Hypothyroxinemia, Pregnancy, Subclinical Hypothyroidism
Conditions
Keywords
Subclinical Hypothyroidism, Hypothyroxinemia, Thyroid, Pregnancy, Intellectual Development
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.
Interventions
DRUGLevothyroxine
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.
DRUGPlacebo for Levothyroxine
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
The George Washington University Biostatistics Center
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
FEMALE
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: 1. Chronic hypertension requiring antihypertensive medication (including diuretics) 2. Epilepsy or other seizure disorder, on medication 3. Active or chronic liver disease (acute hepatitis, chronic active hepatitis) with persistently abnormal liver enzymes 4. Cancer (including melanoma but excluding other skin cancers) 5. Heart disease (tachyrhythmia, class II or greater heart disease or on heart medication). Mitral valve prolapse without arrhythmia is not an exclusion. 6. Asthma, on oral corticosteroids 9. Known illicit drug or alcohol abuse during current pregnancy 10. Delivery at a non-network hospital 11. Participation in another intervention study that influences maternal and fetal morbidity and mortality, or participation in this trial in a previous pregnancy 12. Unwilling or unable to commit to 5 year follow-up of the infant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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. |
| Gestational Diabetes Mellitus | During pregnancy until delivery | A patient is considered to have gestational diabetes if clinically diagnosed with class A1 or A2 |
| Participants With Composite Neonatal Outcome | 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. |
| Week of Gestation at Delivery | Delivery | Gestational age at delivery and preterm birth \< 37 weeks' gestation or \< 34 weeks' gestation |
| 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 |
| Number of Infants Admitted to NICU | Delivery | Admission to NICU |
| Infants With Birth Weight < 10th Percentile (Gestational Age z Score) | Delivery | Birth weight \< 10th percentile (gestational age z score) |
| 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 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 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 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 |
| Number of Days in the Hospital Nursery | Through hospital discharge | Median number of days in the hospital nursery |
| Participants Who Experienced a Stillbirth or Miscarriage | Delivery | Stillbirth or miscarriage. |
Countries
United States
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| Levothyroxine for 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. | 339 |
| Placebo for Levothyroxine - Subclinical Hypothyroidism Placebo for Levothyroxine for the Subclinical Hypothyroidism | 338 |
| Levothyroxine for Hypothyroxinemia 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. | 265 |
| Placebo for Levothyroxine - Hypothyroxinemia Placebo for Levothyroxine for the Hypothyroxinemia | 261 |
| Total | 1,203 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 16 | 12 | 11 | 8 |
Baseline characteristics
| Characteristic | Placebo for Levothyroxine - Subclinical Hypothyroidism | Total | Placebo for Levothyroxine - Hypothyroxinemia | Levothyroxine for Subclinical Hypothyroidism | Levothyroxine for Hypothyroxinemia |
|---|---|---|---|---|---|
| Age, Continuous | 27.3 years STANDARD_DEVIATION 5.7 | 27.7 years STANDARD_DEVIATION 5.7 | 28.0 years STANDARD_DEVIATION 5.8 | 27.7 years STANDARD_DEVIATION 5.7 | 27.8 years STANDARD_DEVIATION 5.7 |
| Baseline free thyroxine (ng/dl Median | 1.02 ng/dl | 0.90 ng/dl | 0.83 ng/dl | 1.01 ng/dl | 0.83 ng/dl |
| Baseline thyrotropin (mU/liter) Median | 4.3 mU/liter | 3.4 mU/liter | 1.4 mU/liter | 4.5 mU/liter | 1.5 mU/liter |
| Body-mass index | 28.2 kg/m^2 STANDARD_DEVIATION 6.4 | 29.0 kg/m^2 STANDARD_DEVIATION 6.6 | 30.2 kg/m^2 STANDARD_DEVIATION 7.1 | 28.1 kg/m^2 STANDARD_DEVIATION 6.4 | 30.3 kg/m^2 STANDARD_DEVIATION 6.4 |
