Clinical trial NCT00388297: Thyroid Therapy for Mild Thyroid Deficiency in Pregnancy
Official title: A Randomized Trial of Thyroxine Therapy for Subclinical Hypothyroidism or Hypothyroxinemia Diagnosed During Pregnancy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Subclinical Hypothyroidism
Hypothyroxinemia
Pregnancy
Keywords: Subclinical Hypothyroidism
Hypothyroxinemia
Thyroid
Pregnancy
Intellectual Development
Lead sponsor: The George Washington University Biostatistics Center
Sponsor class: OTHER
Collaborators: name: National Institute of Neurological Disorders and Stroke (NINDS)
name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2006-10-16
Enrollment: 1203
Sex: FEMALE
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: 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.
timeFrame: 60 months of age
Secondary outcomes:
measure: Week of Gestation at Delivery
timeFrame: Delivery
measure: Number of Participants With Preterm Delivery
timeFrame: Delivery
measure: Selected Cognitive Abilities From the Subscales of the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III)
timeFrame: 60 months
measure: Cognitive and Achievement Levels From the Differential Ability Scales (DAS II)
timeFrame: 36 months
measure: Cognitive and Achievement Levels From Two DAS-II Subtests (Recall of Digits Forward and Recognition of Pictures)
timeFrame: 48 months of age
measure: Cognitive, Motor and Language Scale Scores From the Bayley Certified Scales of Infant Development III Edition
timeFrame: 12 and 24 months of age
measure: Behavioral Problems and Social Competencies at 36 and 60 Months of Age, as Measured by the Child Behavior Checklist (CBCL)
timeFrame: 36 and 60 months of age
measure: Attention Deficit Hyperactivity Disorder (ADHD) Index Score From the Connors' Rating Scales (Parent-S) - Revised
timeFrame: 48 months of age
measure: Participants With Placental Abruption
timeFrame: Duration of pregnancy, delivery
measure: Participants With Gestational Hypertension
timeFrame: During pregnancy and until delivery
measure: Participants With Preeclampsia
timeFrame: Duration of pregnancy, Delivery
measure: Gestational Diabetes Mellitus
timeFrame: During pregnancy until delivery
measure: Participants With Composite Neonatal Outcome
timeFrame: Within 72 hours of delivery.
measure: Participants Who Experienced a Stillbirth or Miscarriage
timeFrame: Delivery
measure: Number of Neonatal Deaths
timeFrame: Through 72 hours post delivery
measure: Number of Infants With Apgar Score 4 at 1 Minute and < 7 at 5 Minutes
timeFrame: 1 minute and 5 minutes post delivery
measure: Number of Infants Admitted to NICU
timeFrame: Delivery
measure: Infants With Birth Weight < 10th Percentile (Gestational Age z Score)
timeFrame: Delivery
measure: Neonatal Head Circumference (Centimeters)
timeFrame: Within 24 hours of birth
measure: Number of Infants With Respiratory Distress Syndrome
timeFrame: Delivery and greater than or equal to 24 hours
measure: Number of Infants With Retinopathy or Prematurity
timeFrame: Through 72 hours of birth
measure: Number of Infants With Necrotizing Enterocolitis
timeFrame: Delivery within 2 weeks of birth
measure: Number of Infants With Bronchopulmonary Dysplasia
timeFrame: Through 72 hours post delivery
measure: Number of Infants With Respiratory Therapy Greater Than or Equal to 1 Day
timeFrame: 72 hours post delivery
measure: Number of Days in the Hospital Nursery
timeFrame: Through hospital discharge
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama - Birmingham
state: Alabama
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Detroit
country: United States
facility: Wayne State University
state: Michigan
city: New York
country: United States
facility: Columbia University
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina - Chapel Hill
state: North Carolina
city: Cleveland
country: United States
facility: Case Western University
state: Ohio
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Sciences University
state: Oregon
city: Pittsburgh
country: United States
facility: University of Pittsburgh Magee Womens Hospital
state: Pennsylvania
city: Providence
country: United States
facility: Brown University
state: Rhode Island
city: Dallas
country: United States
facility: University of Texas - Southwest
state: Texas
city: Galveston
country: United States
facility: University of Texas Medical Branch - Galveston
state: Texas
city: Houston
country: United States
facility: University of Texas-Houston
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Medical Center
state: Utah
Study officials:
affiliation: University of Texas Southwestern Medical Center
name: Brian Casey, MD
role: STUDY_CHAIR
affiliation: NICHD Project Scientist
name: Menachem Miodovnik, MD
role: STUDY_DIRECTOR
References:
citation: 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; for the 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.
citation: 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.