Preexisting Thyroid Disease in Pregnancy: A Brief Overview

Abstract

Maternal thyroid disease, with both an excess or deficiency of thyroid hormone, raises the risk profile of affected pregnancies with regards to preeclampsia, preterm birth, placental problems, thyroid derangement of the fetus and neonate, and neurodevelopment of exposed fetuses later in life. Fortunately, close and tight management of thyroid disease within the fluctuating physiologic milieu of pregnancy offers opportunities to significantly improve perinatal outcomes. However, despite guidelines offered by American College of Obstetrics and Gynecology (ACOG) and American Thyroid Association (ATA), controversy persists regarding interpretation of thyroid labs, screening for disease, surveillance, fetal and placental thyroid physiology, and optimal medication and management strategies. This is a brief overview of what is known and unknown regarding thyroid disease and its impact on maternal, fetal, and pregnancy health.

Introduction

Maternal baseline thyroid disease affects a significant portion of pregnancies annually. According to ACOG, hyperthyroidism affects 0.2–0.7% of all pregnancies, and hypothyroidism is seen in up to 10 of every 1,000 pregnancies.¹ Unfortunately, both hyper- and hypothyroidism increases the likelihood of perinatal complications such as preeclampsia, placental accidents, preterm birth, fetal thyroid, and neurodevelopment and metabolic growth of the fetus. Fortunately, proper surveillance and close management of preexisting thyroid disease can help mitigate this risk.

However, gestational thyroid surveillance is difficult due to normal physiologic alterations to thyroid synthesis with pregnancy. Even among the euthyroid, pregnancy elicits significant physiologic changes involving thyroid regulation to accommodate the needs of both the mother and the fetus; as a result, interpretation of thyroid labs and subsequent management can prove to be challenging. Generally, changes in maternal physiology lead to a compensatory increase in maternal thyroid hormone synthesis to guarantee appropriate maternal and fetal thyroid hormone availability.^2,3

Pregnancy-Induced Alterations to Thyroid Function

Normal changes during the first trimester prompts a transient suppression of TSH and stimulation of thyroxine-binding globulin (TBG) and total T3 and T4 levels. A rise in estrogen in early pregnancy stimulates a two-fold increase in sialyation and glycosylation of TBG in the liver, making it less susceptible to degradation, increasing its circulating concentration. As TBG binds the majority of circulating thyroid hormones, this rise in TBG stimulates a greater demand for total levels of T4 and T3 while free T3 and T4 levels remain unaffected.³

Concurrently, human chorionic gonadotropin (hCG) acts as a weak agonist of the TSH receptor, simultaneously stimulating the thyroid to secrete more T3 and T4 while inducing a partial TSH suppression. During the second trimester and third trimester, when hCG levels have decreased and its suppressive effect on TSH has diminished, there is normalization of TSH in the second trimester with a slight increase in the third. Free T3 and free T4 levels are slightly lower in later gestation due to an increase in thyroid hormone breakdown by placental type 3 deiodinase and urinary iodide clearance after the first trimester.¹ Total T4 and TBG values rise and plateau in the second trimester, thereafter, sustaining a high level for the duration of the third trimester.²

With these normal fluctuations in the thyroid metabolic pathway, target laboratory values that screen and assess thyroid function in pregnancy can be difficult to interpret. TSH and free T4 measurements during pregnancy are utilized in terms of both diagnosis and surveillance of thyroid disease during pregnancy. Previously, the recommended TSH upper-limit cut-offs were 2.5–3.0 mU/l;⁴ however more recently, the literature recognizes racial, ethnic, and population-level variation with both the upper and lower limits of a normal TSH range, which makes the previously recommended blanket cutoff appear arbitrary, more questionable and potentially less relevant.⁵

More than 90% of studies published since 2005 have shown population-based reference ranges for a TSH upper-limit well-above the previously established 3.0 mU/l;⁴ though all studies demonstrated significant depression of the lower threshold for TSH ranges. Some of this population-specific variation is attributed to inconsistent rates of iodine deficiency, nutrition, other environmental exposures, and prevalence of genetic disposition and obesity.⁵ In order to address these findings, the ATA revised recommendations in 2017, suggesting laboratory reference ranges for TSH and thyroid hormones should focus on values relevant to specific populations, prompting clinicians to seek local laboratory values.⁴ If data regarding a specific practice location or similar patient population is not available, both ACOG and the ATA recommends the following adjustments: 1) subtracting 0.5 mU/I from the lower threshold for nonpregnant range for TSH; 2) subtracting 0.5mU/I from the upper threshold for nonpregnant TSH range; and 3) upper range of T3 and T4 increased by 50% after 16 weeks gestation. Regarding the upper range of TSH, the target range with the subtraction of 0.5 mU/l is equivalent to around 4 mU/l for most centers and above original recommendations of 2.5 mU/l or 3.0 mU/l.^1,4