| Nulliparous | 134 Participants | 391 Participants | 64 Participants | 124 Participants | 69 Participants |
| Race/Ethnicity, Customized Black | 25 Participants | 178 Participants | 65 Participants | 27 Participants | 61 Participants |
| Race/Ethnicity, Customized Hispanic | 185 Participants | 636 Participants | 125 Participants | 195 Participants | 131 Participants |
| Race/Ethnicity, Customized Other | 11 Participants | 25 Participants | 2 Participants | 8 Participants | 4 Participants |
| Race/Ethnicity, Customized White | 117 Participants | 364 Participants | 69 Participants | 109 Participants | 69 Participants |
| Region of Enrollment United States | 338 Participants | 1203 Participants | 261 Participants | 339 Participants | 265 Participants |
| Sex: Female, Male Female | 338 Participants | 1203 Participants | 261 Participants | 339 Participants | 265 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Urinary iodine (µg/liter) Median | 196 µg/liter | 194 µg/liter | 191 µg/liter | 199 µg/liter | 185 µg/liter |
| Weeks Gestation at Randomization | 16.7 Weeks STANDARD_DEVIATION 3 | 17.2 Weeks STANDARD_DEVIATION 3 | 17.7 Weeks STANDARD_DEVIATION 2.9 | 16.6 Weeks STANDARD_DEVIATION 3 | 18.0 Weeks STANDARD_DEVIATION 2.8 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 51 / 338 | 41 / 336 | 25 / 261 | 34 / 259 |
| serious Total, serious adverse events | 4 / 339 | 2 / 338 | 3 / 265 | 2 / 261 |
Outcome results
Primary
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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Levothyroxine for Subclinical Hypothyroidism | 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. | 97 score on a scale |
| Placebo for Levothyroxine - Subclinical Hypothyroidism | 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. | 94 score on a scale |
| Levothyroxine for Hypothyroxinemia | 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. | 94 score on a scale |
| Placebo for Levothyroxine - Hypothyroxinemia | 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. | 91 score on a scale |
p-value: 0.7195% CI: [-3, 2]Wilcoxon (Mann-Whitney)
p-value: 0.395% CI: [-4, 1]Wilcoxon (Mann-Whitney)
Secondary
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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Levothyroxine for Subclinical Hypothyroidism | Attention Deficit Hyperactivity Disorder (ADHD) Index Score From the Connors' Rating Scales (Parent-S) - Revised | 48 T-score |
| Placebo for Levothyroxine - Subclinical Hypothyroidism | Attention Deficit Hyperactivity Disorder (ADHD) Index Score From the Connors' Rating Scales (Parent-S) - Revised | 49 T-score |
| Levothyroxine for Hypothyroxinemia | Attention Deficit Hyperactivity Disorder (ADHD) Index Score From the Connors' Rating Scales (Parent-S) - Revised | 50 T-score |
| Placebo for Levothyroxine - Hypothyroxinemia | Attention Deficit Hyperactivity Disorder (ADHD) Index Score From the Connors' Rating Scales (Parent-S) - Revised | 49 T-score |
p-value: 0.3795% CI: [-1, 2]Chi-squared
p-value: 0.9895% CI: [-2, 2]Chi-squared
Secondary
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
Population: 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 | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Levothyroxine for Subclinical Hypothyroidism | Behavioral Problems and Social Competencies at 36 and 60 Months of Age, as Measured by the Child Behavior Checklist (CBCL) | CBCL T score at 36 mo | 46 T-score |
| Levothyroxine for Subclinical Hypothyroidism | Behavioral Problems and Social Competencies at 36 and 60 Months of Age, as Measured by the Child Behavior Checklist (CBCL) | CBCL T score at 60 mo | 44 T-score |
| Placebo for Levothyroxine - Subclinical Hypothyroidism | Behavioral Problems and Social Competencies at 36 and 60 Months of Age, as Measured by the Child Behavior Checklist (CBCL) | CBCL T score at 60 mo | 44 T-score |
| Placebo for Levothyroxine - Subclinical Hypothyroidism | Behavioral Problems and Social Competencies at 36 and 60 Months of Age, as Measured by the Child Behavior Checklist (CBCL) | CBCL T score at 36 mo | 46 T-score |
