- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00388297
Thyroid Therapy for Mild Thyroid Deficiency in Pregnancy (TSH)
A Randomized Trial of Thyroxine Therapy for Subclinical Hypothyroidism or Hypothyroxinemia Diagnosed During Pregnancy
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Published research reports have stimulated national and international controversy regarding the value of maternal thyroxine therapy given to improve neurodevelopment of the fetus in women with variously defined hypothyroidism. These reports have led to conflicting and confusing recommendations as to whether or not all pregnant women in the U.S. should be screened for subclinical hypothyroidism or hypothyroxinemia.
Pregnant women less than 20 weeks gestation will have a blood test to screen for subclinical hypothyroidism or hypothyroxinemia. If eligible for the trial, patients will receive levothyroxine or placebo until delivery. Blood draws will be done at monthly study visits and the dosage will be adjusted based on test results. The children of these patients will have developmental testing done annually until they are 5 years of age.
Comparison(s): thyroxine supplementation versus placebo given during pregnancy to determine whether therapy is effective in improving intellectual ability at 5 years of age.
Study Type
Enrollment (Actual)
Phase
- Phase 3
Contacts and Locations
Study Locations
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Alabama
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Birmingham, Alabama, United States, 35249
- University of Alabama - Birmingham
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Illinois
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Chicago, Illinois, United States, 60611
- Northwestern University
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Michigan
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Detroit, Michigan, United States, 48201
- Wayne State University
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New York
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New York, New York, United States, 10032
- Columbia University
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North Carolina
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Chapel Hill, North Carolina, United States, 27599
- University of North Carolina - Chapel Hill
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Ohio
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Cleveland, Ohio, United States, 44109
- Case Western University
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Columbus, Ohio, United States, 43210
- Ohio State University
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Oregon
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Portland, Oregon, United States, 97239
- Oregon Health & Sciences University
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Pennsylvania
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Pittsburgh, Pennsylvania, United States, 15213
- University of Pittsburgh Magee Womens Hospital
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Rhode Island
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Providence, Rhode Island, United States, 02905
- Brown University
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Texas
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Dallas, Texas, United States, 75235
- University of Texas - Southwest
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Galveston, Texas, United States, 77555
- University of Texas Medical Branch - Galveston
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Houston, Texas, United States, 77030
- University of Texas-Houston
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Utah
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Salt Lake City, Utah, United States, 84132
- University of Utah Medical Center
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
- ADULT
- OLDER_ADULT
- CHILD
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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:
- Major fetal anomaly or demise
- Planned termination of the pregnancy
- History of thyroid cancer or current thyroid disease requiring medication
- Diabetes, on medication (insulin, glyburide)
- Collagen vascular disease (autoimmune disease), such as lupus, scleroderma and polymyalgia rheumatica, on medication
- Receiving anticoagulant therapy
- Depression, currently on treatment with tricyclics or selective serotonin reuptake inhibitors (SSRIs)
Other known serious maternal medical complications including:
- Chronic hypertension requiring antihypertensive medication (including diuretics)
- Epilepsy or other seizure disorder, on medication
- Active or chronic liver disease (acute hepatitis, chronic active hepatitis) with persistently abnormal liver enzymes
- Cancer (including melanoma but excluding other skin cancers)
- Heart disease (tachyrhythmia, class II or greater heart disease or on heart medication). Mitral valve prolapse without arrhythmia is not an exclusion.
- Asthma, on oral corticosteroids
- Known illicit drug or alcohol abuse during current pregnancy
- Delivery at a non-network hospital
- Participation in another intervention study that influences maternal and fetal morbidity and mortality, or participation in this trial in a previous pregnancy
- Unwilling or unable to commit to 5 year follow-up of the infant
Study Plan
How is the study designed?
