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TSH: Thyroid Therapy for Mild Thyroid Deficiency in Pregnancy

Sponsor
The George Washington University Biostatistics Center (Other)
Overall Status
Completed
CT.gov ID
NCT00388297
Collaborator
National Institute of Neurological Disorders and Stroke (NINDS) (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH)
1,203
Enrollment
14
Locations
4
Arms
108
Duration (Months)
85.9
Patients Per Site
0.8
Patients Per Site Per Month

Study Details

Study Description

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
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 Design

Study Type:
Interventional
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 :
Oct 1, 2006
Actual Primary Completion Date :
Aug 1, 2015
Actual Study Completion Date :
Oct 1, 2015

Arms and Interventions

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

Outcome Measures

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. [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 [Delivery]

    Gestational age at delivery and preterm birth < 37 weeks' gestation or < 34 weeks' gestation

  2. Number of Participants With Preterm Delivery [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) [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) [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) [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 [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) [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 [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 [Duration of pregnancy, delivery]

    Clinically significant placental abruption will be determined by centralized (blinded) chart review

  10. Participants With Gestational Hypertension [During pregnancy and until delivery]

    Gestational hypertension defined as patient having a diastolic ≥ 90 during pregnancy without proteinuria

  11. Participants With Preeclampsia [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 [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 [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 [Delivery]

    Stillbirth or miscarriage.

  15. Number of Neonatal Deaths [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 [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 [Delivery]

    Admission to NICU

  18. Infants With Birth Weight < 10th Percentile (Gestational Age z Score) [Delivery]

    Birth weight < 10th percentile (gestational age z score)

  19. Neonatal Head Circumference (Centimeters) [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 [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 [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 [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 [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 [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 [Through hospital discharge]

    Median number of days in the hospital nursery

Eligibility Criteria

Criteria

Ages Eligible for Study:
N/A and Older
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:

  9. Chronic hypertension requiring antihypertensive medication (including diuretics)

  10. Epilepsy or other seizure disorder, on medication

  11. Active or chronic liver disease (acute hepatitis, chronic active hepatitis) with persistently abnormal liver enzymes

  12. Cancer (including melanoma but excluding other skin cancers)

  13. Heart disease (tachyrhythmia, class II or greater heart disease or on heart medication). Mitral valve prolapse without arrhythmia is not an exclusion.

  14. Asthma, on oral corticosteroids

  15. Known illicit drug or alcohol abuse during current pregnancy

  16. Delivery at a non-network hospital

  17. Participation in another intervention study that influences maternal and fetal morbidity and mortality, or participation in this trial in a previous pregnancy

  18. Unwilling or unable to commit to 5 year follow-up of the infant

Contacts and Locations

Locations

Site City State Country Postal Code
1 University of Alabama - Birmingham Birmingham Alabama United States 35249
2 Northwestern University Chicago Illinois United States 60611
3 Wayne State University Detroit Michigan United States 48201
4 Columbia University New York New York United States 10032
5 University of North Carolina - Chapel Hill Chapel Hill North Carolina United States 27599
6 Case Western University Cleveland Ohio United States 44109
7 Ohio State University Columbus Ohio United States 43210
8 Oregon Health & Sciences University Portland Oregon United States 97239
9 University of Pittsburgh Magee Womens Hospital Pittsburgh Pennsylvania United States 15213
10 Brown University Providence Rhode Island United States 02905
11 University of Texas - Southwest Dallas Texas United States 75235
12 University of Texas Medical Branch - Galveston Galveston Texas United States 77555
13 University of Texas-Houston Houston Texas United States 77030
14 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

  • Study Chair: Brian Casey, MD, University of Texas Southwestern Medical Center
  • Study Director: Menachem Miodovnik, MD, NICHD Project Scientist

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

Publications

None provided.
Responsible Party:
The George Washington University Biostatistics Center
ClinicalTrials.gov Identifier:
NCT00388297
Other Study ID Numbers:
  • HD36801-TSH
  • U10HD021410
  • U10HD027869
  • U10HD027917
  • U10HD027860
  • U10HD027915
  • U10HD034116
  • U10HD034208
  • U10HD034136
  • U10HD040500
  • U10HD040485
  • U10HD040544
  • U10HD040545
  • U10HD040560
  • U10HD040512
  • U10HD036801
  • U10HD053118
First Posted:
Oct 16, 2006
Last Update Posted:
Feb 21, 2019
Last Verified:
Feb 1, 2019
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Keywords provided by The George Washington University Biostatistics Center
Subclinical Hypothyroidism
Hypothyroxinemia
Thyroid
Pregnancy
Intellectual Development
Additional relevant MeSH terms:
Hypothyroidism

Study Results

Participant Flow

Recruitment Details This study enrolled women with a singleton pregnancy before 20 weeks gestation who met the criteria for either subclinical hypothyroidism or hypothyroxinemia based on serum thyrotropin and free T4 values. The study was conducted as two multicenter, randomized, placebo-controlled trials at 15 NICHD MFMU network centers.
Pre-assignment Detail 97,228 patients were screened during the recruitment period October 2006 to October 2009, Of the 800 eligible based on subclinical hypothyroidism, 677 completed the 7-day placebo adherence run-in and were randomized. Of the 632 eligible based on hypothyroxinemia, 526 completed the run-in phase and were randomized.
Arm/Group Title Levothyroxine for Subclinical Hypothyroidism Placebo for Levothyroxine - Subclinical Hypothyroidism Levothyroxine for Hypothyroxinemia Placebo for Levothyroxine for Hypothyroxinemia
Arm/Group Description Levothyroxine 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 for Levothyroxine for the Subclinical Hypothyroidism group Levothyroxine 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 for Levothyroxine for the Hypothyroxinemia group
Period Title: Overall Study
STARTED 339 338 265 261
COMPLETED 323 326 254 253
NOT COMPLETED 16 12 11 8