| Levothyroxine for Hypothyroxinemia | Behavioral Problems and Social Competencies at 36 and 60 Months of Age, as Measured by the Child Behavior Checklist (CBCL) | CBCL T score at 36 mo | 48 T-score |
| Levothyroxine for Hypothyroxinemia | Behavioral Problems and Social Competencies at 36 and 60 Months of Age, as Measured by the Child Behavior Checklist (CBCL) | CBCL T score at 60 mo | 45 T-score |
| Placebo for Levothyroxine - Hypothyroxinemia | Behavioral Problems and Social Competencies at 36 and 60 Months of Age, as Measured by the Child Behavior Checklist (CBCL) | CBCL T score at 36 mo | 48 T-score |
| Placebo for Levothyroxine - Hypothyroxinemia | Behavioral Problems and Social Competencies at 36 and 60 Months of Age, as Measured by the Child Behavior Checklist (CBCL) | CBCL T score at 60 mo | 43 T-score |
Comparison: CBCL at 36 monthsp-value: 0.9995% CI: [-2, 2]Chi-squared
Comparison: CBCL at 60 monthsp-value: 0.9695% CI: [-2, 2]Chi-squared
Comparison: CBCL at 36 monthsp-value: 0.6595% CI: [-2, 2]Chi-squared
Comparison: CBCL at 60 monthsp-value: 0.4495% CI: [-3, 1]Chi-squared
Secondary
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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Levothyroxine for Subclinical Hypothyroidism | Cognitive and Achievement Levels From the Differential Ability Scales (DAS II) | 90 score on a scale |
| Placebo for Levothyroxine - Subclinical Hypothyroidism | Cognitive and Achievement Levels From the Differential Ability Scales (DAS II) | 90 score on a scale |
| Levothyroxine for Hypothyroxinemia | Cognitive and Achievement Levels From the Differential Ability Scales (DAS II) | 90 score on a scale |
| Placebo for Levothyroxine - Hypothyroxinemia | Cognitive and Achievement Levels From the Differential Ability Scales (DAS II) | 89 score on a scale |
p-value: 0.995% CI: [-2, 3]Chi-squared
p-value: 0.6495% CI: [-3, 2]Chi-squared
Secondary
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
Population: 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 | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Levothyroxine for Subclinical Hypothyroidism | Cognitive and Achievement Levels From Two DAS-II Subtests (Recall of Digits Forward and Recognition of Pictures) | Median Recall of Digits Forward Score | 84 score on a scale |
| Levothyroxine for Subclinical Hypothyroidism | Cognitive and Achievement Levels From Two DAS-II Subtests (Recall of Digits Forward and Recognition of Pictures) | Median Recognition of Pictures Score | 74 score on a scale |
| Placebo for Levothyroxine - Subclinical Hypothyroidism | Cognitive and Achievement Levels From Two DAS-II Subtests (Recall of Digits Forward and Recognition of Pictures) | Median Recognition of Pictures Score | 74 score on a scale |
| Placebo for Levothyroxine - Subclinical Hypothyroidism | Cognitive and Achievement Levels From Two DAS-II Subtests (Recall of Digits Forward and Recognition of Pictures) | Median Recall of Digits Forward Score | 84 score on a scale |
| Levothyroxine for Hypothyroxinemia | Cognitive and Achievement Levels From Two DAS-II Subtests (Recall of Digits Forward and Recognition of Pictures) | Median Recall of Digits Forward Score | 91 score on a scale |
| Levothyroxine for Hypothyroxinemia | Cognitive and Achievement Levels From Two DAS-II Subtests (Recall of Digits Forward and Recognition of Pictures) | Median Recognition of Pictures Score | 84 score on a scale |
| Placebo for Levothyroxine - Hypothyroxinemia | Cognitive and Achievement Levels From Two DAS-II Subtests (Recall of Digits Forward and Recognition of Pictures) | Median Recall of Digits Forward Score | 74 score on a scale |
| Placebo for Levothyroxine - Hypothyroxinemia | Cognitive and Achievement Levels From Two DAS-II Subtests (Recall of Digits Forward and Recognition of Pictures) | Median Recognition of Pictures Score | 74 score on a scale |
Comparison: Analysis for recall of digits forwardp-value: 0.695% CI: [-5, 7]Chi-squared
Comparison: Analysis for recall of digits forwardp-value: 0.2295% CI: [-8, 0]Chi-squared
Comparison: Analysis for Recognition of Picturesp-value: 0.5295% CI: [-6, 0]Chi-squared
