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.
Published research reports have stimulated national and international controversy regarding the value of maternal thyroxine therapy given to improve neurodevelopment of the fetus in women with variously defined hypothyroidism. These reports have led to conflicting and confusing recommendations as to whether or not all pregnant women in the U.S. should be screened for subclinical hypothyroidism or hypothyroxinemia. Pregnant women less than 20 weeks gestation will have a blood test to screen for subclinical hypothyroidism or hypothyroxinemia. If eligible for the trial, patients will receive levothyroxine or placebo until delivery. Blood draws will be done at monthly study visits and the dosage will be adjusted based on test results. The children of these patients will have developmental testing done annually until they are 5 years of age. Comparison(s): thyroxine supplementation versus placebo given during pregnancy to determine whether therapy is effective in improving intellectual ability at 5 years of age.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
1,203
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.
University of Alabama - Birmingham
Birmingham, Alabama, United States
Northwestern University
Chicago, Illinois, United States
Wayne State University
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.
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
Week of Gestation at Delivery
Gestational age at delivery and preterm birth \< 37 weeks' gestation or \< 34 weeks' gestation
Time frame: Delivery
Number of Participants With Preterm Delivery
Preterm delivery at less than 37 weeks or less than 34 weeks gestation
Time frame: Delivery
Selected Cognitive Abilities From the Subscales of the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III)
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
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Detroit, Michigan, United States
Columbia University
New York, New York, United States
University of North Carolina - Chapel Hill
Chapel Hill, North Carolina, United States
Case Western University
Cleveland, Ohio, United States
Ohio State University
Columbus, Ohio, United States
Oregon Health & Sciences University
Portland, Oregon, United States
University of Pittsburgh Magee Womens Hospital
Pittsburgh, Pennsylvania, United States
Brown University
Providence, Rhode Island, United States
...and 4 more locations
Cognitive and Achievement Levels From the Differential Ability Scales (DAS II)
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
Cognitive and Achievement Levels From Two DAS-II Subtests (Recall of Digits Forward and Recognition of Pictures)
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
Cognitive, Motor and Language Scale Scores From the Bayley Certified Scales of Infant Development III Edition
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
Behavioral Problems and Social Competencies at 36 and 60 Months of Age, as Measured by the Child Behavior Checklist (CBCL)
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
Attention Deficit Hyperactivity Disorder (ADHD) Index Score From the Connors' Rating Scales (Parent-S) - Revised
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
Participants With Placental Abruption
Clinically significant placental abruption will be determined by centralized (blinded) chart review
Time frame: Duration of pregnancy, delivery
Participants With Gestational Hypertension
Gestational hypertension defined as patient having a diastolic ≥ 90 during pregnancy without proteinuria
Time frame: During pregnancy and until delivery
Participants With Preeclampsia
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
Gestational Diabetes Mellitus
A patient is considered to have gestational diabetes if clinically diagnosed with class A1 or A2
Time frame: During pregnancy until delivery
Participants With Composite Neonatal Outcome
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.
Participants Who Experienced a Stillbirth or Miscarriage
Stillbirth or miscarriage.
Time frame: Delivery
Number of Neonatal Deaths
Fetal and neonatal death
Time frame: Through 72 hours post delivery
Number of Infants With Apgar Score 4 at 1 Minute and < 7 at 5 Minutes
Apgar score \< 4 at 1 minute and \< 7 at 5 minutes
Time frame: 1 minute and 5 minutes post delivery
Number of Infants Admitted to NICU
Admission to NICU
Time frame: Delivery
Infants With Birth Weight < 10th Percentile (Gestational Age z Score)
Birth weight \< 10th percentile (gestational age z score)
Time frame: Delivery
Neonatal Head Circumference (Centimeters)
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
Number of Infants With Respiratory Distress Syndrome
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
Number of Infants With Retinopathy or Prematurity
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
Number of Infants With Necrotizing Enterocolitis
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
Number of Infants With Bronchopulmonary Dysplasia
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
Number of Infants With Respiratory Therapy Greater Than or Equal to 1 Day
oxygen therapy (FiO2 ≥ 0.40) for greater than or equal to 24 hours
Time frame: 72 hours post delivery
Number of Days in the Hospital Nursery
Median number of days in the hospital nursery
Time frame: Through hospital discharge