Baseline Characteristics

Arm/Group Title Levothyroxine for Subclinical Hypothyroidism Placebo for Levothyroxine - Subclinical Hypothyroidism Levothyroxine for Hypothyroxinemia Placebo for Levothyroxine - Hypothyroxinemia Total
Arm/Group Description Levothyroxine 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 for Levothyroxine for the Subclinical Hypothyroidism Levothyroxine 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 for Levothyroxine for the Hypothyroxinemia Total of all reporting groups
Overall Participants 339 338 265 261 1203
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]
27.7
(5.7)
27.3
(5.7)
27.8
(5.7)
28.0
(5.8)
27.7
(5.7)
Sex: Female, Male (Count of Participants)
Female
339
100%
338
100%
265
100%
261
100%
1203
100%
Male
0
0%
0
0%
0
0%
0
0%
0
0%
Race/Ethnicity, Customized (Count of Participants)
Black
27
8%
25
7.4%
61
23%
65
24.9%
178
14.8%
Hispanic
195
57.5%
185
54.7%
131
49.4%
125
47.9%
636
52.9%
White
109
32.2%
117
34.6%
69
26%
69
26.4%
364
30.3%
Other
8
2.4%
11
3.3%
4
1.5%
2
0.8%
25
2.1%
Region of Enrollment (Count of Participants)
United States
339
100%
338
100%
265
100%
261
100%
1203
100%
Body-mass index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]
28.1
(6.4)
28.2
(6.4)
30.3
(6.4)
30.2
(7.1)
29.0
(6.6)
Nulliparous (Count of Participants)
Count of Participants [Participants]
124
36.6%
134
39.6%
69
26%
64
24.5%
391
32.5%
Baseline thyrotropin (mU/liter) Median (mU/liter) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [mU/liter]
4.5
4.3
1.5
1.4
3.4
Baseline free thyroxine (ng/dl Median (ng/dl) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [ng/dl]
1.01
1.02
0.83
0.83
0.90
Urinary iodine (µg/liter) Median (µg/liter) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [µg/liter]
199
196
185
191
194
Weeks Gestation at Randomization (Weeks) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Weeks]
16.6
(3.0)
16.7
(3.0)
18.0
(2.8)
17.7
(2.9)
17.2
(3.0)

Outcome Measures

1. Primary Outcome
Title 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.
Description 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+
Time Frame 60 months of age

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Levothyroxine for Subclinical Hypothyroidism Placebo for Levothyroxine - Subclinical Hypothyroidism Levothyroxine for Hypothyroxinemia Placebo for Levothyroxine - Hypothyroxinemia
Arm/Group Description Levothyroxine 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 for Levothyroxine for the Subclinical Hypothyroidism Levothyroxine 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 for Levothyroxine for the Hypothyroxinemia
Measure Participants 323 326 254 253
Median (95% Confidence Interval) [score on a scale]
97
94
94
91
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Subclinical Hypothyroidism, Placebo for Levothyroxine - Subclinical Hypothyroidism
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.71
Comments
Method Wilcoxon (Mann-Whitney)
Comments
Method of Estimation Estimation Parameter Hodges-Lehmann estimate
Estimated Value 0
Confidence Interval (2-Sided) 95%
-3 to 2
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Hypothyroxinemia, Placebo for Levothyroxine - Hypothyroxinemia
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.30
Comments
Method Wilcoxon (Mann-Whitney)
Comments
Method of Estimation Estimation Parameter Hodges-Lehmann estimate
Estimated Value -1
Confidence Interval (2-Sided) 95%
-4 to 1
Parameter Dispersion Type:
Value:
Estimation Comments
2. Secondary Outcome
Title Week of Gestation at Delivery
Description Gestational age at delivery and preterm birth < 37 weeks' gestation or < 34 weeks' gestation
Time Frame Delivery

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Levothyroxine for Subclinical Hypothyroidism Placebo for Levothyroxine - Subclinical Hypothyroidism Levothyroxine for Hypothyroxinemia Placebo for Levothyroxine - Hypothyroxinemia
Arm/Group Description Levothyroxine 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 for Levothyroxine for the Subclinical Hypothyroidism Levothyroxine 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 for Levothyroxine for the Hypothyroxinemia
Measure Participants 339 338 263 261
Mean (Standard Deviation) [weeks]
39.1
(2.5)
38.9
(3.1)
39.0
(2.4)
38.8
(3.1)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Subclinical Hypothyroidism, Placebo for Levothyroxine - Subclinical Hypothyroidism
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.57
Comments
Method Wilcoxon (Mann-Whitney)
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Hypothyroxinemia, Placebo for Levothyroxine - Hypothyroxinemia
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.46
Comments
Method Wilcoxon (Mann-Whitney)
Comments
3. Secondary Outcome
Title Number of Participants With Preterm Delivery
Description Preterm delivery at less than 37 weeks or less than 34 weeks gestation
Time Frame Delivery

