How should thyroid‑stimulating hormone (TSH) be interpreted in each trimester of pregnancy and what are the recommended treatments for overt and subclinical hypo‑ and hyperthyroidism in pregnant women?

TSH Interpretation and Treatment in Pregnancy

Trimester-Specific TSH Reference Ranges

Use trimester-specific reference ranges for TSH interpretation in pregnancy, as standard non-pregnant ranges lead to misdiagnosis and inappropriate treatment decisions. 1, 2

First Trimester TSH Targets

• Target TSH < 2.5 mIU/L for women with known hypothyroidism or positive thyroid antibodies 1, 3, 2
• The reference range varies by gestational week: TSH remains near non-pregnant values until week 6, then decreases by approximately 0.4 mIU/L during weeks 7-12 4, 5
• Population-specific ranges show significant variation: Greek cohort 0.05-2.53 mIU/L 6, Bulgarian cohort 0.38-2.91 mIU/L 7, Chinese populations show upper limits much higher than 2.5 mIU/L 5
• Using a uniform 2.5 mIU/L cutoff throughout the entire first trimester leads to overdiagnosis and unnecessary treatment 4, 5

Second Trimester TSH Targets

• Reference ranges: Greek cohort 0.18-2.73 mIU/L 6, Bulgarian cohort 0.72-4.22 mIU/L 7
• TSH values are typically higher in the second trimester compared to the first trimester (median 1.29 vs 1.00 mIU/L) 8
• Individual women show high correlation between first and second trimester TSH values (r=0.75), meaning elevated TSH in one trimester predicts elevation in the next 8

Third Trimester TSH Targets

• Target range 0.3-3.5 mIU/L per ATA guidelines 4
• Continue monitoring and dose adjustment to maintain euthyroidism 2

---

Treatment of Overt Hypothyroidism in Pregnancy

Initiate levothyroxine immediately for any pregnant woman with elevated TSH and low free T4, as untreated overt hypothyroidism causes preeclampsia, low birth weight, placental abruption, fetal death, and permanent neurodevelopmental deficits in the child. 1, 2

For Women with Pre-existing Hypothyroidism

• Increase levothyroxine dose by 25-30% (approximately 25 µg for a patient on 75 µg) immediately upon pregnancy confirmation, without waiting for TSH results 2
• Fetal harm can occur before maternal symptoms appear, so empirical dose increase is mandatory 2
• Women adequately treated before conception or receiving early treatment do not experience increased perinatal morbidity 2

Initial Dosing for New Diagnosis

• Start levothyroxine at full replacement dose (approximately 1.6 mcg/kg/day) for TSH ≥10 mIU/L 3
• For pregnant women or those planning pregnancy, treat any TSH elevation immediately, targeting TSH <2.5 mIU/L in the first trimester 3, 2

Monitoring Protocol

• Check TSH and free T4 every 4 weeks until stable, then at minimum once per trimester 3
• Target TSH <2.5 mIU/L in first trimester, then within trimester-specific reference ranges 3, 2
• Adjust levothyroxine by 12.5-25 mcg increments based on TSH results 3
• Maintain free T4 in the high-normal range using the lowest possible medication dose 1, 2

Critical Timing Considerations

• First and second trimester euthyroidism is essential for normal fetal cognitive development, as the fetus relies entirely on maternal thyroid hormone during this period 2
• Hypothyroidism during the first trimester is specifically linked to cognitive impairment in offspring 2
• Iodine deficiency increases risk of congenital cretinism (mental retardation and neuropsychological defects); iodine therapy in first and second trimesters significantly reduces neurologic abnormalities 1

---

Treatment of Subclinical Hypothyroidism in Pregnancy

Treat subclinical hypothyroidism (elevated TSH with normal free T4) in pregnancy with levothyroxine, as it is associated with preeclampsia, low birth weight, and impaired neuropsychological development in offspring. 2

Treatment Indications

• Any TSH elevation above trimester-specific reference ranges warrants treatment in pregnancy 3, 2
• Pregnant women with positive TPO antibodies and any TSH elevation require treatment due to higher progression risk 3
• Women planning pregnancy with elevated TSH require treatment before conception, not during pregnancy 3

