics Center 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
Last Update Posted: September 13, 2016
Last Verified: September 2016
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

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

Additional relevant MeSH terms:
Thyroid Diseases
Endocrine System Diseases