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Levothyroxine for Subclinical Hypothyroidism Placebo for Levothyroxine - Subclinical Hypothyroidism Levothyroxine for Hypothyroxinemia Placebo for Levothyroxine - Hypothyroxinemia
Arm/Group Description Levothyroxine 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 for Levothyroxine for the Subclinical Hypothyroidism Levothyroxine 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 for Levothyroxine for the Hypothyroxinemia
Measure Participants 339 338 263 261
Preterm birth < 34 wk
9
2.7%
10
3%
10
3.8%
7
2.7%
Preterm birth < 37 wk
31
9.1%
37
10.9%
31
11.7%
20
7.7%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Subclinical Hypothyroidism, Placebo for Levothyroxine - Subclinical Hypothyroidism
Comments Analysis for < 34 weeks
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.81
Comments
Method Chi-squared
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Hypothyroxinemia, Placebo for Levothyroxine - Hypothyroxinemia
Comments Analysis for <34 weeks
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.47
Comments
Method Chi-squared
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Subclinical Hypothyroidism, Placebo for Levothyroxine - Subclinical Hypothyroidism
Comments Analysis for <37 weeks
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.44
Comments
Method Chi-squared
Comments
Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Hypothyroxinemia, Placebo for Levothyroxine - Hypothyroxinemia
Comments Analysis for < 37 weeks
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.11
Comments
Method Chi-squared
Comments
Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Subclinical Hypothyroidism, Placebo for Levothyroxine - Subclinical Hypothyroidism
Comments Bayley-III Motor (24 months)
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.31
Comments
Method Chi-squared
Comments
Method of Estimation Estimation Parameter Hodges-Lehmann
Estimated Value 0
Confidence Interval (2-Sided) 95%
0 to 3
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Subclinical Hypothyroidism, Placebo for Levothyroxine - Subclinical Hypothyroidism
Comments Bayley-II Language (24 months)
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.30
Comments
Method Chi-squared
Comments
Method of Estimation Estimation Parameter Hodges-Lehmann
Estimated Value 0
Confidence Interval (2-Sided) 95%
0 to 3
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 7
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Hypothyroxinemia, Placebo for Levothyroxine - Hypothyroxinemia
Comments Bayley-III Cognitive (12 months)
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.89
Comments
Method Chi-squared
Comments
Method of Estimation Estimation Parameter Hodges-Lehmann
Estimated Value 0
Confidence Interval (2-Sided) 95%
0 to 0
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 8
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Hypothyroxinemia, Placebo for Levothyroxine - Hypothyroxinemia
Comments Bayley-III Motor (12 months)
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.54
Comments
Method Chi-squared
Comments
Method of Estimation Estimation Parameter Hodges-Lehmann
Estimated Value 0
Confidence Interval (2-Sided) 95%
0 to 3
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 9
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Hypothyroxinemia, Placebo for Levothyroxine - Hypothyroxinemia
Comments Bayley-III Language (12 months)
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.92
Comments
Method Chi-squared
Comments
Method of Estimation Estimation Parameter Hodges-Lehmann
Estimated Value 0
Confidence Interval (2-Sided) 95%
-3 to 3
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 10
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Hypothyroxinemia, Placebo for Levothyroxine - Hypothyroxinemia
Comments Bayley-III Cognitive (24 months)
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.70
Comments
Method Chi-squared
Comments
Method of Estimation Estimation Parameter Hodges-Lehmann
Estimated Value 0
Confidence Interval (2-Sided) 95%
0 to 0
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 11
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Hypothyroxinemia, Placebo for Levothyroxine - Hypothyroxinemia
Comments Bayley-III Motor (24 months)
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.20
Comments
Method Chi-squared
Comments
Method of Estimation Estimation Parameter Hodges-Lehmann
Estimated Value 0
Confidence Interval (2-Sided) 95%
-3 to 0
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 12
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Hypothyroxinemia, Placebo for Levothyroxine - Hypothyroxinemia
Comments Bayley-II Language (24 months)
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.71
Comments
Method Chi-squared
Comments
Method of Estimation Estimation Parameter Hodges-Lehmann
Estimated Value 0
Confidence Interval (2-Sided) 95%
-3 to 2
Parameter Dispersion Type:
Value:
Estimation Comments
4. Secondary Outcome
Title Selected Cognitive Abilities From the Subscales of the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III)
Description 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.
Time Frame 60 months

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Levothyroxine for Subclinical Hypothyroidism Placebo for Levothyroxine - Subclinical Hypothyroidism Levothyroxine for Hypothyroxinemia Placebo for Levothyroxine - Hypothyroxinemia
Arm/Group Description Levothyroxine 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 for Levothyroxine for the Subclinical Hypothyroidism Levothyroxine 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 for Levothyroxine for the Hypothyroxinemia
Measure Participants 311 314 243 243
Median (95% Confidence Interval) [score on a scale]
97
95
94
92
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Subclinical Hypothyroidism, Placebo for Levothyroxine - Subclinical Hypothyroidism
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.89
Comments
Method Chi-squared
Comments
Method of Estimation Estimation Parameter Hodges-Lehmann
Estimated Value 0
Confidence Interval (2-Sided) 95%
-3 to 2
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Hypothyroxinemia, Placebo for Levothyroxine - Hypothyroxinemia
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.48
Comments
Method Chi-squared
Comments
Method of Estimation Estimation Parameter Hodges-Lehmann
Estimated Value -1
Confidence Interval (2-Sided) 95%
-3 to 2
Parameter Dispersion Type:
Value:
Estimation Comments
5. Secondary Outcome
Title Cognitive and Achievement Levels From the Differential Ability Scales (DAS II)
Description 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
Time Frame 36 months

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Levothyroxine for Subclinical Hypothyroidism Placebo for Levothyroxine - Subclinical Hypothyroidism Levothyroxine for Hypothyroxinemia Placebo for Levothyroxine - Hypothyroxinemia
Arm/Group Description Levothyroxine 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 for Levothyroxine for the Subclinical Hypothyroidism Levothyroxine 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 for Levothyroxine for the Hypothyroxinemia
Measure Participants 304 308 244 235
Median (95% Confidence Interval) [score on a scale]
90
90
90
89
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Subclinical Hypothyroidism, Placebo for Levothyroxine - Subclinical Hypothyroidism
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.90
Comments
Method Chi-squared
Comments
Method of Estimation Estimation Parameter Hodges-Lehmann
Estimated Value 0
Confidence Interval (2-Sided) 95%
-2 to 3
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Hypothyroxinemia, Placebo for Levothyroxine - Hypothyroxinemia
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.64
Comments
Method Chi-squared
Comments
Method of Estimation Estimation Parameter Hodges-Lehmann
Estimated Value -1
Confidence Interval (2-Sided) 95%
-3 to 2
Parameter Dispersion Type:
Value:
Estimation Comments
6. Secondary Outcome
Title Cognitive and Achievement Levels From Two DAS-II Subtests (Recall of Digits Forward and Recognition of Pictures)
Description 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
Time Frame 48 months of age

