What are the changes in thyroxine (T4) and thyroid‑stimulating hormone (TSH) levels during pregnancy, and how should levothyroxine therapy be screened, dosed, and monitored in pregnant women?

Thyroxine Levels and Management During Pregnancy

Physiological Changes in Thyroid Function During Pregnancy

Pregnancy induces profound alterations in thyroid physiology that necessitate increased levothyroxine requirements in women with pre-existing hypothyroidism. 1

Key Physiological Adaptations

• Thyroxine requirements increase by 25-50% during pregnancy, with the median onset of increase occurring as early as the fifth week of gestation 1
• The increased levothyroxine dose plateaus by approximately week 16 of gestation and remains elevated until delivery 1
• TSH reference intervals shift during pregnancy: 0.1-2.5 mIU/L for the first trimester and 0.2-3.0 mIU/L for the second trimester 2
• Pregnancy increases thyroxine-binding globulin (TBG) concentrations, which affects total T4 measurements but should not affect properly calibrated free T4 assays 3

Pharmacokinetic Changes

• The area under the curve for levothyroxine is 23.0 ngh/mL in pregnancy compared to 14.8 ngh/mL in nonpregnant women 4
• Median serum half-life extends to 32.1 hours during pregnancy versus 24.1 hours in the nonpregnant state 4

---

Screening and Diagnosis During Pregnancy

Screening should be targeted to pregnant women with symptoms of thyroid disease, a history of thyroid disease, or presence of thyroid nodules or goiter. 5

Who Should Be Screened

• Women with symptoms of thyroid disease (fatigue, weight changes, temperature intolerance) 5
• Women with a personal history of thyroid disease or thyroid nodules 5
• Women with goiter on physical examination 5
• Universal screening for hypothyroidism in all pregnant women is not currently recommended by ACOG, as further evidence is needed to document treatment efficacy 5

Diagnostic Testing Approach

• Measure TSH as the primary screening test, with sensitivity above 98% and specificity greater than 92% 6
• If TSH is abnormal, measure free T4 to distinguish between subclinical hypothyroidism (normal free T4) and overt hypothyroidism (low free T4) 6
• Consider measuring anti-TPO antibodies to identify autoimmune etiology, which predicts higher progression risk (4.3% per year vs 2.6% in antibody-negative individuals) 6

---

Levothyroxine Dosing in Pregnancy

Women with pre-existing hypothyroidism should increase their levothyroxine dose by approximately 30% as soon as pregnancy is confirmed. 1

Initial Dose Adjustment

• Increase levothyroxine immediately upon pregnancy confirmation rather than waiting for TSH elevation, as increased requirements begin as early as the fifth week of gestation 1
• The mean levothyroxine dose needed during pregnancy is approximately 150 mcg/day, though individual requirements vary widely 7
• Up to 75% of women with treated hypothyroidism require higher doses during pregnancy to maintain normal TSH levels 7

Dosing for New-Onset Hypothyroidism in Pregnancy

• For patients <70 years without cardiac disease, start with full replacement dose of approximately 1.6 mcg/kg/day 6
• For patients >70 years or with cardiac disease, start with 25-50 mcg/day and titrate gradually 6
• Target TSH <2.5 mIU/L in the first trimester to minimize risks to fetal neurodevelopment 6

Critical Timing Considerations

• Levothyroxine requirements increase as early as 4-8 weeks of gestation, though increases can occur as late as the third trimester 7
• The increased dose requirement plateaus by week 16 and persists throughout gestation 1
• Postpartum, immediately return to the pre-pregnancy levothyroxine dose after delivery, as TSH levels return to preconception values 8

---

Monitoring Protocol During Pregnancy

Monitor TSH levels once each trimester after the dosage is stabilized, with more frequent monitoring during dose titration. 7

Monitoring Schedule

• Check TSH approximately every 2-4 weeks during the first trimester while adjusting doses 9
• Once stabilized, assess TSH once each trimester throughout pregnancy 7
• After dose adjustment, recheck TSH and free T4 in 6-8 weeks to evaluate response 6
• Postpartum reassessment should be done at 6-12 weeks after returning to pre-pregnancy dose 7

Target Ranges

• Maintain TSH within trimester-specific reference ranges: 0.1-2.5 mIU/L (first trimester), 0.2-3.0 mIU/L (second trimester) 2
• Aim for TSH <2.5 mIU/L in the first trimester for optimal fetal outcomes 6
• Maintain free T4 in the normal reference range throughout pregnancy 9

Dose Adjustment Strategy

• Increase levothyroxine by 12.5-25 mcg increments based on TSH results 6
• The increment needed can be estimated from the serum TSH concentration during pregnancy 7
• If TSH remains elevated despite dose increases, confirm medication adherence and timing of administration 6

---

Risks of Untreated or Inadequately Treated Hypothyroidism

Untreated maternal hypothyroidism is associated with serious adverse outcomes for both mother and fetus, including impaired fetal cognitive development and increased mortality. 8, 1

Maternal Risks

• Spontaneous abortion 8
• Gestational hypertension and pre-eclampsia 8
• Stillbirth and premature delivery 8
• Low milk supply in hypothyroid lactating mothers 8

Fetal and Neonatal Risks

• Impaired neurocognitive development and permanent cognitive deficits in offspring 8
• Low birth weight 6
• Increased fetal mortality 1
• Potential adverse effects on overall physical growth and maturation 8

---

Special Considerations and Common Pitfalls

Medication Administration

• Take levothyroxine on an empty stomach, 30-60 minutes before breakfast, for optimal absorption 6
• Administer at least 4 hours apart from iron, calcium supplements, or antacids 8
• Avoid soybean flour, cottonseed meal, walnuts, and dietary fiber, which may decrease absorption 8
• Grapefruit juice may delay absorption and reduce bioavailability 8

Critical Safety Considerations

• Never discontinue levothyroxine during pregnancy, even if TSH normalizes, as requirements remain elevated throughout gestation 8
• Before initiating or increasing levothyroxine, rule out concurrent adrenal insufficiency, as thyroid hormone can precipitate adrenal crisis 6
• In suspected central hypothyroidism, always start corticosteroids before levothyroxine 6

Common Pitfalls to Avoid

• Waiting for TSH elevation before increasing the dose in women with known hypothyroidism—increase immediately upon pregnancy confirmation 1
• Using non-pregnancy-specific TSH reference ranges, which leads to underdiagnosis and undertreatment 2
• Failing to return to pre-pregnancy dose postpartum, risking iatrogenic hyperthyroidism 8
• Measuring total T4 instead of free T4, as TBG elevation in pregnancy widens the effective T4 range and reduces diagnostic discrimination 3
• Adjusting doses too frequently before reaching steady state—wait 6-8 weeks between adjustments 6

Breastfeeding Considerations

• Levothyroxine is present in human milk but no adverse effects on breastfed infants have been reported 8
• Adequate levothyroxine treatment during lactation may normalize milk production in hypothyroid mothers with low milk supply 8
• Continue appropriate levothyroxine dosing throughout lactation 8