Comparison: Analysis for Recognition of Picturesp-value: 0.9195% CI: [-4, 0]Chi-squared
Secondary
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
Population: 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 | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Levothyroxine for Subclinical Hypothyroidism | Cognitive, Motor and Language Scale Scores From the Bayley Certified Scales of Infant Development III Edition | Median 12 mo cognitive score | 100 score on a scale |
| Levothyroxine for Subclinical Hypothyroidism | Cognitive, Motor and Language Scale Scores From the Bayley Certified Scales of Infant Development III Edition | Median 12 mo motor score | 97 score on a scale |
| Levothyroxine for Subclinical Hypothyroidism | Cognitive, Motor and Language Scale Scores From the Bayley Certified Scales of Infant Development III Edition | Median 12 mo language score | 94 score on a scale |
| Levothyroxine for Subclinical Hypothyroidism | Cognitive, Motor and Language Scale Scores From the Bayley Certified Scales of Infant Development III Edition | Median 24 mo cognitive score | 90 score on a scale |
| Levothyroxine for Subclinical Hypothyroidism | Cognitive, Motor and Language Scale Scores From the Bayley Certified Scales of Infant Development III Edition | Median 24 mo motor score | 97 score on a scale |
| Levothyroxine for Subclinical Hypothyroidism | Cognitive, Motor and Language Scale Scores From the Bayley Certified Scales of Infant Development III Edition | Median 24 mo language score | 89 score on a scale |
| Placebo for Levothyroxine - Subclinical Hypothyroidism | Cognitive, Motor and Language Scale Scores From the Bayley Certified Scales of Infant Development III Edition | Median 24 mo language score | 91 score on a scale |
| Placebo for Levothyroxine - Subclinical Hypothyroidism | Cognitive, Motor and Language Scale Scores From the Bayley Certified Scales of Infant Development III Edition | Median 24 mo cognitive score | 90 score on a scale |
| Placebo for Levothyroxine - Subclinical Hypothyroidism | Cognitive, Motor and Language Scale Scores From the Bayley Certified Scales of Infant Development III Edition | Median 12 mo cognitive score | 100 score on a scale |
| Placebo for Levothyroxine - Subclinical Hypothyroidism | Cognitive, Motor and Language Scale Scores From the Bayley Certified Scales of Infant Development III Edition | Median 12 mo language score | 94 score on a scale |
| Placebo for Levothyroxine - Subclinical Hypothyroidism | Cognitive, Motor and Language Scale Scores From the Bayley Certified Scales of Infant Development III Edition | Median 12 mo motor score | 97 score on a scale |
| Placebo for Levothyroxine - Subclinical Hypothyroidism | Cognitive, Motor and Language Scale Scores From the Bayley Certified Scales of Infant Development III Edition | Median 24 mo motor score | 97 score on a scale |
| Levothyroxine for Hypothyroxinemia | Cognitive, Motor and Language Scale Scores From the Bayley Certified Scales of Infant Development III Edition | Median 12 mo motor score | 97 score on a scale |
| Levothyroxine for Hypothyroxinemia | Cognitive, Motor and Language Scale Scores From the Bayley Certified Scales of Infant Development III Edition | Median 12 mo language score | 94 score on a scale |
| Levothyroxine for Hypothyroxinemia | Cognitive, Motor and Language Scale Scores From the Bayley Certified Scales of Infant Development III Edition | Median 24 mo cognitive score | 90 score on a scale |
| Levothyroxine for Hypothyroxinemia | Cognitive, Motor and Language Scale Scores From the Bayley Certified Scales of Infant Development III Edition | Median 24 mo language score | 89 score on a scale |
| Levothyroxine for Hypothyroxinemia | Cognitive, Motor and Language Scale Scores From the Bayley Certified Scales of Infant Development III Edition | Median 24 mo motor score | 97 score on a scale |
| Levothyroxine for Hypothyroxinemia | Cognitive, Motor and Language Scale Scores From the Bayley Certified Scales of Infant Development III Edition | Median 12 mo cognitive score | 100 score on a scale |