Fetal Thyroid

Monitoring maternal thyroid values in the setting of both hyper- and hypothyroidism is critical in ensuring proper fetal development and optimizing for overall pregnancy health. This is due to the reliance of the fetus on maternally-derived thyroid hormones and iodine to facilitate thyroid gland maturation and general physiologic development. The fetal thyroid is utilizing maternal iodine to secrete T4 as early as 10–12 weeks gestation.² By 18–20 weeks gestation, the fetal pituitary stimulates and modulates fetal thyroid hormone secretion. Even then, the fetus is still reliant on maternal thyroid hormone and iodine. Even at birth, 30% of the T4 found in cord blood is maternally derived.¹ For this reason, clinicians adjust medication to achieve a free T4 level that is high-normal to ensure adequate levels to maintain fetal health and development; however emerging data suggests that this cutoff may lead to overtreatment.⁶ That said, why maternal thyroid is still so heavily concentrated even in late gestation, when the fetal thyroid is more mature, is incompletely understood.^7,8

The placenta plays a role in modulating maternal contribution of thyroid support and promoting fetal thyroid function as well. Placenta and fetal pancreas are a significant source of thyroid releasing hormone (TRH).⁹ TRH from these sources with relation to the maturing fetal hypothalamic pituitary axis is poorly understood, though some suspect it plays a role in prematurity and fetal lung maturation.¹⁰

Maternal thyroid disease, Rith Noth an excess or deficiency of thyroid hormone, raises the risk profile of affected pregnancies with regards to preeclampsia, preterm birth, placental problems, thyroid derangement of the fetus and neonate, and neurodevelopment of exposed fetuses later in life.

Hyperthyroidism

The vast majority of cases of hyperthyroidism is due to Grave’s disease (90%) with immunoglobulins that stimulate thyroid hormone production, resulting in elevated thyroid hormone levels and severe depression of TSH levels. Though the placenta regulates and diminishes the amount of maternal thyroid hormone that can cross into the fetal circulation, excessive hormone levels are known to override this regulatory mechanism with a detrimental effect on the fetus, elevating the risk of miscarriage and stillbirth. For this reason, treatment with antithyroid medications/thioamides is critical in decreasing this risk. Also, close ultrasound surveillance of the fetus throughout the pregnancy, monitoring both fetal well-being, fetal heart and growth is critical. Symptoms seen with hyperthyroidism overlaps with common complaints seen with pregnancy or preeclampsia: nausea, vomiting, tachycardia, hypertension, heat intolerance, sweating. There is also concern about weight loss and appropriate maternal weight gain during the pregnancy.

Maternal hyperthyroidism is associated with an elevated risk of preeclampsia, preterm birth, fetal thyroid abnormalities (both hyper- and hypothyroidism), fetal growth restriction, and fetal goiter. As it is an autoimmune disease, there is an elevated risk of gestational diabetes as well. The US Preventative Taskforce recommends aspirin as an effective prophylaxis against preeclampsia for high-risk mothers at a nightly dose of 81–150mg. Additionally, aspirin has been shown to decrease the risk and diminish the severity of preeclampsia, reduce perinatal mortality and growth restriction, and lower the risk of preterm birth.¹¹

Preterm birth and preeclampsia are a source of concern among affected pregnancies, but the direct effect of maternal antibodies on the fetal thyroid gland can pose a greater threat. The antibodies produced with Grave’s disease can cross the placenta and cause hyper- or hypothyroidism in the fetus, prompting fetal hyperthyroidism (1–5% of affected pregnancies) and fetal thyrotoxicosis in rare cases (1% of affected pregnancies).⁷ Fetal thyrotoxicosis presents as elevated heart rate, growth restriction, hydrops from heart failure, and fetal goiter. Usually, a good indication of whether a fetus is at risk is the thyroid receptor antibody (TrAB) (this is used interchangeably with thyroid stimulating immunoglobulin or TSI) measurement early in gestation. If it is two to three times more than normal, a fetus is deemed high-risk, warranting close ultrasound surveillance for signs of thyroid disease.⁴