Design Details
- Primary Purpose: TREATMENT
- Allocation: RANDOMIZED
- Interventional Model: SINGLE_GROUP
- Masking: TRIPLE
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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EXPERIMENTAL: Levothyroxine for Subclinical Hypothyroidism
100 µg of Levothryoxine for participants with subclinical hypothyroidism
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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.
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PLACEBO_COMPARATOR: Placebo for Levothyroxine - Subclinincal Hypothyroidism
Placebo for Levothyroxine for participants with subclinical hypothyroidism
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EXPERIMENTAL: Levothyroxine for Hypothyroxinemia - Hypothyroxinemia
50 µg of Levothyroxine for participants with hypothyroxinemia
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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.
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PLACEBO_COMPARATOR: Placebo for Levothyroxine
Placebo for Levothyroxine for participants with hypothyroxinemia
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Intellectual Function of Children at 5 Years of Age in Women Diagnosed With a) Subclinical Hypothyroidism or b) Hypothyroxinemia During the First Half of Pregnancy, or Death.
Time Frame: 60 months of age
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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+ |
60 months of age
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Week of Gestation at Delivery
Time Frame: Delivery
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Gestational age at delivery and preterm birth < 37 weeks' gestation or < 34 weeks' gestation
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Delivery
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Number of Participants With Preterm Delivery
Time Frame: Delivery
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Preterm delivery at less than 37 weeks or less than 34 weeks gestation
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Delivery
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Selected Cognitive Abilities From the Subscales of the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III)
Time Frame: 60 months
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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. |
60 months
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Cognitive and Achievement Levels From the Differential Ability Scales (DAS II)
Time Frame: 36 months
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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 |
36 months
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Cognitive and Achievement Levels From Two DAS-II Subtests (Recall of Digits Forward and Recognition of Pictures)
Time Frame: 48 months of age
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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 |
48 months of age
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Cognitive, Motor and Language Scale Scores From the Bayley Certified Scales of Infant Development III Edition
Time Frame: 12 and 24 months of age
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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
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12 and 24 months of age
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Behavioral Problems and Social Competencies at 36 and 60 Months of Age, as Measured by the Child Behavior Checklist (CBCL)
Time Frame: 36 and 60 months of age
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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.
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36 and 60 months of age
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Attention Deficit Hyperactivity Disorder (ADHD) Index Score From the Connors' Rating Scales (Parent-S) - Revised
Time Frame: 48 months of age
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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.
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48 months of age
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Participants With Placental Abruption
Time Frame: Duration of pregnancy, delivery
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Clinically significant placental abruption will be determined by centralized (blinded) chart review
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Duration of pregnancy, delivery
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Participants With Gestational Hypertension
Time Frame: During pregnancy and until delivery
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Gestational hypertension defined as patient having a diastolic ≥ 90 during pregnancy without proteinuria
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During pregnancy and until delivery
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Participants With Preeclampsia
Time Frame: Duration of pregnancy, Delivery
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Preeclampsia defined as patient having a diastolic ≥ 90 during pregnancy with at least 1 + proteinuria.
Preeclampsia will also include HELLP syndrome or eclampsia.
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Duration of pregnancy, Delivery
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Gestational Diabetes Mellitus
Time Frame: During pregnancy until delivery
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A patient is considered to have gestational diabetes if clinically diagnosed with class A1 or A2
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During pregnancy until delivery
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Participants With Composite Neonatal Outcome
Time Frame: Within 72 hours of delivery.
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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.
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Within 72 hours of delivery.
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Participants Who Experienced a Stillbirth or Miscarriage
Time Frame: Delivery
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Stillbirth or miscarriage.