| Placebo for Levothyroxine - Hypothyroxinemia | Cognitive, Motor and Language Scale Scores From the Bayley Certified Scales of Infant Development III Edition | Median 24 mo motor score | 97 score on a scale |
| Placebo for Levothyroxine - Hypothyroxinemia | Cognitive, Motor and Language Scale Scores From the Bayley Certified Scales of Infant Development III Edition | Median 24 mo language score | 89 score on a scale |
| Placebo for Levothyroxine - Hypothyroxinemia | Cognitive, Motor and Language Scale Scores From the Bayley Certified Scales of Infant Development III Edition | Median 12 mo motor score | 97 score on a scale |
| Placebo for Levothyroxine - Hypothyroxinemia | Cognitive, Motor and Language Scale Scores From the Bayley Certified Scales of Infant Development III Edition | Median 24 mo cognitive score | 90 score on a scale |
| Placebo for Levothyroxine - Hypothyroxinemia | Cognitive, Motor and Language Scale Scores From the Bayley Certified Scales of Infant Development III Edition | Median 12 mo cognitive score | 100 score on a scale |
| Placebo for Levothyroxine - Hypothyroxinemia | Cognitive, Motor and Language Scale Scores From the Bayley Certified Scales of Infant Development III Edition | Median 12 mo language score | 94 score on a scale |
Comparison: Bayley II Cognitive (12 months)p-value: 0.6395% CI: [0, 0]Chi-squared
Comparison: Bayley II Motor (12 mo)p-value: 0.8395% CI: [0, 3]Chi-squared
Comparison: Bayley-III Language (12 months)p-value: 0.4895% CI: [0, 3]Chi-squared
Comparison: Bayley-III Cognitive (24 months)p-value: 0.5995% CI: [0, 0]Chi-squared
Secondary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Levothyroxine for Subclinical Hypothyroidism | Gestational Diabetes Mellitus | 25 Participants |
| Placebo for Levothyroxine - Subclinical Hypothyroidism | Gestational Diabetes Mellitus | 22 Participants |
| Levothyroxine for Hypothyroxinemia | Gestational Diabetes Mellitus | 21 Participants |
| Placebo for Levothyroxine - Hypothyroxinemia | Gestational Diabetes Mellitus | 24 Participants |
p-value: 0.66Chi-squared
p-value: 0.62Chi-squared
Secondary
Infants With Birth Weight < 10th Percentile (Gestational Age z Score)
Birth weight \< 10th percentile (gestational age z score)
Time frame: Delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Levothyroxine for Subclinical Hypothyroidism | Infants With Birth Weight < 10th Percentile (Gestational Age z Score) | 33 Participants |
| Placebo for Levothyroxine - Subclinical Hypothyroidism | Infants With Birth Weight < 10th Percentile (Gestational Age z Score) | 27 Participants |
| Levothyroxine for Hypothyroxinemia | Infants With Birth Weight < 10th Percentile (Gestational Age z Score) | 23 Participants |
| Placebo for Levothyroxine - Hypothyroxinemia | Infants With Birth Weight < 10th Percentile (Gestational Age z Score) | 20 Participants |
p-value: 0.45Chi-squared
p-value: 0.68Chi-squared
Secondary
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levothyroxine for Subclinical Hypothyroidism | Neonatal Head Circumference (Centimeters) | 33.9 centimeters | Standard Deviation 1.8 |
| Placebo for Levothyroxine - Subclinical Hypothyroidism | Neonatal Head Circumference (Centimeters) | 33.9 centimeters | Standard Deviation 1.7 |
| Levothyroxine for Hypothyroxinemia | Neonatal Head Circumference (Centimeters) | 33.9 centimeters | Standard Deviation 1.8 |
| Placebo for Levothyroxine - Hypothyroxinemia | Neonatal Head Circumference (Centimeters) | 34.2 centimeters | Standard Deviation 1.6 |
p-value: 0.46Wilcoxon (Mann-Whitney)
p-value: 0.19Wilcoxon (Mann-Whitney)
Secondary
Number of Days in the Hospital Nursery
Median number of days in the hospital nursery
Time frame: Through hospital discharge
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Levothyroxine for Subclinical Hypothyroidism | Number of Days in the Hospital Nursery | 2 days |
| Placebo for Levothyroxine - Subclinical Hypothyroidism | Number of Days in the Hospital Nursery | 2 days |
| Levothyroxine for Hypothyroxinemia | Number of Days in the Hospital Nursery | 2 days |