Fetal thyrotoxicosis is very rare because the normal immunologic changes of pregnancy suppress maternal antibody levels with increasing gestation. However, in the third trimester, there is greater permeability of the placenta to maternal antibodies in the fetal circulation; this is when the fetus is at the highest risk. Furthermore, formerly hyperthyroid mothers who have since been ablated still have antibodies that can affect the fetus; in such cases TrAB/TSI measurements are still useful in screening the risk for fetal thyroid disease. Treatment is maternal oral medication; in especially difficult cases, umbilical blood sampling may be necessary to test cord blood thyroid levels and administer IV medication.⁷

For treatment, either methimazole or propylthiouracil is typically used; however, both medications pose specific, potential risks to the pregnancy. Methimazole is infamously associated with certain congenital anomalies if used in the first trimester, specifically aplasia cutis as well as esophageal and choanal atresia; a study on 5,700 pregnancies found methimazole exposure in the first trimester increases the risk of congenital malformations twofold.¹² On the other hand, propylthiouracil (PTU) is associated with liver toxicity. Some guidelines recommend PTU in the first trimester with transition to methimazole in the second and third trimester to balance their risk-benefit profiles. Given the rarity of the risks described, many clinicians opt to maintain patients on their pre-pregnancy regimens, as consistent thyroid control is imperative in maintaining pregnancy health. In transitioning from one drug to another between the first and second trimester, there may be some difficulty in achieving immediate maternal thyroid control at a critical time of fetal thyroid development.

Regardless of the thioamide chosen, there is a risk of leukopenia which affects 10% of patients when starting the medication, which does not necessitate cessation; however, in the very rare chance (1%) that agranulocytosis develops, medication should be stopped.¹ Both medications do cross the placenta so the lowest dose to achieve control is recommended. That said after birth, the medication effect clears quickly. With fetal thyroid affected by maternal antibodies, the effect lasts significantly longer as maternal antibodies persist in the fetal circulation for some time after birth, necessitating surveillance and treatment.

If maternal tachycardia and palpitations are present, as is common with Grave’s disease, beta blockers (usually propranolol) are utilized; that said, some level of tachycardia is normal with pregnancy, if it is below 120 bpm. Good control is also imperative to ward off the risk of thyroid storm, which presents in 1–2% of hyperthyroid pregnancies.¹

Hypothyroidism

Hypothyroidism with pregnancy is typically seen with Hashimoto’s thyroiditis. On laboratory assessment, the TSH is elevated while free T4 is decreased, but as mentioned before, given the dependence of fetal physiology on maternal thyroid support, current clinical guidelines recommend that free T4 levels should be maintained on the higher end of normal; according to the ATA, there is also consideration using total T4 in lieu of free T4 levels, with thresholds corrected for rises in thyroid-binding globulin.⁴ Typically, affected mothers present with fatigue, cold intolerance, and weight gain. While the risk profile is similar to hyperthyroidism (increased likelihood of preterm birth, preeclampsia, placental accidents, stillbirth, and miscarriage), adequate control with medication greatly diminishes the risk. Fortunately, unlike Grave’s disease, thyroid inhibitory antibodies do not cross the placenta in most cases at a level that can cause significant thyroid impairment in the fetus; as a result, the prevalence of fetal hypothyroidism in the offspring of women with Hashimoto thyroiditis is estimated to be only about 1 in 180,000 neonates.¹²

In certain areas of the world, maternal iodine deficiency, as opposed to autoimmune antibody exposure, is more likely to result in insufficient maternal and fetal thyroid synthesis. The developing fetal thyroid is highly dependent on maternal iodine that crosses the placenta for adequate thyroid hormone synthesis and metabolic support; inadequate iodine stores can lead to overstimulated TSH levels, fetal hypothyroidism, and eventually fetal goiter. In the United States, maternal iodine deficiency is believed to be uncommon; that said, iodine supplementation is inconsistent within food sources (even fortified ones such salt and bread) and even prenatal vitamin formulations. A recent NHANES assessment of urinary iodide concentration (UIC) found that the mean value was less than the suggested values by the World Health Organization that are representative of adequate iodide stores.¹³ Furthermore, maternal iodine stores are increasingly depleted over gestation and especially utilized in the postpartum period as iodine concentrates in breastmilk; adequate repletion is necessary especially during lactation. During pregnancy and lactation, respectively 220 μg and 290 μg of iodine are necessary to support the health of fetus and infant properly. Unfortunately, the prevalence of iodine deficiency among lactating mothers in the Unites States is not well characterized.⁴

