What is the clinical significance of low thyroxine (T4) and normal thyroid-stimulating hormone (TSH) levels in a pregnant patient?

Clinical Significance of Low T4 and Normal TSH in Pregnancy

Low T4 with normal TSH in pregnancy represents isolated maternal hypothyroxinemia (IMH), a condition that requires careful timing-based assessment and may necessitate treatment depending on when it is identified during gestation.

Understanding Isolated Maternal Hypothyroxinemia

Isolated hypothyroxinemia is defined as low free T4 (FT4) with normal TSH levels during pregnancy 1. This pattern differs fundamentally from overt hypothyroidism (elevated TSH with low FT4) and subclinical hypothyroidism (elevated TSH with normal FT4) 2.

The clinical significance depends critically on when during pregnancy this pattern is identified:

First Trimester IMH

• IMH identified in the first trimester does not appear to increase the risk of adverse pregnancy outcomes 3
• Women with first-trimester IMH who received levothyroxine treatment showed no improvement in pregnancy outcomes compared to those who remained untreated 3
• The incidence of isolated hypothyroxinemia is approximately 150 times higher than congenital hypothyroidism, making it a relatively common finding 1

Second Trimester IMH

IMH identified in the second trimester carries substantially different risks and represents a more concerning clinical scenario:

• Significantly increased incidence of macrosomia (adjusted odds ratio 1.942,95% CI 1.076-3.503) when BMI in early pregnancy was <25 kg/m² 3
• Significantly increased risk of gestational hypertension (adjusted odds ratio 4.203,95% CI 1.611-10.968) when BMI in early pregnancy was <25 kg/m² 3
• The incidence of both macrosomia and gestational hypertension was significantly higher compared to controls 3

Distinguishing IMH from Other Thyroid Conditions

It is critical to differentiate isolated hypothyroxinemia from true hypothyroidism, as management differs substantially:

• Overt hypothyroidism presents with elevated TSH and low FT4, requiring immediate levothyroxine treatment to prevent preeclampsia, low birth weight, and neurodevelopmental effects in offspring 2, 4
• Subclinical hypothyroidism presents with elevated TSH and normal FT4, and is associated with increased risk of hypertensive disorders of pregnancy, premature rupture of membranes, and neonatal complications when untreated 4
• Isolated hypothyroxinemia presents with normal TSH and low FT4, with timing-dependent clinical significance 3, 1

Pregnancy-Specific Thyroid Physiology

Normal pregnancy causes physiological changes in thyroid function that must be considered when interpreting results:

• TSH reference ranges shift downward during pregnancy, with upper normal limits of 2.5 mIU/L in the first trimester and 3.0 mIU/L for the remainder of pregnancy 1
• Pregnancy increases thyroid hormone requirements by 25-50% in women with pre-existing hypothyroidism 5, 6
• Hyperemesis gravidarum can cause biochemical hyperthyroidism with undetectable TSH and elevated FT4 due to high hCG levels in the first trimester, which must be distinguished from pathological thyroid disease 7

Clinical Management Algorithm

For First Trimester IMH:

• Confirm the diagnosis by repeating thyroid function tests after 3-6 weeks, as 30-60% of abnormal values normalize spontaneously 8
• Reassure the patient that first-trimester IMH does not increase adverse pregnancy outcomes 3
• Do not initiate levothyroxine treatment based solely on first-trimester IMH, as treatment does not improve outcomes 3
• Schedule follow-up thyroid function testing in the second trimester, as thyroid status can change and second-trimester IMH carries different risks 3

For Second Trimester IMH:

• Consider levothyroxine treatment given the association with macrosomia and gestational hypertension, particularly in women with BMI <25 kg/m² 3
• Monitor closely for gestational hypertension with regular blood pressure assessments 3
• Assess fetal growth with serial ultrasounds to detect macrosomia early 3
• Recheck thyroid function every 4 weeks after initiating treatment to ensure adequate response 5, 6

For Women with Pre-existing Hypothyroidism:

• Increase levothyroxine dose by 25-50% immediately upon pregnancy confirmation in women with pre-existing hypothyroidism 5, 6
• Target TSH <2.5 mIU/L in the first trimester and maintain FT4 in the high-normal range throughout pregnancy 8, 1
• Monitor TSH and FT4 every 4 weeks until stable, then at minimum once per trimester 5, 6
• Most women (86.5%) require dose increases during pregnancy, with optimal timing in the first trimester 6

Critical Pitfalls to Avoid

• Never assume normal TSH excludes clinically significant thyroid dysfunction in pregnancy—isolated hypothyroxinemia with normal TSH can still impact outcomes depending on timing 3
• Do not use non-pregnancy-specific TSH reference ranges, as failure to use trimester-specific ranges leads to misinterpretation 7, 1
• Avoid discontinuing levothyroxine during pregnancy in women with pre-existing hypothyroidism, as untreated maternal hypothyroidism increases risk of preeclampsia, low birth weight, and permanent neurodevelopmental deficits 5
• Do not wait for symptoms to develop before checking TSH in at-risk women, as fetal harm can occur before maternal symptoms appear 8
• Never overlook the need for second-trimester thyroid function follow-up, even if first-trimester results were normal, as IMH identified in the second trimester carries substantially higher risks 3

Maternal and Fetal Risks of Untreated Hypothyroidism

While isolated hypothyroxinemia has timing-dependent significance, true hypothyroidism (elevated TSH) during pregnancy carries substantial risks:

• Untreated maternal hypothyroidism increases risk of preeclampsia, gestational hypertension, stillbirth, and premature delivery 2, 5
• Inadequate treatment is associated with low birth weight and potential cognitive impairment in offspring 2, 8
• Maternal hypothyroidism may have adverse effects on fetal neurocognitive development, particularly when present in the first and second trimesters 5, 1
• Children born to women with hypothyroidism during gestation had significantly lower scores in neuropsychological tests related to intelligence, attention, language, and school performance in multiple studies 1

Evidence Quality Considerations

The distinction between first and second-trimester IMH is based on a prospective cohort study of 3,398 women in an iodine-sufficient area, providing robust evidence for timing-dependent clinical significance 3. However, professional organizations lack consensus on universal screening, and some studies have not confirmed neurodevelopmental effects of mild maternal thyroid dysfunction 1. The evidence supporting treatment of isolated hypothyroxinemia is weaker than for overt or subclinical hypothyroidism, particularly for first-trimester IMH where treatment showed no benefit 3.