Outcome Measure Data

Analysis Population Description
For all outcomes except the primary outcome, the potential follow-up cohort consisted of 335 children in the levothyroxine group and 329 in the placebo group for the mothers with subclinical hypothyroidism and for the hypothyroxinemia group - 260 children in the levothyroxine group and 255 children in the placebo group.
Arm/Group Title Levothyroxine for Subclinical Hypothyroidism Placebo for Levothyroxine - Subclinical Hypothyroidism Levothyroxine for Hypothyroxinemia Placebo for Levothyroxine - Hypothyroxinemia
Arm/Group Description Levothyroxine 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 for Levothyroxine for the Subclinical Hypothyroidism Levothyroxine 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 for Levothyroxine for the Hypothyroxinemia
Measure Participants 335 329 260 255
Median Recall of Digits Forward Score
84
84
91
74
Median Recognition of Pictures Score
74
74
84
74
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Subclinical Hypothyroidism, Placebo for Levothyroxine - Subclinical Hypothyroidism
Comments Analysis for recall of digits forward
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.60
Comments
Method Chi-squared
Comments
Method of Estimation Estimation Parameter Hodges-Lehmann
Estimated Value 0
Confidence Interval (2-Sided) 95%
-5 to 7
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Hypothyroxinemia, Placebo for Levothyroxine - Hypothyroxinemia
Comments Analysis for recall of digits forward
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.22
Comments
Method Chi-squared
Comments
Method of Estimation Estimation Parameter Hodges-Lehmann
Estimated Value 0
Confidence Interval (2-Sided) 95%
-8 to 0
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Subclinical Hypothyroidism, Placebo for Levothyroxine - Subclinical Hypothyroidism
Comments Analysis for Recognition of Pictures
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.52
Comments
Method Chi-squared
Comments
Method of Estimation Estimation Parameter Hodges-Lehmann
Estimated Value 0
Confidence Interval (2-Sided) 95%
-6 to 0
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Hypothyroxinemia, Placebo for Levothyroxine - Hypothyroxinemia
Comments Analysis for Recognition of Pictures
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.91
Comments
Method Chi-squared
Comments
Method of Estimation Estimation Parameter Hodges-Lehmann
Estimated Value 0
Confidence Interval (2-Sided) 95%
-4 to 0
Parameter Dispersion Type:
Value:
Estimation Comments
7. Secondary Outcome
Title Cognitive, Motor and Language Scale Scores From the Bayley Certified Scales of Infant Development III Edition
Description 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
Time Frame 12 and 24 months of age

Outcome Measure Data

Analysis Population Description
For all outcomes except the primary outcome the potential follow-up cohort in the subclinical hypothyroidism groups consisted of 335 children in the levothyroxine group and 329 in the placebo group, and for the hypothyroxinema groups: 254 children in the levothryoxine group and 253 children in the placebo group.
Arm/Group Title Levothyroxine for Subclinical Hypothyroidism Placebo for Levothyroxine - Subclinical Hypothyroidism Levothyroxine for Hypothyroxinemia Placebo for Levothyroxine - Hypothyroxinemia
Arm/Group Description Levothyroxine 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 for Levothyroxine for the Subclinical Hypothyroidism Levothyroxine 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 for Levothyroxine for the Hypothyroxinemia
Measure Participants 323 326 254 253
Median 12 mo cognitive score
100
100
100
100
Median 12 mo motor score
97
97
97
97
Median 12 mo language score
94
94
94
94
Median 24 mo cognitive score
90
90
90
90
Median 24 mo motor score
97
97
97
97
Median 24 mo language score
89
91
89
89
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Subclinical Hypothyroidism, Placebo for Levothyroxine - Subclinical Hypothyroidism
Comments Bayley II Cognitive (12 months)
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.63
Comments
Method Chi-squared
Comments
Method of Estimation Estimation Parameter Hodges-Lehmann
Estimated Value 0
Confidence Interval (2-Sided) 95%
0 to 0
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Subclinical Hypothyroidism, Placebo for Levothyroxine - Subclinical Hypothyroidism
Comments Bayley II Motor (12 mo)
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.83
Comments
Method Chi-squared
Comments
Method of Estimation Estimation Parameter Hodges-Lehmann
Estimated Value 0
Confidence Interval (2-Sided) 95%
0 to 3
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Subclinical Hypothyroidism, Placebo for Levothyroxine - Subclinical Hypothyroidism
Comments Bayley-III Language (12 months)
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.48
Comments
Method Chi-squared
Comments
Method of Estimation Estimation Parameter Hodges-Lehmann
Estimated Value 0
Confidence Interval (2-Sided) 95%
0 to 3
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Subclinical Hypothyroidism, Placebo for Levothyroxine - Subclinical Hypothyroidism
Comments Bayley-III Cognitive (24 months)
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.59
Comments
Method Chi-squared
Comments
Method of Estimation Estimation Parameter Hodges-Lehmann
Estimated Value 0
Confidence Interval (2-Sided) 95%
0 to 0
Parameter Dispersion Type:
Value:
Estimation Comments
8. Secondary Outcome
Title Behavioral Problems and Social Competencies at 36 and 60 Months of Age, as Measured by the Child Behavior Checklist (CBCL)
Description 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.
Time Frame 36 and 60 months of age

Outcome Measure Data

Analysis Population Description
The potential follow-up cohort consisted of 335 children in the levothyroxine group and 329 in the placebo group for subclinical hypothyroidism and for hypothyroxinemia - 260 children in the levothyroxine group and 255 in the placebo group. A Child Behavior Checklist T score of less than 60 is considered to be in the normal range.
Arm/Group Title Levothyroxine for Subclinical Hypothyroidism Placebo for Levothyroxine - Subclinical Hypothyroidism Levothyroxine for Hypothyroxinemia Placebo for Levothyroxine - Hypothyroxinemia
Arm/Group Description Levothyroxine 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 for Levothyroxine for the Subclinical Hypothyroidism Levothyroxine 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 for Levothyroxine for the Hypothyroxinemia
Measure Participants 335 314 260 255
CBCL T score at 36 mo
46
46
48
48
CBCL T score at 60 mo
44
44
45
43
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Subclinical Hypothyroidism, Placebo for Levothyroxine - Subclinical Hypothyroidism
Comments CBCL at 36 months
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.99
Comments
Method Chi-squared
Comments
Method of Estimation Estimation Parameter Hodges-Lehmann
Estimated Value 0
Confidence Interval (2-Sided) 95%
-2 to 2
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Subclinical Hypothyroidism, Placebo for Levothyroxine - Subclinical Hypothyroidism
Comments CBCL at 60 months
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.96
Comments
Method Chi-squared
Comments
Method of Estimation Estimation Parameter Hodges-Lehmann
Estimated Value 0
Confidence Interval (2-Sided) 95%
-2 to 2
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Hypothyroxinemia, Placebo for Levothyroxine - Hypothyroxinemia
Comments CBCL at 36 months
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.65
Comments
Method Chi-squared
Comments
Method of Estimation Estimation Parameter Hodges-Lehmann
Estimated Value 0
Confidence Interval (2-Sided) 95%
-2 to 2
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Hypothyroxinemia, Placebo for Levothyroxine - Hypothyroxinemia
Comments CBCL at 60 months
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.44
Comments
Method Chi-squared
Comments
Method of Estimation Estimation Parameter Hodges-Lehmann
Estimated Value -1
Confidence Interval (2-Sided) 95%
-3 to 1
Parameter Dispersion Type:
Value:
Estimation Comments
9. Secondary Outcome
Title Attention Deficit Hyperactivity Disorder (ADHD) Index Score From the Connors' Rating Scales (Parent-S) - Revised
Description 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.
Time Frame 48 months of age