| Placebo for Levothyroxine - Hypothyroxinemia | Number of Days in the Hospital Nursery | 2 days |
p-value: 0.43Wilcoxon (Mann-Whitney)
p-value: 0.39Wilcoxon (Mann-Whitney)
Secondary
Number of Infants Admitted to NICU
Admission to NICU
Time frame: Delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Levothyroxine for Subclinical Hypothyroidism | Number of Infants Admitted to NICU | 29 Participants |
| Placebo for Levothyroxine - Subclinical Hypothyroidism | Number of Infants Admitted to NICU | 21 Participants |
| Levothyroxine for Hypothyroxinemia | Number of Infants Admitted to NICU | 31 Participants |
| Placebo for Levothyroxine - Hypothyroxinemia | Number of Infants Admitted to NICU | 31 Participants |
p-value: 0.24Chi-squared
p-value: 0.97Chi-squared
Secondary
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
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Levothyroxine for Subclinical Hypothyroidism | Number of Infants With Apgar Score 4 at 1 Minute and < 7 at 5 Minutes | Apgar < 4 at 1 minute | 6 Participants |
| Levothyroxine for Subclinical Hypothyroidism | Number of Infants With Apgar Score 4 at 1 Minute and < 7 at 5 Minutes | Apgar < 7 at 5 minutes | 2 Participants |
| Placebo for Levothyroxine - Subclinical Hypothyroidism | Number of Infants With Apgar Score 4 at 1 Minute and < 7 at 5 Minutes | Apgar < 7 at 5 minutes | 3 Participants |
| Placebo for Levothyroxine - Subclinical Hypothyroidism | Number of Infants With Apgar Score 4 at 1 Minute and < 7 at 5 Minutes | Apgar < 4 at 1 minute | 7 Participants |
| Levothyroxine for Hypothyroxinemia | Number of Infants With Apgar Score 4 at 1 Minute and < 7 at 5 Minutes | Apgar < 4 at 1 minute | 6 Participants |
| Levothyroxine for Hypothyroxinemia | Number of Infants With Apgar Score 4 at 1 Minute and < 7 at 5 Minutes | Apgar < 7 at 5 minutes | 2 Participants |
| Placebo for Levothyroxine - Hypothyroxinemia | Number of Infants With Apgar Score 4 at 1 Minute and < 7 at 5 Minutes | Apgar < 4 at 1 minute | 7 Participants |
| Placebo for Levothyroxine - Hypothyroxinemia | Number of Infants With Apgar Score 4 at 1 Minute and < 7 at 5 Minutes | Apgar < 7 at 5 minutes | 4 Participants |
Comparison: Apgar at 1 min \< 4p-value: 0.76Chi-squared
Comparison: Apgar \> 4 at 1 minutep-value: 0.76Chi-squared
Comparison: Apgar \< 7 at 5 minutesp-value: 0.69Chi-squared
Comparison: Apgar \< 7 at 5 minutesp-value: 0.45Chi-squared
Secondary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Levothyroxine for Subclinical Hypothyroidism | Number of Infants With Bronchopulmonary Dysplasia | 0 Participants |
| Placebo for Levothyroxine - Subclinical Hypothyroidism | Number of Infants With Bronchopulmonary Dysplasia | 1 Participants |
| Levothyroxine for Hypothyroxinemia | Number of Infants With Bronchopulmonary Dysplasia | 0 Participants |
| Placebo for Levothyroxine - Hypothyroxinemia | Number of Infants With Bronchopulmonary Dysplasia | 1 Participants |
p-value: 0.5Fisher Exact
p-value: 0.49Fisher Exact
Secondary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Levothyroxine for Subclinical Hypothyroidism | Number of Infants With Necrotizing Enterocolitis | 1 Participants |
| Placebo for Levothyroxine - Subclinical Hypothyroidism | Number of Infants With Necrotizing Enterocolitis | 1 Participants |
| Levothyroxine for Hypothyroxinemia | Number of Infants With Necrotizing Enterocolitis | 2 Participants |
| Placebo for Levothyroxine - Hypothyroxinemia | Number of Infants With Necrotizing Enterocolitis | 0 Participants |
p-value: 1Fisher Exact
p-value: 0.5Fisher Exact
Secondary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Levothyroxine for Subclinical Hypothyroidism | Number of Infants With Respiratory Distress Syndrome | 9 Participants |
| Placebo for Levothyroxine - Subclinical Hypothyroidism | Number of Infants With Respiratory Distress Syndrome | 6 Participants |
| Levothyroxine for Hypothyroxinemia | Number of Infants With Respiratory Distress Syndrome | 4 Participants |
| Placebo for Levothyroxine - Hypothyroxinemia | Number of Infants With Respiratory Distress Syndrome | 5 Participants |
p-value: 0.45Chi-squared