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Delivery
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Number of Neonatal Deaths
Time Frame: Through 72 hours post delivery
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Fetal and neonatal death
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Through 72 hours post delivery
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Number of Infants With Apgar Score 4 at 1 Minute and < 7 at 5 Minutes
Time Frame: 1 minute and 5 minutes post delivery
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Apgar score < 4 at 1 minute and < 7 at 5 minutes
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1 minute and 5 minutes post delivery
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Number of Infants Admitted to NICU
Time Frame: Delivery
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Admission to NICU
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Delivery
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Infants With Birth Weight < 10th Percentile (Gestational Age z Score)
Time Frame: Delivery
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Birth weight < 10th percentile (gestational age z score)
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Delivery
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Neonatal Head Circumference (Centimeters)
Time Frame: Within 24 hours of birth
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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
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Within 24 hours of birth
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Number of Infants With Respiratory Distress Syndrome
Time Frame: Delivery and greater than or equal to 24 hours
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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.
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Delivery and greater than or equal to 24 hours
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Number of Infants With Retinopathy or Prematurity
Time Frame: Through 72 hours of birth
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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
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Through 72 hours of birth
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Number of Infants With Necrotizing Enterocolitis
Time Frame: Delivery within 2 weeks of birth
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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
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Delivery within 2 weeks of birth
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Number of Infants With Bronchopulmonary Dysplasia
Time Frame: Through 72 hours post delivery
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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
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Through 72 hours post delivery
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Number of Infants With Respiratory Therapy Greater Than or Equal to 1 Day
Time Frame: 72 hours post delivery
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oxygen therapy (FiO2 ≥ 0.40) for greater than or equal to 24 hours
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72 hours post delivery
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Number of Days in the Hospital Nursery
Time Frame: Through hospital discharge
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Median number of days in the hospital nursery
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Through hospital discharge
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Collaborators and Investigators
Collaborators
Investigators
- Study Chair: Brian Casey, MD, University of Texas Southwestern Medical Center
Publications and helpful links
General Publications
- Smid MC, Metz TD, McMillin GA, Mele L, Casey BM, Reddy UM, Wapner RJ, Thorp JM, Saade GR, Tita ATN, Miller ES, Rouse DJ, Sibai B, Costantine MM, Mercer BM, Caritis SN; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network*. Prenatal Nicotine or Cannabis Exposure and Offspring Neurobehavioral Outcomes. Obstet Gynecol. 2022 Jan 1;139(1):21-30. doi: 10.1097/AOG.0000000000004632.
- Casey BM, Thom EA, Peaceman AM, Varner MW, Sorokin Y, Hirtz DG, Reddy UM, Wapner RJ, Thorp JM Jr, Saade G, Tita AT, Rouse DJ, Sibai B, Iams JD, Mercer BM, Tolosa J, Caritis SN, VanDorsten JP; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Treatment of Subclinical Hypothyroidism or Hypothyroxinemia in Pregnancy. N Engl J Med. 2017 Mar 2;376(9):815-825. doi: 10.1056/NEJMoa1606205.
Helpful Links
Study record dates
Study Major Dates
Study Start
Primary Completion (ACTUAL)
Study Completion (ACTUAL)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (ESTIMATE)
Study Record Updates
Last Update Posted (ACTUAL)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- HD36801-TSH
- U10HD036801 (U.S. NIH Grant/Contract)
- U10HD021410 (U.S. NIH Grant/Contract)
- U10HD027869 (U.S. NIH Grant/Contract)
- U10HD027917 (U.S. NIH Grant/Contract)
- U10HD027860 (U.S. NIH Grant/Contract)
- U10HD034116 (U.S. NIH Grant/Contract)
- U10HD034208 (U.S. NIH Grant/Contract)
- U10HD034136 (U.S. NIH Grant/Contract)
- U10HD040500 (U.S. NIH Grant/Contract)
- U10HD040485 (U.S. NIH Grant/Contract)
- U10HD040544 (U.S. NIH Grant/Contract)
- U10HD040545 (U.S. NIH Grant/Contract)
- U10HD040560 (U.S. NIH Grant/Contract)
- U10HD040512 (U.S. NIH Grant/Contract)
- U10HD027915 (U.S. NIH Grant/Contract)
- U10HD053118 (U.S. NIH Grant/Contract)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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