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Levothyroxine for Subclinical Hypothyroidism Placebo for Levothyroxine - Subclinical Hypothyroidism Levothyroxine for Hypothyroxinemia Placebo for Levothyroxine - Hypothyroxinemia
Arm/Group Description Levothyroxine 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 for Levothyroxine for the Subclinical Hypothyroidism Levothyroxine 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 for Levothyroxine for the Hypothyroxinemia
Measure Participants 302 303 238 228
Median (95% Confidence Interval) [T-score]
48
49
50
49
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Subclinical Hypothyroidism, Placebo for Levothyroxine - Subclinical Hypothyroidism
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.37
Comments
Method Chi-squared
Comments
Method of Estimation Estimation Parameter Hodges-Lehmann
Estimated Value 0
Confidence Interval (2-Sided) 95%
-1 to 2
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Hypothyroxinemia, Placebo for Levothyroxine - Hypothyroxinemia
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.98
Comments
Method Chi-squared
Comments
Method of Estimation Estimation Parameter Hodges-Lehmann
Estimated Value 0
Confidence Interval (2-Sided) 95%
-2 to 2
Parameter Dispersion Type:
Value:
Estimation Comments
10. Secondary Outcome
Title Participants With Placental Abruption
Description Clinically significant placental abruption will be determined by centralized (blinded) chart review
Time Frame Duration of pregnancy, delivery

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Levothyroxine for Subclinical Hypothyroidism Placebo for Levothyroxine - Subclinical Hypothyroidism Levothyroxine for Hypothyroxinemia Placebo for Levothyroxine - Hypothyroxinemia
Arm/Group Description Levothyroxine 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 for Levothyroxine for the Subclinical Hypothyroidism Levothyroxine 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 for Levothyroxine for the Hypothyroxinemia
Measure Participants 339 338 263 261
Count of Participants [Participants]
1
0.3%
5
1.5%
3
1.1%
2
0.8%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Subclinical Hypothyroidism, Placebo for Levothyroxine - Subclinical Hypothyroidism
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.12
Comments
Method Chi-squared
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Hypothyroxinemia, Placebo for Levothyroxine - Hypothyroxinemia
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 1.00
Comments
Method Chi-squared
Comments
11. Secondary Outcome
Title Participants With Gestational Hypertension
Description Gestational hypertension defined as patient having a diastolic ≥ 90 during pregnancy without proteinuria
Time Frame During pregnancy and until delivery

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Levothyroxine for Subclinical Hypothyroidism Placebo for Levothyroxine - Subclinical Hypothyroidism Levothyroxine for Hypothyroxinemia Placebo for Levothyroxine - Hypothyroxinemia
Arm/Group Description Levothyroxine 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 for Levothyroxine for the Subclinical Hypothyroidism Levothyroxine 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 for Levothyroxine for the Hypothyroxinemia
Measure Participants 339 338 263 261
Count of Participants [Participants]
33
9.7%
36
10.7%
20
7.5%
24
9.2%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Subclinical Hypothyroidism, Placebo for Levothyroxine - Subclinical Hypothyroidism
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.69
Comments
Method Chi-squared
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Hypothyroxinemia, Placebo for Levothyroxine - Hypothyroxinemia
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.51
Comments
Method Chi-squared
Comments
12. Secondary Outcome
Title Participants With Preeclampsia
Description Preeclampsia defined as patient having a diastolic ≥ 90 during pregnancy with at least 1 + proteinuria. Preeclampsia will also include HELLP syndrome or eclampsia.
Time Frame Duration of pregnancy, Delivery

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Levothyroxine for Subclinical Hypothyroidism Placebo for Levothyroxine - Subclinical Hypothyroidism Levothyroxine for Hypothyroxinemia Placebo for Levothyroxine - Hypothyroxinemia
Arm/Group Description Levothyroxine 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 for Levothyroxine for the Subclinical Hypothyroidism Levothyroxine 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 for Levothyroxine for the Hypothyroxinemia
Measure Participants 339 338 263 261
Count of Participants [Participants]
22
6.5%
20
5.9%
9
3.4%
11
4.2%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Subclinical Hypothyroidism, Placebo for Levothyroxine - Subclinical Hypothyroidism
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.76
Comments
Method Chi-squared
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Hypothyroxinemia, Placebo for Levothyroxine - Hypothyroxinemia
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.64
Comments
Method Chi-squared
Comments
13. Secondary Outcome
Title Gestational Diabetes Mellitus
Description A patient is considered to have gestational diabetes if clinically diagnosed with class A1 or A2
Time Frame During pregnancy until delivery

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Levothyroxine for Subclinical Hypothyroidism Placebo for Levothyroxine - Subclinical Hypothyroidism Levothyroxine for Hypothyroxinemia Placebo for Levothyroxine - Hypothyroxinemia
Arm/Group Description Levothyroxine 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 for Levothyroxine for the Subclinical Hypothyroidism Levothyroxine 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 for Levothyroxine for the Hypothyroxinemia
Measure Participants 339 338 263 261
Count of Participants [Participants]
25
7.4%
22
6.5%
21
7.9%
24
9.2%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Subclinical Hypothyroidism, Placebo for Levothyroxine - Subclinical Hypothyroidism
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.66
Comments
Method Chi-squared
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Hypothyroxinemia, Placebo for Levothyroxine - Hypothyroxinemia
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.62
Comments
Method Chi-squared
Comments
14. Secondary Outcome
Title Participants With Composite Neonatal Outcome
Description 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.
Time Frame Within 72 hours of delivery.

