The risks of untreated overt hypothyroidism in pregnancy are well documented (Table 13.1). Several studies have now also associated subclinical hypothyroidism during the first half of pregnancy with an increased risk of miscarriage [5], preterm delivery [5,6], and neuropsychological deficiencies in the offspring [7]. Maternal thyroid hormones are believed to be crucial for the normal development of the placenta and the fetus, particularly the central nervous system, especially in the first trimester of pregnancy prior to the onset of fetal thyroid hormone production in mid‐trimester [8]. There is good evidence that adequate treatment of overt hypothyroidism and the rapid normalization of thyroid function during pregnancy is associated with good obstetric outcomes [3,5]. However, two large clinical trials that assessed if the screening for and treatment of subclinical hypothyroidism from the first and early second trimesters have shown no treatment benefit in relation to offspring neurodevelopmental outcomes [9,10]. The secondary outcomes of pregnancy complications also showed no significant differences between treatment arms. Some have argued that this is because treatment was commenced too late in pregnancy. The issue of whether to treat subclinical hypothyroidism, if found preconception, remains controversial. In cases of ART, a meta‐analysis of studies suggested that levothyroxine treatment to achieve a TSH less than 2.5 mU/L prior to conception could improve live birth rates [11]. On the other hand, in cases of euthyroidism, simply having TPO antibodies does not warrant levothyroxine treatment preconception or during pregnancy as this does not change pregnancy outcome [12].
Table 13.1 Obstetric complications associated with untreated overt maternal hypothyroidism [21].
| Miscarriage (first and second trimesters) Pregnancy‐induced hypertension Preeclampsia Anemia Postpartum hemorrhage | Preterm birth Low birthweight Stillbirth Perinatal death |
Hyperthyroidism
Over 90% of hyperthyroidism in pregnancy is secondary to Graves’ disease. In this condition, TSH receptor antibodies stimulate the thyroid gland resulting in elevated free T4 and free T3 concentrations in the circulation, which suppress TSH production by the pituitary gland. Uncontrolled maternal thyrotoxicosis is associated with many complications in pregnancy (Table 13.2). The transplacental passage of TSH receptor antibodies may cause fetal or neonatal hyperthyroidism in less than 1% of cases while anti‐thyroid drugs can induce fetal hypothyroidism.
There has been an unproven causal link between carbimazole (CBZ) or methimazole (MMI) and the rare benign scalp condition of aplasia cutis, esophageal atresia, choanal atresia and dysmorphic facial features in the fetus [13]. Associations of CBZ/MMI with other congenital anomalies involving the musculoskeletal, urinary, cardiovascular and respiratory systems have also been described [14]. Similarly, propylthiouracil (PTU) has also been associated with mainly head/neck and urinary anomalies, with overall a slightly lower teratogenic risk than CBZ/MMI. Compared with the unexposed, offspring exposed to either drug had around 1.5 times the risk of having a congenital anomaly [14]. Both drugs show no significant differences in their potential to induce fetal hypothyroidism [15]. The evaluation of children exposed to either drug also showed no difference in neurodevelopmental assessments compared to unexposed siblings [16]. Hence PTU is currently favored over carbimazole/MMI in women planning a pregnancy. Because PTU is associated with the rare side effect of severe liver impairment (1:10,000), some have advocated converting treatment back to carbimazole in the second and third trimesters.
Table 13.2 Complications associated with uncontrolled maternal thyrotoxicosis [22]
| Thyroid storm (first and second trimesters) Maternal congestive cardiac failure Preeclmpsia Placental abruption Preterm delivery | Miscarriage Fetal growth restriction Fetal thyrotoxicosis Fetal hypothyroidism Stillbirth Perinatal death |
Management options
Adequate treatment and control of both hypothyroid and hyperthyroid disease in pregnancy is associated with good obstetric outcome. Because the optimization of thyroid hormone status is critical, particularly in 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