The Effect of Thyroid Hormone Levels in Pregnant Women on the Intelligence Quotient (IQ) of Their Children

Summary:

The purpose of the proposed study is to test the hypothesis that the key thyroid-related
factor in early fetal brain development is T4 derived from the maternal circulation.
According to this hypothesis, low circulating maternal levels of free T4 may adversely
influence fetal brain development, even when the mother is clinically euthyroid (i.e. has
normal TSH levels).

Specific Aims:

The proposed project aims to determine whether free T4 levels at or below the 3rd centile in
euthyroid women during early pregnancy are associated with reduced neuropsychological
development in their offspring. We will recruit a cohort of 5,000 pregnant women whose serum
samples have been submitted for routine prenatal screening for Down syndrome and neural tube
defects in the early second trimester of pregnancy. After the women provide consent,
thyroid-stimulating hormone (TSH) measurements will be performed. The women defined as
euthyroid by TSH measurement will comprise the study group. Free T4 measurements will be
performed on their stored sera after delivery. Then, a nested case-control study design will
be used. Inclusion criteria will include: liveborn, singleton infant delivered in Maine at
36 weeks or later, weighing at least 2,500 grams, and with no reported congenital anomalies.
Multiple gestations will be excluded. Eligible women with free T4 measurements below the 3rd
percentile (cases) will each be matched with a woman/infant pair with normal free T4
measurements (controls). Overall, 100 offspring in each category will undergo
neurodevelopmental testing at age 2 years, using a test battery that will focus on language
development and attainment of milestones and motor development. The study will have an 80%
power to detect a 6 point difference in full scale IQ.

Study Timeline:

Phase 1. Preparation for Recruitment (months 1-4):

Validate reference ranges for TSH and Free T4 Assays; Implement clinical reporting and
management system for TSH measurements; design and implement a Data Management System;
develop Provider and patient materials; visit offices to introduce the project; develop
informed consent.

Phase 2. Active Recruitment (months 4-24):

Recruit 5,000 pregnant women, classified as euthyroid based on second trimester TSH
measurements; measure free T4 measured in stored serum aliquots after the pregnancies have
delivered.

Phase 3. Identification of Study Subjects (months 18-36):

Identify 100 cases (euthyroid women fulfilling all inclusion criteria and with free T4
measurements at or below the 3rd centile) and 100 matched controls (normal free T4) among
the 5,000 euthyroid recruits.

Phase 4. Locate/Recruit Cases and Controls (months 20-38):

Locate and re-recruit the women/infant pairs identified in phase 3; obtain newborn
hypothyroidism screening results.

Phase 5. Neurodevelopmental Testing (months 36-58):

Perform neurodevelopmental testing and measure other thyroid analytes (total T4, T3 and
thyroid antibodies) in the cases and controls.

Phase 6. Data Analysis (months 59-60):

Compare demographic data, along with pregnancy- and delivery-related information, between
case and control mother/child pairs to verify matching and to compare non-matched variables
between the two groups. Include covariates that differ significantly between cases and
controls (and that might be related to neurodevelopment) in a more refined model to
determine whether the unadjusted findings are robust.

Significance:

The knowledge gained from this study will expand our understanding of the role that thyroid
hormone plays in normal pregnancy. If the hypothesis under study in this proposal proves to
be correct, it will define a broader group of pregnancies in which fetal brain development
might be suboptimal. The primary benefit to documenting such a problem would be the
opportunity to develop strategies for identifying and treating high risk women to avoid the
adverse consequences in their children.

Inclusion Criteria:

- Pregnant female

- Normal TSH in second trimester

- Singleton pregnancy

- Term infant weighing 2500g or more

- No congenital abnormalities noted on birth record

- Delivery in Maine at 36 weeks or later

Exclusion Criteria:

- TSH levels outside normal range in second trimester

- Pre-existing hypothyroidism, treated

- More than one fetus

- Premature and/or low birth weight infant

- Congenital abnormalities noted on birth record