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Levothyroxine for Subclinical Hypothyroidism Placebo for Levothyroxine - Subclinical Hypothyroidism Levothyroxine for Hypothyroxinemia Placebo for Levothyroxine - Hypothyroxinemia
Arm/Group Description Levothyroxine 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 for Levothyroxine for the Subclinical Hypothyroidism Levothyroxine 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 for Levothyroxine for the Hypothyroxinemia
Measure Participants 339 338 263 261
Count of Participants [Participants]
7
2.1%
12
3.6%
5
1.9%
7
2.7%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Subclinical Hypothyroidism, Placebo for Levothyroxine - Subclinical Hypothyroidism
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.24
Comments
Method Chi-squared
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Hypothyroxinemia, Placebo for Levothyroxine - Hypothyroxinemia
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.55
Comments
Method Chi-squared
Comments
15. Secondary Outcome
Title Participants Who Experienced a Stillbirth or Miscarriage
Description Stillbirth or miscarriage.
Time Frame Delivery

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Levothyroxine for Subclinical Hypothyroidism Placebo for Levothyroxine - Subclinical Hypothyroidism Levothyroxine for Hypothyroxinemia Placebo for Levothyroxine - Hypothyroxinemia
Arm/Group Description Levothyroxine 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 for Levothyroxine for the Subclinical Hypothyroidism Levothyroxine 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 for Levothyroxine for the Hypothyroxinemia
Measure Participants 339 338 263 261
Count of Participants [Participants]
4
1.2%
7
2.1%
2
0.8%
5
1.9%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Subclinical Hypothyroidism, Placebo for Levothyroxine - Subclinical Hypothyroidism
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.36
Comments
Method Chi-squared
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Hypothyroxinemia, Placebo for Levothyroxine - Hypothyroxinemia
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.28
Comments
Method Chi-squared
Comments
16. Secondary Outcome
Title Number of Neonatal Deaths
Description Fetal and neonatal death
Time Frame Through 72 hours post delivery

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Levothyroxine for Subclinical Hypothyroidism Placebo for Levothyroxine - Subclinical Hypothyroidism Levothyroxine for Hypothyroxinemia Placebo for Levothyroxine - Hypothyroxinemia
Arm/Group Description Levothyroxine 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 for Levothyroxine for the Subclinical Hypothyroidism Levothyroxine 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 for Levothyroxine for the Hypothyroxinemia
Measure Participants 339 338 263 261
Count of Participants [Participants]
0
0%
1
0.3%
1
0.4%
1
0.4%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Subclinical Hypothyroidism, Placebo for Levothyroxine - Subclinical Hypothyroidism
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.50
Comments
Method Chi-squared
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Hypothyroxinemia, Placebo for Levothyroxine - Hypothyroxinemia
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 1.00
Comments
Method Chi-squared
Comments
17. Secondary Outcome
Title Number of Infants With Apgar Score 4 at 1 Minute and < 7 at 5 Minutes
Description Apgar score < 4 at 1 minute and < 7 at 5 minutes
Time Frame 1 minute and 5 minutes post delivery

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Levothyroxine for Subclinical Hypothyroidism Placebo for Levothyroxine - Subclinical Hypothyroidism Levothyroxine for Hypothyroxinemia Placebo for Levothyroxine - Hypothyroxinemia
Arm/Group Description Levothyroxine 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 for Levothyroxine for the Subclinical Hypothyroidism Levothyroxine 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 for Levothyroxine for the Hypothyroxinemia
Measure Participants 339 338 263 261
Apgar < 4 at 1 minute
6
1.8%
7
2.1%
6
2.3%
7
2.7%
Apgar < 7 at 5 minutes
2
0.6%
3
0.9%
2
0.8%
4
1.5%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Subclinical Hypothyroidism, Placebo for Levothyroxine - Subclinical Hypothyroidism
Comments Apgar at 1 min < 4
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.76
Comments
Method Chi-squared
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Hypothyroxinemia, Placebo for Levothyroxine - Hypothyroxinemia
Comments Apgar > 4 at 1 minute
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.76
Comments
Method Chi-squared
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Subclinical Hypothyroidism, Placebo for Levothyroxine - Subclinical Hypothyroidism
Comments Apgar < 7 at 5 minutes
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.69
Comments
Method Chi-squared
Comments
Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Hypothyroxinemia, Placebo for Levothyroxine - Hypothyroxinemia
Comments Apgar < 7 at 5 minutes
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.45
Comments
Method Chi-squared
Comments
18. Secondary Outcome
Title Number of Infants Admitted to NICU
Description Admission to NICU
Time Frame Delivery

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Levothyroxine for Subclinical Hypothyroidism Placebo for Levothyroxine - Subclinical Hypothyroidism Levothyroxine for Hypothyroxinemia Placebo for Levothyroxine - Hypothyroxinemia
Arm/Group Description Levothyroxine 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 for Levothyroxine for the Subclinical Hypothyroidism Levothyroxine 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 for Levothyroxine for the Hypothyroxinemia
Measure Participants 339 338 263 261
Count of Participants [Participants]
29
8.6%
21
6.2%
31
11.7%
31
11.9%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Subclinical Hypothyroidism, Placebo for Levothyroxine - Subclinical Hypothyroidism
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.24
Comments
Method Chi-squared
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Hypothyroxinemia, Placebo for Levothyroxine - Hypothyroxinemia
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.97
Comments
Method Chi-squared
Comments
19. Secondary Outcome
Title Infants With Birth Weight < 10th Percentile (Gestational Age z Score)
Description Birth weight < 10th percentile (gestational age z score)
Time Frame Delivery

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Levothyroxine for Subclinical Hypothyroidism Placebo for Levothyroxine - Subclinical Hypothyroidism Levothyroxine for Hypothyroxinemia Placebo for Levothyroxine - Hypothyroxinemia
Arm/Group Description Levothyroxine 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 for Levothyroxine for the Subclinical Hypothyroidism Levothyroxine 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 for Levothyroxine for the Hypothyroxinemia
Measure Participants 339 338 263 261
Count of Participants [Participants]
33
9.7%
27
8%
23
8.7%
20
7.7%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Subclinical Hypothyroidism, Placebo for Levothyroxine - Subclinical Hypothyroidism
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.45
Comments
Method Chi-squared
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Hypothyroxinemia, Placebo for Levothyroxine - Hypothyroxinemia
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.68
Comments
Method Chi-squared
Comments
20. Secondary Outcome
Title Neonatal Head Circumference (Centimeters)
Description 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
Time Frame Within 24 hours of birth

