In a pregnant woman with normal thyroid‑stimulating hormone (TSH) and normal triiodothyronine (T3) but low free thyroxine (T4), what is the appropriate diagnosis and management?

Normal TSH with Low Free T4 in Pregnancy: Isolated Maternal Hypothyroxinemia

In a pregnant woman with normal TSH, normal T3, but low free T4, the diagnosis is isolated maternal hypothyroxinemia (IMH), and the appropriate management depends critically on the trimester of detection and the degree of T4 reduction.

Understanding the Physiological Context

During normal pregnancy, thyroid function undergoes significant changes 1:

• Free T4 levels naturally decline as pregnancy progresses, with slight elevation in early pregnancy followed by gradual decrease, reaching slightly depressed values in the third trimester while remaining within normal range 1
• TSH gradually increases during pregnancy, with second and third trimester values significantly higher than postpartum, though typically remaining within normal limits 1
• Total T4 and T3 increase steadily starting in the late first trimester due to elevated thyroid-binding globulin, reaching approximately 1.5 times postpartum values 1

These physiological changes mean that standard non-pregnant reference ranges may not apply, and pregnancy-specific reference ranges should be used when available 1.

Defining Isolated Maternal Hypothyroxinemia

IMH is characterized by low free T4 (typically below the 5th or 10th percentile for gestational age) with normal TSH and absence of thyroid autoantibodies 2, 3. This differs fundamentally from:

• Subclinical hypothyroidism (elevated TSH with normal free T4) 4
• Overt hypothyroidism (elevated TSH with low free T4) 4
• Gestational transient hyperthyroxinemia (suppressed TSH with elevated free T4) 5

Critical Distinction: First vs. Second Trimester Detection

First Trimester IMH

For IMH detected in the first trimester, current evidence does NOT support routine levothyroxine treatment 3:

• A prospective cohort study of 3,398 women found no association between first-trimester IMH and adverse pregnancy outcomes compared with controls 3
• Treatment with levothyroxine in first-trimester IMH did not improve pregnancy outcomes in women who chose to receive it 3
• A Brazilian prospective study of 596 women similarly found no association between first-trimester IMH and obstetric or neonatal outcomes 2

However, there is important historical and mechanistic concern about first-trimester hypothyroxinemia 6:

• The fetal brain depends entirely on maternal T4 during the first trimester before fetal thyroid function begins (17-19 weeks gestation) 6, 7
• T4 is the required substrate for ontogenically regulated T3 generation in developing brain structures 6
• Normal maternal T3 does not prevent potential damage from low T4 supply, and may mask hypothyroxinemia if only TSH is measured 6

Second Trimester IMH

IMH identified in the second trimester carries significantly increased risk and warrants closer attention 3:

• Significantly higher incidence of macrosomia (p = 0.022) and gestational hypertension (p = 0.018) compared with controls 3
• IMH in second trimester is an independent risk factor for macrosomia (adjusted OR 1.942,95% CI 1.076-3.503) and gestational hypertension (adjusted OR 4.203,95% CI 1.611-10.968) when maternal BMI <25 kg/m² 3

Recommended Management Algorithm

Step 1: Confirm the Diagnosis

• Verify that TSH is truly normal using pregnancy-specific reference ranges (ideally <2.5 mIU/L in first trimester) 8
• Confirm low free T4 using pregnancy-specific reference ranges or <5th-10th percentile for gestational age 2
• Exclude thyroid autoimmunity by measuring anti-TPO antibodies; if positive, this is NOT isolated hypothyroxinemia and requires different management 4, 2
• Assess for iron deficiency, as this is strongly associated with hypothyroxinemia (20.7% vs 8.4% in iron-replete women) 2

Step 2: Determine Trimester and Severity

First Trimester (Before 12-13 Weeks):

• If free T4 is only mildly reduced (between 5th-10th percentile) and TSH is normal:

  • Observation with repeat testing in 2-3 weeks is reasonable 5
  • Correct iron deficiency if present with supplementation 2
  • Recheck thyroid function at transition to second trimester (12-14 weeks) 3

• If free T4 is severely reduced (<5th percentile) despite normal TSH:

  • Consider levothyroxine treatment given the critical importance of maternal T4 for fetal brain development 6
  • Target free T4 in the upper half of the normal range 5
  • This represents a cautious approach despite lack of definitive trial evidence, prioritizing the irreversible nature of potential neurodevelopmental harm 6

Second Trimester (13-27 Weeks):

• IMH detected in second trimester warrants more aggressive management 3:
  • Consider levothyroxine treatment to normalize free T4, particularly if BMI <25 kg/m² 3
  • Monitor closely for gestational hypertension and fetal macrosomia 3
  • Recheck thyroid function every 4 weeks until normalized 8

Third Trimester (≥28 Weeks):

• Mild physiological reduction in free T4 is expected and may not require intervention if TSH remains normal 1
• Focus on monitoring for complications rather than aggressive normalization 1

Step 3: Exclude Other Causes

Before attributing low T4 to isolated hypothyroxinemia, exclude:

• Inadequate iodine intake – the most common cause of hypothyroxinemia in pregnancy worldwide 6
• Recent illness or hospitalization – can transiently suppress thyroid function 8
• Medications affecting thyroid function (lithium, amiodarone, interferon) 8
• Central hypothyroidism – though this would typically present with low-normal or low TSH, not normal TSH 8

Step 4: If Treatment Is Initiated

Levothyroxine dosing and monitoring:

• Start with low dose (25-50 mcg daily) 8
• Target free T4 in upper half of normal range and TSH <2.5 mIU/L in first trimester 8, 5
• Recheck thyroid function every 4 weeks until stable, then each trimester 8
• Adjust dose by 12.5-25 mcg increments based on results 8
• Take levothyroxine on empty stomach, 30-60 minutes before breakfast, separated from iron supplements by at least 4 hours 8

Critical Pitfalls to Avoid

• Do not use non-pregnant reference ranges for free T4 or TSH in pregnancy – this leads to misdiagnosis 1
• Do not assume normal T3 compensates for low T4 – T3 does not cross the placenta efficiently and cannot substitute for T4 in fetal brain development 6
• Do not screen only TSH in pregnancy – isolated hypothyroxinemia will be missed if free T4 is not measured 6
• Do not ignore iron deficiency – this is a major contributor to hypothyroxinemia and should be corrected regardless of levothyroxine decision 2
• Do not fail to recheck thyroid function in second trimester even if first trimester was normal – new-onset IMH in second trimester carries significant risk 3
• Do not confuse IMH with gestational transient hyperthyroxinemia (GTH) – GTH has suppressed TSH and elevated T4, requires no treatment, and resolves spontaneously 5

Special Considerations

The evidence base for treating first-trimester IMH is conflicting:

• Recent prospective studies show no benefit from treatment 2, 3
• Older mechanistic and epidemiological data suggest potential harm from untreated hypothyroxinemia 6
• The irreversible nature of neurodevelopmental damage argues for a cautious approach when T4 is severely reduced 6

This creates a clinical dilemma where:

• Mild first-trimester IMH (free T4 between 5th-10th percentile) can reasonably be observed with close monitoring 2, 3
• Severe first-trimester IMH (free T4 <5th percentile) may warrant treatment despite lack of trial evidence, given the critical window for fetal brain development and irreversibility of potential harm 6
• Second-trimester IMH has clearer evidence of adverse outcomes and stronger rationale for treatment 3

Iron deficiency is a modifiable risk factor present in a substantial proportion of women with hypothyroxinemia and should always be addressed 2.