Currently, with hypothyroidism, the risk of miscarriage is significant with poorly controlled hypothyroidism. Various studies estimate the risk of miscarriage is three- to four-fold higher with uncontrolled Hashimoto’s thyroiditis.¹⁴ For example, a study on 2,500 Dutch women found a linear correlation between TSH levels at initial obstetric visits and miscarriage.¹⁵

That said, proper management with medication appears to help. Levothyroxine remains the gold-standard in the treatment of pregnant patients with hypothyroidism worldwide. Adequate management with levothyroxine has been shown to decrease the risk of miscarriage and preterm births significantly among mothers with Hashimoto thyroiditis.¹⁶ Finally, unlike thioamides, levothyroxine does not cross the placenta and only in small quantities, not unlike maternal thyroid hormones in general.

Children of hypothyroid mothers also have an elevated risk of developmental problems later in life and potentially certain types of cancer. In 2015, a National Finnish Birth Cohort evaluation of 9,362 women and 9,479 children found that maternal hypothyroidism correlates with impaired neuropsychological development and scholastic performance later in life.¹⁷ In utero-exposure to autoimmune thyroid disease has also been reported to increase the risk of childhood acute lymphoblastic leukemia (ALL) in the offspring. A population-based case-control study in Finland of approximately 11,000 patients found the increased risk of lymphomas to be 3.66-fold when comparing mothers with hypothyroidism and those with normal thyroid function. It is unknown whether current goals for management affect outcomes regarding childhood ALL or neuropsychologic outcomes later in life.¹⁸

Areas of Controversy

In the management and screening of thyroid disease in pregnancy, there are few areas where the ATA recommendations differ from what ACOG suggests in clinical guidelines. For example, the ATA suggests mothers with thyroid disease have labs checked every four weeks, while ACOG recommends every four to six weeks.

There is even greater disagreement on euthyroid women who have laboratory evidence of thyroid autoimmunity with a positive thyroid peroxidase antibody or thyroglobulin antibody. Euthyroid women with thyroid autoimmunity can present with subclinical disease, but the clinical relevance of this finding is debatable, especially if a viable pregnancy is already achieved. Various studies have inconsistently demonstrated an elevated risk of miscarriage, stillbirth.^19,20 That said, the TABLET trial performed in the United Kingdom found treatment of euthyroid mothers with thyroid autoimmunity with levothyroxine did not alter the rate livebirths in this cohort.²¹

As seen in hypothyroidism, there is concern that subclinical hypothyroidism can affect later developmental progress of exposed children. A cohort study in the Chinese population published in 2010 studied pregnant women with isolated subclinical hypothyroidism, hypothyroxinemia, or euthyroid labs with elevated titers of anti-TPO antibodies and subsequent neuropsychological development in their offspring. Standardized intellectual and motor evaluation performed at 25–30 months of age confirmed that all three maternal thyroid abnormalities tested at 16–20 weeks’ gestation were separately associated with a statistically significant lower motor and intellectual development.²² Given the potential impact of subclinical autoimmune thyroid disease on pregnancy and offspring, there continues to be debate about the utility of treatment in preventing these outcomes.

The ATA recommends checking TSH of euthyroid women with thyroid autoimmunity at the start of pregnancy and every four weeks. However, ACOG does not address this recommendation specifically but mentions that empiric treatment of this patient population does not affect pregnancy loss or neurocognitive outcomes of children later in life at ages three and five based on the Controlled Antenatal Thyroid Screening Trial in 2012 and the Maternal Fetal Medicine Units Network Trial in 2017.^23,24 Furthermore, the practice bulletin mentions that the likelihood of overt thyroid disease presenting during pregnancy among euthyroid women with thyroid autoimmunity and subclinical hypothyroidism is low. Checking for thyroid autoimmunity is not commonly done in our practice after pregnancy has been achieved but may be considered in the setting of recurrent early pregnancy loss and infertility.

Conclusion

Thyroid management in pregnancy has many well-established guidelines to improve perinatal outcomes, but clinical protocols are coming under scrutiny as certain set laboratory thresholds and subsequent interventions are of questionable relevance and long-term utility. In the coming years, increasing efforts to create community-based standards for management and a more personalized approach to thyroid disease during pregnancy may help optimize care in the future.