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Levothyroxine for Subclinical Hypothyroidism Placebo for Levothyroxine - Subclinical Hypothyroidism Levothyroxine for Hypothyroxinemia Placebo for Levothyroxine - Hypothyroxinemia
Arm/Group Description Levothyroxine 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 for Levothyroxine for the Subclinical Hypothyroidism Levothyroxine 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 for Levothyroxine for the Hypothyroxinemia
Measure Participants 339 338 263 261
Mean (Standard Deviation) [centimeters]
33.9
(1.8)
33.9
(1.7)
33.9
(1.8)
34.2
(1.6)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Subclinical Hypothyroidism, Placebo for Levothyroxine - Subclinical Hypothyroidism
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.46
Comments
Method Wilcoxon (Mann-Whitney)
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Hypothyroxinemia, Placebo for Levothyroxine - Hypothyroxinemia
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.19
Comments
Method Wilcoxon (Mann-Whitney)
Comments
21. Secondary Outcome
Title Number of Infants With Respiratory Distress Syndrome
Description 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.
Time Frame Delivery and greater than or equal to 24 hours

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Levothyroxine for Subclinical Hypothyroidism Placebo for Levothyroxine - Subclinical Hypothyroidism Levothyroxine for Hypothyroxinemia Placebo for Levothyroxine - Hypothyroxinemia
Arm/Group Description Levothyroxine 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 for Levothyroxine for the Subclinical Hypothyroidism Levothyroxine 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 for Levothyroxine for the Hypothyroxinemia
Measure Participants 339 338 263 261
Count of Participants [Participants]
9
2.7%
6
1.8%
4
1.5%
5
1.9%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Subclinical Hypothyroidism, Placebo for Levothyroxine - Subclinical Hypothyroidism
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.45
Comments
Method Chi-squared
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Hypothyroxinemia, Placebo for Levothyroxine - Hypothyroxinemia
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.75
Comments
Method Chi-squared
Comments
22. Secondary Outcome
Title Number of Infants With Retinopathy or Prematurity
Description 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
Time Frame Through 72 hours of birth

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Levothyroxine for Subclinical Hypothyroidism Placebo for Levothyroxine - Subclinical Hypothyroidism Levothyroxine for Hypothyroxinemia Placebo for Levothyroxine - Hypothyroxinemia
Arm/Group Description Levothyroxine 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 for Levothyroxine for the Subclinical Hypothyroidism Levothyroxine 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 for Levothyroxine for the Hypothyroxinemia
Measure Participants 339 338 263 261
Count of Participants [Participants]
1
0.3%
0
0%
0
0%
0
0%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Subclinical Hypothyroidism, Placebo for Levothyroxine - Subclinical Hypothyroidism
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 1.00
Comments
Method Fisher Exact
Comments
23. Secondary Outcome
Title Number of Infants With Necrotizing Enterocolitis
Description 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
Time Frame Delivery within 2 weeks of birth

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Levothyroxine for Subclinical Hypothyroidism Placebo for Levothyroxine - Subclinical Hypothyroidism Levothyroxine for Hypothyroxinemia Placebo for Levothyroxine - Hypothyroxinemia
Arm/Group Description Levothyroxine 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 for Levothyroxine for the Subclinical Hypothyroidism Levothyroxine 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 for Levothyroxine for the Hypothyroxinemia
Measure Participants 339 338 263 261
Count of Participants [Participants]
1
0.3%
1
0.3%
2
0.8%
0
0%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Subclinical Hypothyroidism, Placebo for Levothyroxine - Subclinical Hypothyroidism
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 1.00
Comments
Method Fisher Exact
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Hypothyroxinemia, Placebo for Levothyroxine - Hypothyroxinemia
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.50
Comments
Method Fisher Exact
Comments
24. Secondary Outcome
Title Number of Infants With Bronchopulmonary Dysplasia
Description 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
Time Frame Through 72 hours post delivery

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Levothyroxine for Subclinical Hypothyroidism Placebo for Levothyroxine - Subclinical Hypothyroidism Levothyroxine for Hypothyroxinemia Placebo for Levothyroxine - Hypothyroxinemia
Arm/Group Description Levothyroxine 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 for Levothyroxine for the Subclinical Hypothyroidism Levothyroxine 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 for Levothyroxine for the Hypothyroxinemia
Measure Participants 339 338 263 261
Count of Participants [Participants]
0
0%
1
0.3%
0
0%
1
0.4%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Subclinical Hypothyroidism, Placebo for Levothyroxine - Subclinical Hypothyroidism
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.50
Comments
Method Fisher Exact
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Hypothyroxinemia, Placebo for Levothyroxine - Hypothyroxinemia
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.49
Comments
Method Fisher Exact
Comments
25. Secondary Outcome
Title Number of Infants With Respiratory Therapy Greater Than or Equal to 1 Day
Description oxygen therapy (FiO2 ≥ 0.40) for greater than or equal to 24 hours
Time Frame 72 hours post delivery

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Levothyroxine for Subclinical Hypothyroidism Placebo for Levothyroxine - Subclinical Hypothyroidism Levothyroxine for Hypothyroxinemia Placebo for Levothyroxine - Hypothyroxinemia
Arm/Group Description Levothyroxine 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 for Levothyroxine for the Subclinical Hypothyroidism Levothyroxine 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 for Levothyroxine for the Hypothyroxinemia
Measure Participants 339 338 263 261
Count of Participants [Participants]
11
3.2%
11
3.3%
13
4.9%
12
4.6%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Subclinical Hypothyroidism, Placebo for Levothyroxine - Subclinical Hypothyroidism
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.99
Comments
Method Chi-squared
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Hypothyroxinemia, Placebo for Levothyroxine - Hypothyroxinemia
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.85
Comments
Method Chi-squared
Comments
26. Secondary Outcome
Title Number of Days in the Hospital Nursery
Description Median number of days in the hospital nursery
Time Frame Through hospital discharge

