Thyroid Therapy for Mild Thyroid Deficiency in Pregnancy

Phase 3

Completed

Conditions: Pregnancy
Subclinical Hypothyroidism
Hypothyroxinemia

Interventions: Drug: Placebo for Levothyroxine
Drug: Levothyroxine

Registration Number: NCT00388297

Lead Sponsor: The George Washington University Biostatistics Center

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

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 1203

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:
1. Chronic hypertension requiring antihypertensive medication (including diuretics)
2. Epilepsy or other seizure disorder, on medication
3. Active or chronic liver disease (acute hepatitis, chronic active hepatitis) with persistently abnormal liver enzymes
4. Cancer (including melanoma but excluding other skin cancers)
5. Heart disease (tachyrhythmia, class II or greater heart disease or on heart medication). Mitral valve prolapse without arrhythmia is not an exclusion.
6. Asthma, on oral corticosteroids
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 & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Placebo for Levothyroxine - Subclinincal Hypothyroidism	Placebo for Levothyroxine	Placebo for Levothyroxine for participants with subclinical hypothyroidism
Placebo for Levothyroxine	Placebo for Levothyroxine	Placebo for Levothyroxine for participants with hypothyroxinemia
Levothyroxine for Subclinical Hypothyroidism	Levothyroxine	100 µg of Levothryoxine for participants with subclinical hypothyroidism
Levothyroxine for Hypothyroxinemia - Hypothyroxinemia	Levothyroxine	50 µg of Levothyroxine for participants with hypothyroxinemia

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
Week of Gestation at Delivery	Delivery	Gestational age at delivery and preterm birth \< 37 weeks' gestation or \< 34 weeks' gestation
Number of Participants With Preterm Delivery	Delivery	Preterm delivery at less than 37 weeks or less than 34 weeks gestation
Selected Cognitive Abilities From the Subscales of the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III)	60 months	Standardized full-scale IQ scores from the Wechsler Preschool and Primary Scale of Intelligence III (WPPSI-III) at 5 years of age. Quotient and Composite scores have a mean of 100 and a standard deviation of 15. Subtest scaled scores have a mean of 10 and a standard deviation of 3. For Quotient and Composite score: below 70 is Extremely Low, 70-79 is Borderline, 80-89 is Low Average, 90-109 is Average, 110-119 is High Average, 120-129 is Superior, 130+ is Very Superior.
Cognitive and Achievement Levels From the Differential Ability Scales (DAS II)	36 months	Overall general conceptual ability score as measured by the DAS-II at 36 months of age. GCA General Conceptual Ability Classification ≥ 130 Very high 120-129 High 110-119 Above average 90-109 Average 80-89 Below average 70-79 Low ≤ 69 Very low
Cognitive and Achievement Levels From Two DAS-II Subtests (Recall of Digits Forward and Recognition of Pictures)	48 months of age	Cognitive and achievement levels from two DAS-II subtests (Recall of Digits Forward and Recognition of Pictures) GCA General Conceptual Ability Classification ≥ 130 Very high 120-129 High 110-119 Above average 90-109 Average 80-89 Below average 70-79 Low ≤ 69 Very low
Cognitive, Motor and Language Scale Scores From the Bayley Certified Scales of Infant Development III Edition	12 and 24 months of age	Composite scores are derived for cognitive, language, and motor development and scaled to a metric, with a mean of 100, standard deviation of 15, and range of 40 to 160. Results can also be expressed as percentile ranks relative to the standardization sample, with a mean and median of 50 and range from 1 to 99
Behavioral Problems and Social Competencies at 36 and 60 Months of Age, as Measured by the Child Behavior Checklist (CBCL)	36 and 60 months of age	Behavioral problems and social competencies at 36 and 60 months of age, as measured by the Child Behavior Checklist (CBCL). The CBCL is filled out by the caregiver. Each of the 100 questions indicates a behavior for which the caregiver scores as Not True (0), Sometimes True (1), or Often True (2). The scores for all the questions are then summed and evaluated against the normative data/T-scores. A Tscore of less than 60 is considered to be in the normal range. A T score of 60-63 is a borderline, and a T score of more than 63 is in the clinical range. Lower scores represent better outcomes.
Attention Deficit Hyperactivity Disorder (ADHD) Index Score From the Connors' Rating Scales (Parent-S) - Revised	48 months of age	The Conners' Rating Scales-Revised were used to assess attention deficit-hyperactivity disorder (ADHD). A T score of 45 to 55 is considered to be typical or average; a T score of 44 or less is not a concern, a T score of 56 to 60 is considered to be a borderline score, and a T score of 61 or higher indicates a possible or clinically significant problem.
Participants With Placental Abruption	Duration of pregnancy, delivery	Clinically significant placental abruption will be determined by centralized (blinded) chart review
Participants With Gestational Hypertension	During pregnancy and until delivery	Gestational hypertension defined as patient having a diastolic ≥ 90 during pregnancy without proteinuria
Gestational Diabetes Mellitus	During pregnancy until delivery	A patient is considered to have gestational diabetes if clinically diagnosed with class A1 or A2
Participants Who Experienced a Stillbirth or Miscarriage	Delivery	Stillbirth or miscarriage.
Number of Neonatal Deaths	Through 72 hours post delivery	Fetal and neonatal death
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
Infants With Birth Weight < 10th Percentile (Gestational Age z Score)	Delivery	Birth weight \< 10th percentile (gestational age z score)
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.
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
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.
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.
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
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
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
Number of Infants Admitted to NICU	Delivery	Admission to NICU
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
Number of Days in the Hospital Nursery	Through hospital discharge	Median number of days in the hospital nursery

Trial Locations

Locations (14): University of Utah Medical Center
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Salt Lake City, Utah, United States
Oregon Health & Sciences University
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Portland, Oregon, United States
Wayne State University
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Detroit, Michigan, United States
University of Alabama - Birmingham
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Birmingham, Alabama, United States
Case Western University
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Cleveland, Ohio, United States
Columbia University
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New York, New York, United States
University of North Carolina - Chapel Hill
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Chapel Hill, North Carolina, United States
Ohio State University
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Columbus, Ohio, United States
University of Texas Medical Branch - Galveston
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Galveston, Texas, United States
University of Pittsburgh Magee Womens Hospital
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Pittsburgh, Pennsylvania, United States
University of Texas - Southwest
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Dallas, Texas, United States
Brown University
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Providence, Rhode Island, United States
University of Texas-Houston
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Houston, Texas, United States
Northwestern University
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Chicago, Illinois, United States