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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

Tracking Information
First Submitted Date  ICMJE October 12, 2006
First Posted Date  ICMJE October 16, 2006
Results First Submitted Date  ICMJE October 24, 2018
Results First Posted Date  ICMJE January 30, 2019
Last Update Posted Date February 21, 2019
Study Start Date  ICMJE October 2006
Actual Primary Completion Date August 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 9, 2019)
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+
Original Primary Outcome Measures  ICMJE
 (submitted: October 12, 2006)
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
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 9, 2019)
  • Week of Gestation at Delivery [ Time Frame: Delivery ]
    Gestational age at delivery and preterm birth < 37 weeks' gestation or < 34 weeks' gestation
  • Number of Participants With Preterm Delivery [ Time Frame: Delivery ]
    Preterm delivery at less than 37 weeks or less than 34 weeks gestation
  • 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.
  • 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
  • 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
  • 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
  • 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.
  • 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.
  • Participants With Placental Abruption [ Time Frame: Duration of pregnancy, delivery ]
    Clinically significant placental abruption will be determined by centralized (blinded) chart review
  • Participants With Gestational Hypertension [ Time Frame: During pregnancy and until delivery ]
    Gestational hypertension defined as patient having a diastolic ≥ 90 during pregnancy without proteinuria
  • 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.
  • 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
  • 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.
  • Participants Who Experienced a Stillbirth or Miscarriage [ Time Frame: Delivery ]
    Stillbirth or miscarriage.
  • Number of Neonatal Deaths [ Time Frame: Through 72 hours post delivery ]
    Fetal and neonatal death
  • 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
  • Number of Infants Admitted to NICU [ Time Frame: Delivery ]
    Admission to NICU
  • Infants With Birth Weight < 10th Percentile (Gestational Age z Score) [ Time Frame: Delivery ]
    Birth weight < 10th percentile (gestational age z score)
  • 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
  • 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.
  • 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
  • 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
  • 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
  • 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
  • Number of Days in the Hospital Nursery [ Time Frame: Through hospital discharge ]
    Median number of days in the hospital nursery
Original Secondary Outcome Measures  ICMJE
 (submitted: October 12, 2006)
  • Developmental delay at 12 and 24 months, using the Bayley Scales for Motor Development Index (MDI) and Psychomotor Development Index (PDI)
  • Attention deficit at 48 months, using the Connors Rating Scales and the Developmental Neuropsychological Assessment (NEPSY) attention subtests
  • Behavioral problems and social competencies at 36 and 60 months of age, as measured by the Child Behavior Checklist (CBCL)
  • Fetal growth
  • Preterm delivery
  • Preeclampsia
  • Abruption
  • Stillbirth
  • Development of postpartum thyroid dysfunction
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Thyroid Therapy for Mild Thyroid Deficiency in Pregnancy
Official Title  ICMJE A Randomized Trial of Thyroxine Therapy for Subclinical Hypothyroidism or Hypothyroxinemia Diagnosed During Pregnancy
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.
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  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE
  • Subclinical Hypothyroidism
  • Hypothyroxinemia
  • Pregnancy
Intervention  ICMJE
  • 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.
  • Drug: Placebo for Levothyroxine
Study Arms  ICMJE
  • Experimental: Levothyroxine for Subclinical Hypothyroidism
    100 µg of Levothryoxine for participants with subclinical hypothyroidism
    Intervention: Drug: Levothyroxine
  • Placebo Comparator: Placebo for Levothyroxine - Subclinincal Hypothyroidism
    Placebo for Levothyroxine for participants with subclinical hypothyroidism
    Intervention: Drug: Placebo for Levothyroxine
  • Experimental: Levothyroxine for Hypothyroxinemia - Hypothyroxinemia
    50 µg of Levothyroxine for participants with hypothyroxinemia
    Intervention: Drug: Levothyroxine
  • Placebo Comparator: Placebo for Levothyroxine
    Placebo for Levothyroxine for participants with hypothyroxinemia
    Intervention: Drug: Placebo for Levothyroxine
Publications * Casey BM, Thom EA, Peaceman AM, Varner MW, Sorokin Y, Hirtz DG, Reddy UM, Wapner RJ, Thorp JM Jr, Saade G, Tita AT, Rouse DJ, Sibai B, Iams JD, Mercer BM, Tolosa J, Caritis SN, VanDorsten JP; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Treatment of Subclinical Hypothyroidism or Hypothyroxinemia in Pregnancy. N Engl J Med. 2017 Mar 2;376(9):815-825. doi: 10.1056/NEJMoa1606205.

*   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: December 16, 2009)
1203
Original Enrollment  ICMJE
 (submitted: October 12, 2006)
1000
Actual Study Completion Date  ICMJE October 2015
Actual Primary Completion Date August 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE Child, Adult, Older Adult
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00388297
Other Study ID Numbers  ICMJE 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 )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
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.
Responsible Party The George Washington University Biostatistics Center
Study Sponsor  ICMJE The George Washington University Biostatistics Center
Collaborators  ICMJE
  • National Institute of Neurological Disorders and Stroke (NINDS)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Investigators  ICMJE
Study Chair: Brian Casey, MD University of Texas Southwestern Medical Center
Study Director: Menachem Miodovnik, MD NICHD Project Scientist
PRS Account The George Washington University Biostatistics Center
Verification Date February 2019

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