the first trimester of pregnancy to reduce risks of miscarriage and impaired neurodevelopment in the offspring, thyroid disease should ideally be well controlled prior to conception with clear management plans in place for when pregnancy is first confirmed.
Hypothyroidism
A clinical practice guideline [1], based on clinical evidence and the consensus opinion of an international panel of Endocrinology experts, has recommended that in women with preexisting hypothyroidism, the TSH level should be kept below 2.5 mU/L before embarking on a pregnancy. When pregnant, levothyroxine doses should be increased by 4–6 weeks of gestation and by an increment of around 30% of the existing dose because thyroxine requirements are known to increase at the start of pregnancy in the vast majority of cases. Thyroid function should be checked 30–40 days after every dosage change. Results should be interpreted using trimester‐specific reference ranges where available, keeping the TSH within the lower half of the respective ranges. Otherwise TSH concentrations should be kept below 2.5 mU/L throughout pregnancy. (See Table 13.3)
Table 13.3 Recommendations for thyroid function monitoring in pregnancy in the absence of trimester‐specific reference ranges.
| TSH target (mU/L) | Thyroxine adjustments (average daily dose) | Thyroid function test monitoring | |
|---|---|---|---|
| Preconception First trimester Second and third trimesters Postpartum | Below 2.5 Below 2.5 Below 2.5 Nonpregnant range | Adjust by 25–50 μg at a time Increase thyroxine by 30–50% when pregnancy confirmed Adjust by 12.5–25 μg at a time Reduce thyroxine back to prepregnancy dose | 4–6 weeks after each dose change Every 4–6 weeks 4–6 weeks after dose changes. If stable, at least once in each trimester 6 weeks postpartum |
Another set of guidelines, issued by the British Thyroid Association and Association of Clinical Biochemists [8], recommend that at the diagnosis of pregnancy, thyroxine should be increased by 25 or 50 μg. When adjusting thyroxine treatment during pregnancy TSH should be kept towards the lower end of the normal range (ideally between 0.4 and 2.0 mU/L), and free T4 at the upper end of the normal range throughout pregnancy using trimester specific reference ranges. Thyroid function should ideally be tested preconception, at the diagnosis of pregnancy, at antenatal booking and monitored at least once in each trimester of pregnancy.
Just as in pregnancy, thyroxine requirements are also increased with controlled ovarian hyperstimulation during assisted reproduction. Thus, women already on thyroxine replacement should also have a dosage increase in the region of 20–30% at the start of such infertility treatment [17].
The woman in Case History 1 should increase her thyroxine dose by 25 μg at a time with thyroid function tests performed 4–6 weeks after each dose increment until the TSH concentration is below 2.5 mU/L, before commencing IVF treatment. At the start of ovarian stimulation, she should be advised to increase her dose of thyroxine by 25 μg daily. As soon as she has a positive pregnancy test, she should be advised to increase thyroxine by a further 25 μg on 2–3 days a week (approximately 30% of her prepregnancy dose). At the same time, she should also have her TSH and free T4 concentrations tested and if results suggest inadequate thyroid hormone replacement, a further dose increase of 25 μg on the remaining days of the week may be appropriate. The aim would be to anticipate increased dose requirements and prevent abnormalities in thyroid function test results during pregnancy. As there has been no evidence that subclinical or mild hyperthyroidism is associated with any adverse outcome [18] the balance of risk is in favor of thyroxine dose increases in maternal hypothyroidism. Dose change recommendations should be made promptly, and thyroid function checks made 4–6 weeks later on every occasion.
Hyperthyroidism
In Case History 2, TSH is very low suggesting the presence of TSH stimulating antibodies in the circulation even though carbimazole has successfully brought the free T4 and free T3 levels into the normal range. It is, therefore, unwise to stop treatment abruptly at this stage.
Given the risks of active Graves’ disease and antithyroid medication in pregnancy, the woman should be given the option of deferring ICSI treatment until the disease becomes quiescent again off‐treatment or is definitively treated. Carbimazole dosage could be gradually reduced then stopped under the careful monitoring of an endocrinologist. If the disease cannot be controlled with such conservative measures, a more definitive therapeutic approach with radioiodine thyroid ablation or a subtotal thyroidectomy could be considered.
If the woman chooses to proceed with ICSI while on antithyroid medication, her treatment should be converted from carbimazole to PTU (see Table 13.4 for conversion) in consultation with her endocrinologist.
Thyroid function tests should be performed 4–6 weeks after each dosage change. The aim preconceptually and during pregnancy is to maintain the free T4 level in the upper third of the normal range on as low a dose of antithyroid medication as possible to protect the fetus from hypothyroidism [11]. It is common to find that TSH concentrations remain low or fully suppressed and is thus not a good indicator of disease control.
Once thyroid function test results are stable on PTU, ICSI treatment may be commenced. During ovulation stimulation, PTU dosage may need to be reduced because of increased thyroxine requirements. Thyroid function should be checked during controlled ovarian stimulation (COS). Thyroid function should be checked again as soon as pregnancy is confirmed and at 2– to 4–weekly intervals thereafter [1,19]. Keeping the free T4 in the upper end of the normal range is particularly critical in the first trimester of pregnancy when even mild hypothyroidism should be avoided given the risks to the pregnancy and the fetus outlined in the previous section. It is not unusual for Graves’ disease to go into remission in the second half of pregnancy and PTU can often be tailed off or stopped altogether.
Table 13.4 The conversion of carbimazole to propylthiouracil (PTU) treatment in hyperthyroidism.
| Carbimazole (administered once a day) | Propylthiouracil (PTU; administered twice a day) |
| 10 mg o.d. | Total 100mg/day given 50mg b.d. |
| 30 mg o.d. | Total 300mg/day given 150mg b.d. |
| 60 mg o.d. | Total 600mg/day given 300mg b.d. |
In addition to regular assessments of maternal blood pressure and urine as screening tests for preeclampsia, fetal growth should be monitored with regular ultrasound scans during the third trimester.
The levels of TSH receptor antibodies should be quantified during pregnancy to help predict the risk of fetal thyrotoxicosis. Levels that are greater than 3 times the upper limit of normal confer a higher risk of fetal and neonatal thyrotoxicosis [20]. Regular fetal heart auscultation for persistent fetal tachycardia can be used to screen for fetal thyrotoxicosis at each antenatal visit from 16 weeks’ gestation onwards, around the time when the fetal thyroid gland is believed to begin releasing