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Levothyroxine for Subclinical Hypothyroidism Placebo for Levothyroxine - Subclinical Hypothyroidism Levothyroxine for Hypothyroxinemia Placebo for Levothyroxine - Hypothyroxinemia
Arm/Group Description Levothyroxine 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 for Levothyroxine for the Subclinical Hypothyroidism Levothyroxine 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 for Levothyroxine for the Hypothyroxinemia
Measure Participants 339 338 263 261
Median (95% Confidence Interval) [days]
2
2
2
2
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Subclinical Hypothyroidism, Placebo for Levothyroxine - Subclinical Hypothyroidism
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.43
Comments
Method Wilcoxon (Mann-Whitney)
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Levothyroxine for Hypothyroxinemia, Placebo for Levothyroxine - Hypothyroxinemia
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.39
Comments
Method Wilcoxon (Mann-Whitney)
Comments

Adverse Events

Time Frame Data on adverse events was collected for each participant beginning with enrollment through the final 5-year follow-up with the mother and child.
Adverse Event Reporting Description The at-risk population for non-serious adverse events (side effects) was based on patients who had been seen for a least one study visit where side effect information was assessed, so the at-risk population for side effects varies from the total number of patients randomized and assessed for serious adverse events.
Arm/Group Title Levothyroxine for Subclinical Hypothyroidism Placebo for Levothyroxine - Subclinincal Hypothyroidism Levothyroxine for Hypothyroxinemia - Hypothyroxinemia Placebo for Levothyroxine
Arm/Group Description 100 µg of Levothryoxine for participants with subclinical hypothyroidism 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 for Levothyroxine for participants with subclinical hypothyroidism Placebo for Levothyroxine 50 µg of Levothyroxine for participants with hypothyroxinemia 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 for Levothyroxine for participants with hypothyroxinemia Placebo for Levothyroxine
All Cause Mortality
Levothyroxine for Subclinical Hypothyroidism Placebo for Levothyroxine - Subclinincal Hypothyroidism Levothyroxine for Hypothyroxinemia - Hypothyroxinemia Placebo for Levothyroxine
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total / (NaN) / (NaN) / (NaN) / (NaN)
Serious Adverse Events
Levothyroxine for Subclinical Hypothyroidism Placebo for Levothyroxine - Subclinincal Hypothyroidism Levothyroxine for Hypothyroxinemia - Hypothyroxinemia Placebo for Levothyroxine
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 4/339 (1.2%) 2/338 (0.6%) 3/265 (1.1%) 2/261 (0.8%)
Blood and lymphatic system disorders
Thrombocytopenia 0/339 (0%) 0 0/338 (0%) 0 0/265 (0%) 0 1/261 (0.4%) 1
Cardiac disorders
Maternal atrial fibrillation 0/339 (0%) 0 0/338 (0%) 0 1/265 (0.4%) 1 0/261 (0%) 0
Ear and labyrinth disorders
Neonatal Severe Hearing Loss 1/339 (0.3%) 1 0/338 (0%) 0 0/265 (0%) 0 0/261 (0%) 0
Endocrine disorders
Hashimoto's thryoiditis 0/339 (0%) 0 1/338 (0.3%) 1 0/265 (0%) 0 0/261 (0%) 0
General disorders
Maternal death 0/339 (0%) 0 0/338 (0%) 0 1/265 (0.4%) 1 0/261 (0%) 0
Pregnancy, puerperium and perinatal conditions
Chest/abdominal pain 1/339 (0.3%) 1 0/338 (0%) 0 0/265 (0%) 0 0/261 (0%) 0
Irregular fetal heart rate 1/339 (0.3%) 1 0/338 (0%) 0 0/265 (0%) 0 0/261 (0%) 0
IUGR, non-reassuring 0/339 (0%) 0 1/338 (0.3%) 1 0/265 (0%) 0 0/261 (0%) 0
Abnormal Doppler 0/339 (0%) 0 0/338 (0%) 0 1/265 (0.4%) 1 0/261 (0%) 0
Neonatal Hypoxic-Ischemic Encephalopathy 0/339 (0%) 0 0/338 (0%) 0 0/265 (0%) 0 1/261 (0.4%) 1
Psychiatric disorders
Autism Spectrum Disorder 1/339 (0.3%) 1 0/338 (0%) 0 0/265 (0%) 0 0/261 (0%) 0
Other (Not Including Serious) Adverse Events
Levothyroxine for Subclinical Hypothyroidism Placebo for Levothyroxine - Subclinincal Hypothyroidism Levothyroxine for Hypothyroxinemia - Hypothyroxinemia Placebo for Levothyroxine
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 51/338 (15.1%) 41/336 (12.2%) 25/261 (9.6%) 34/259 (13.1%)
Gastrointestinal disorders
Vomiting/Nausea 18/338 (5.3%) 8/336 (2.4%) 10/261 (3.8%) 15/259 (5.8%)
General disorders
Nervousness 4/338 (1.2%) 3/336 (0.9%) 2/261 (0.8%) 2/259 (0.8%)
Fatigue 4/338 (1.2%) 4/336 (1.2%) 4/261 (1.5%) 5/259 (1.9%)
Headaches 10/338 (3%) 8/336 (2.4%) 3/261 (1.1%) 4/259 (1.5%)
Other side effects 18/338 (5.3%) 13/336 (3.9%) 4/261 (1.5%) 10/259 (3.9%)
Respiratory, thoracic and mediastinal disorders
shortness of breath 3/338 (0.9%) 5/336 (1.5%) 2/261 (0.8%) 2/259 (0.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

Name/Title Elizabeth Thom, Ph.D.
Organization The George Washington University Biostatistics Center
Phone 301-881-9260
Email e_thom@bsc.gwu.edu
Responsible Party:
The George Washington University Biostatistics Center
ClinicalTrials.gov Identifier:
NCT00388297
Other Study ID Numbers:
  • HD36801-TSH
  • U10HD021410
  • U10HD027869
  • U10HD027917
  • U10HD027860
  • U10HD027915
  • U10HD034116
  • U10HD034208
  • U10HD034136
  • U10HD040500
  • U10HD040485
  • U10HD040544
  • U10HD040545
  • U10HD040560
  • U10HD040512
  • U10HD036801
  • U10HD053118
First Posted:
Oct 16, 2006
Last Update Posted:
Feb 21, 2019
Last Verified:
Feb 1, 2019