p-value: 0.75Chi-squared
Secondary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Levothyroxine for Subclinical Hypothyroidism | Number of Infants With Respiratory Therapy Greater Than or Equal to 1 Day | 11 Participants |
| Placebo for Levothyroxine - Subclinical Hypothyroidism | Number of Infants With Respiratory Therapy Greater Than or Equal to 1 Day | 11 Participants |
| Levothyroxine for Hypothyroxinemia | Number of Infants With Respiratory Therapy Greater Than or Equal to 1 Day | 13 Participants |
| Placebo for Levothyroxine - Hypothyroxinemia | Number of Infants With Respiratory Therapy Greater Than or Equal to 1 Day | 12 Participants |
p-value: 0.99Chi-squared
p-value: 0.85Chi-squared
Secondary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Levothyroxine for Subclinical Hypothyroidism | Number of Infants With Retinopathy or Prematurity | 1 Participants |
| Placebo for Levothyroxine - Subclinical Hypothyroidism | Number of Infants With Retinopathy or Prematurity | 0 Participants |
| Levothyroxine for Hypothyroxinemia | Number of Infants With Retinopathy or Prematurity | 0 Participants |
| Placebo for Levothyroxine - Hypothyroxinemia | Number of Infants With Retinopathy or Prematurity | 0 Participants |
p-value: 1Fisher Exact
Secondary
Number of Neonatal Deaths
Fetal and neonatal death
Time frame: Through 72 hours post delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Levothyroxine for Subclinical Hypothyroidism | Number of Neonatal Deaths | 0 Participants |
| Placebo for Levothyroxine - Subclinical Hypothyroidism | Number of Neonatal Deaths | 1 Participants |
| Levothyroxine for Hypothyroxinemia | Number of Neonatal Deaths | 1 Participants |
| Placebo for Levothyroxine - Hypothyroxinemia | Number of Neonatal Deaths | 1 Participants |
p-value: 0.5Chi-squared
p-value: 1Chi-squared
Secondary
Number of Participants With Preterm Delivery
Preterm delivery at less than 37 weeks or less than 34 weeks gestation
Time frame: Delivery
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Levothyroxine for Subclinical Hypothyroidism | Number of Participants With Preterm Delivery | Preterm birth < 34 wk | 9 Participants |
| Levothyroxine for Subclinical Hypothyroidism | Number of Participants With Preterm Delivery | Preterm birth < 37 wk | 31 Participants |
| Placebo for Levothyroxine - Subclinical Hypothyroidism | Number of Participants With Preterm Delivery | Preterm birth < 37 wk | 37 Participants |
| Placebo for Levothyroxine - Subclinical Hypothyroidism | Number of Participants With Preterm Delivery | Preterm birth < 34 wk | 10 Participants |
| Levothyroxine for Hypothyroxinemia | Number of Participants With Preterm Delivery | Preterm birth < 34 wk | 10 Participants |
| Levothyroxine for Hypothyroxinemia | Number of Participants With Preterm Delivery | Preterm birth < 37 wk | 31 Participants |
| Placebo for Levothyroxine - Hypothyroxinemia | Number of Participants With Preterm Delivery | Preterm birth < 34 wk | 7 Participants |
| Placebo for Levothyroxine - Hypothyroxinemia | Number of Participants With Preterm Delivery | Preterm birth < 37 wk | 20 Participants |
Comparison: Analysis for \< 34 weeksp-value: 0.81Chi-squared
Comparison: Analysis for \<34 weeksp-value: 0.47Chi-squared
Comparison: Analysis for \<37 weeksp-value: 0.44Chi-squared
Comparison: Analysis for \< 37 weeksp-value: 0.11Chi-squared
Comparison: Bayley-III Motor (24 months)p-value: 0.3195% CI: [0, 3]Chi-squared
Comparison: Bayley-II Language (24 months)p-value: 0.395% CI: [0, 3]Chi-squared
Comparison: Bayley-III Cognitive (12 months)p-value: 0.8995% CI: [0, 0]Chi-squared
Comparison: Bayley-III Motor (12 months)p-value: 0.5495% CI: [0, 3]Chi-squared
Comparison: Bayley-III Language (12 months)p-value: 0.9295% CI: [-3, 3]Chi-squared
Comparison: Bayley-III Cognitive (24 months)p-value: 0.795% CI: [0, 0]Chi-squared
Comparison: Bayley-III Motor (24 months)p-value: 0.295% CI: [-3, 0]Chi-squared
Comparison: Bayley-II Language (24 months)p-value: 0.7195% CI: [-3, 2]Chi-squared
Secondary
Participants Who Experienced a Stillbirth or Miscarriage
Stillbirth or miscarriage.