Dosing and Monitoring

• Start levothyroxine at appropriate dose based on TSH level and pregnancy status 3
• Target TSH <2.5 mIU/L in first trimester 3, 2
• Monitor TSH every 4 weeks until stable, then at minimum once per trimester 3
• Levothyroxine requirements typically increase by 25-50% during pregnancy in women with pre-existing hypothyroidism 3

Distinguishing from Isolated Hypothyroxinemia

• Measure TPO antibodies in pregnant women with isolated hypothyroxinemia (normal TSH, low free T4) to exclude autoimmune thyroid disease 2
• Positive TPO antibodies reclassify the condition as subclinical hypothyroidism, which warrants levothyroxine therapy 2
• Do not mistake isolated hypothyroxinemia for subclinical hypothyroidism; the latter (elevated TSH, normal free T4) requires levothyroxine treatment during pregnancy 2

---

Treatment of Hyperthyroidism in Pregnancy

Treat hyperthyroidism in pregnant women with a thioamide (propylthiouracil or methimazole), maintaining free T4 or FTI in the high-normal range using the lowest possible thioamide dosage. 1

Medication Selection

• Recent studies found no significant differences between propylthiouracil and methimazole in mean free T4 or TSH levels in newborn cord-blood samples 1
• Similar rates of fetal anomalies for both agents, with no cases of aplasia cutis reported 1
• Women treated with propylthiouracil or methimazole can breastfeed safely 1

Monitoring and Dose Adjustment

• Measure free T4 or FTI every 2-4 weeks to guide dose adjustment 1
• Until thioamide therapy reduces thyroid hormone levels, use a beta blocker (e.g., propranolol) to reduce symptoms 1
• Monitor women with Graves' disease for normal heart rate and appropriate growth 1

Management of Side Effects

• Agranulocytosis presents with sore throat and fever; if these symptoms develop, obtain a complete blood cell count immediately and discontinue the thioamide 1
• Other side effects include hepatitis, vasculitis, and thrombocytopenia 1
• Although suppression of fetal and neonatal thyroid function can occur with thioamide therapy, it is usually transient and treatment is rarely required 1

Special Considerations

• Thyroidectomy should be reserved for women who do not respond to thioamide therapy 1
• Radioactive iodine (I-131) is absolutely contraindicated in pregnant women 1
• If inadvertent I-131 exposure occurred before 10 weeks gestation, fetal thyroid is unlikely to have been ablated 1
• If exposure occurred after 10 weeks, the woman needs to consider the risk of induced congenital hypothyroidism and whether pregnancy should be continued 1
• Women should not breastfeed after I-131 exposure 1
• The newborn's physician must be aware that the mother has Graves' disease because of the associated risk of neonatal thyroid dysfunction 1

---

Common Pitfalls and Caveats

Diagnostic Pitfalls

• Do not use non-pregnant reference ranges for TSH interpretation in pregnancy—this leads to missed diagnoses and untreated hypothyroidism 1, 2, 7
• Recognize that TSH reference ranges vary significantly by population, ethnicity, iodine status, and geographic location 7, 6, 5
• TSH values show high within-person consistency between trimesters (r=0.75), so elevated first trimester TSH predicts second trimester elevation 8
• 74% of women with TSH above 98th centile in second trimester were already above 95th centile in first trimester 8

Treatment Pitfalls

• Never wait for TSH results before increasing levothyroxine in a pregnant woman with known hypothyroidism—fetal harm can occur before maternal symptoms appear 2
• Avoid TSH targets >2.5 mIU/L in the first trimester, as even subclinical hypothyroidism is associated with adverse pregnancy outcomes 2
• Inadequate treatment of hypothyroidism is associated with low birth weight and potential cognitive impairment in offspring 1, 2
• Using uniform TSH limits for the entire first trimester leads to frequent misclassification and unnecessary treatment 4

Monitoring Pitfalls

• Do not assume thyroid function remains stable throughout pregnancy—levothyroxine requirements increase by 25-50% in women with pre-existing hypothyroidism 3
• Failure to monitor thyroid function every trimester risks inadequate treatment during critical periods of fetal brain development 2
• TPO antibody status can change during pregnancy; serially monitor women with isolated hypothyroxinemia for seroconversion 2