Time frame: Delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Levothyroxine for Subclinical Hypothyroidism | Participants Who Experienced a Stillbirth or Miscarriage | 4 Participants |
| Placebo for Levothyroxine - Subclinical Hypothyroidism | Participants Who Experienced a Stillbirth or Miscarriage | 7 Participants |
| Levothyroxine for Hypothyroxinemia | Participants Who Experienced a Stillbirth or Miscarriage | 2 Participants |
| Placebo for Levothyroxine - Hypothyroxinemia | Participants Who Experienced a Stillbirth or Miscarriage | 5 Participants |
p-value: 0.36Chi-squared
p-value: 0.28Chi-squared
Secondary
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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Levothyroxine for Subclinical Hypothyroidism | Participants With Composite Neonatal Outcome | 7 Participants |
| Placebo for Levothyroxine - Subclinical Hypothyroidism | Participants With Composite Neonatal Outcome | 12 Participants |
| Levothyroxine for Hypothyroxinemia | Participants With Composite Neonatal Outcome | 5 Participants |
| Placebo for Levothyroxine - Hypothyroxinemia | Participants With Composite Neonatal Outcome | 7 Participants |
p-value: 0.24Chi-squared
p-value: 0.55Chi-squared
Secondary
Participants With Gestational Hypertension
Gestational hypertension defined as patient having a diastolic ≥ 90 during pregnancy without proteinuria
Time frame: During pregnancy and until delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Levothyroxine for Subclinical Hypothyroidism | Participants With Gestational Hypertension | 33 Participants |
| Placebo for Levothyroxine - Subclinical Hypothyroidism | Participants With Gestational Hypertension | 36 Participants |
| Levothyroxine for Hypothyroxinemia | Participants With Gestational Hypertension | 20 Participants |
| Placebo for Levothyroxine - Hypothyroxinemia | Participants With Gestational Hypertension | 24 Participants |
p-value: 0.69Chi-squared
p-value: 0.51Chi-squared
Secondary
Participants With Placental Abruption
Clinically significant placental abruption will be determined by centralized (blinded) chart review
Time frame: Duration of pregnancy, delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Levothyroxine for Subclinical Hypothyroidism | Participants With Placental Abruption | 1 Participants |
| Placebo for Levothyroxine - Subclinical Hypothyroidism | Participants With Placental Abruption | 5 Participants |
| Levothyroxine for Hypothyroxinemia | Participants With Placental Abruption | 3 Participants |
| Placebo for Levothyroxine - Hypothyroxinemia | Participants With Placental Abruption | 2 Participants |
p-value: 0.12Chi-squared
p-value: 1Chi-squared
Secondary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Levothyroxine for Subclinical Hypothyroidism | Participants With Preeclampsia | 22 Participants |
| Placebo for Levothyroxine - Subclinical Hypothyroidism | Participants With Preeclampsia | 20 Participants |
| Levothyroxine for Hypothyroxinemia | Participants With Preeclampsia | 9 Participants |
| Placebo for Levothyroxine - Hypothyroxinemia | Participants With Preeclampsia | 11 Participants |
p-value: 0.76Chi-squared
p-value: 0.64Chi-squared
Secondary
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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Levothyroxine for Subclinical Hypothyroidism | Selected Cognitive Abilities From the Subscales of the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III) | 97 score on a scale |
| Placebo for Levothyroxine - Subclinical Hypothyroidism | Selected Cognitive Abilities From the Subscales of the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III) | 95 score on a scale |
| Levothyroxine for Hypothyroxinemia | Selected Cognitive Abilities From the Subscales of the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III) | 94 score on a scale |
| Placebo for Levothyroxine - Hypothyroxinemia | Selected Cognitive Abilities From the Subscales of the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III) | 92 score on a scale |
p-value: 0.8995% CI: [-3, 2]Chi-squared
p-value: 0.4895% CI: [-3, 2]Chi-squared
Secondary
Week of Gestation at Delivery
Gestational age at delivery and preterm birth \< 37 weeks' gestation or \< 34 weeks' gestation
Time frame: Delivery
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levothyroxine for Subclinical Hypothyroidism | Week of Gestation at Delivery | 39.1 weeks | Standard Deviation 2.5 |
| Placebo for Levothyroxine - Subclinical Hypothyroidism | Week of Gestation at Delivery | 38.9 weeks | Standard Deviation 3.1 |
| Levothyroxine for Hypothyroxinemia | Week of Gestation at Delivery | 39.0 weeks | Standard Deviation 2.4 |
| Placebo for Levothyroxine - Hypothyroxinemia | Week of Gestation at Delivery | 38.8 weeks | Standard Deviation 3.1 |
p-value: 0.57Wilcoxon (Mann-Whitney)
p-value: 0.46Wilcoxon (Mann-Whitney)