IX. Thyroid nodules and thyroid cancer
Q53: What is the prevalence of thyroid nodules during pregnancy?
There are 3 studies that evaluated the prevalence of thyroid nodules in pregnant women and the effect of pregnancy on nodule size. All three studies were conducted in areas of mild to moderate iodine deficiency (Belgium, China, Germany). The prevalence of thyroid nodules varied between 3 and 21% and increased with the number of pregnancies.
Question 54: What is the prevalence of thyroid cancer in pregnancy?
A study from pregnant women in China (n=212) found a prevalence of thyroid nodules of 15.3% (34/212) and a prevalence of thyroid cancer of 0. The California Cancer Center, USA, retrospectively analyzed all maternal deaths from 1991 to 1999 locally (n=4,846,505). The incidence of thyroid cancer in pregnant women was 14.4 per 100,000, with papillary thyroid cancer being the most common type of pathology. The rates of thyroid cancer diagnosed at different times were: 3.3/100,000 before delivery, 0.3/100,000 at delivery and 10.8/100,000 one year after delivery.
Question 55: What is the impact of pregnancy on the prognosis of thyroid cancer?
Seven studies compared the prognosis of women diagnosed with differentiated thyroid cancer during pregnancy, one year postpartum, and at other times, and six of these studies found no differences in prognosis. However, a 2010 report showed that patients with differentiated thyroid cancer diagnosed during pregnancy or one year postpartum had a poorer prognosis. Estrogen receptor alpha was expressed in these thyroid cancers, suggesting that poor prognosis may be estrogen-related. It is important to note that none of the above studies were RCT studies and all were retrospective, so the significance of evidence-based medicine is limited.
Question 56: What is the risk of surgery for thyroid cancer in pregnancy?
Nine studies between 1986 and 2008 evaluated the negative effects of thyroid cancer resection in 113 pregnant women. Most of these procedures were performed in the fourth to sixth trimester of pregnancy. No maternal or fetal complications were reported in any of these studies. Thyroid surgery during pregnancy should be performed in the 4th to 6th month of gestation to reduce the incidence of maternal and fetal complications. This is because surgical anesthesia in the first trimester affects fetal organogenesis and causes spontaneous abortion; surgery in the 7th to 9th trimester predisposes to preterm delivery.
Question 57: What is the management of differentiated thyroid cancer in pregnancy?
The recently published ATA guidelines recommend that patients with cytologically confirmed papillary thyroid cancer detected early in pregnancy should be monitored with ultrasound; if the tumor increases significantly in size (50% increase in volume and 20% increase in diameter) during the first 24 weeks of pregnancy, surgery should be performed immediately. However, if the tumor remains stable until mid-pregnancy, or if it is diagnosed in the middle or end of pregnancy, surgery should be performed after delivery. Surgery in the fourth to sixth trimester is also feasible when the patient has other serious co-morbidities. Thyroid hormone suppression therapy should be considered for differentiated thyroid cancer diagnosed by FNA if surgery is postponed to the postpartum period [120].
Recommendation 9-1: Fine needle aspiration (FNA) of the thyroid may be performed during pregnancy. If a benign thyroid nodule is considered likely, it can be postponed until after delivery. (Recommendation level A)
Recommendation 9-2: Thyroid nuclear scan and 131 iodine therapy are contraindicated during pregnancy. (Recommendation level A)
Recommendation 9-3: Because the prognosis of differentiated thyroid cancer (DTC) in pregnancy is similar to that of non-pregnant patients, surgery for DTC in pregnancy can be postponed to the postpartum period. (Recommendation level B)
Recommendation 9-4: For DTC with withholding surgery, review thyroid ultrasound every 3 months to detect the rate of tumor growth. Give L-T4 suppressive therapy with the treatment goal of controlling serum TSH at 0.1~1.5mIU/L. (Recommendation level E)
Recommendation 9-5: If the DTC tumor continues to increase in size during the first half of pregnancy, or if lymph node metastasis occurs, surgical treatment is recommended. (Recommendation level B)
Recommendation 9-6: The timing of surgery for DTC should be chosen in the late T2 stage. The risk to mother and fetus is reduced at this time. (Recommendation level B)
Question 58: What is the management of thyroid nodules of suspected malignancy in pregnancy?
No prospective studies have been reported in this area. The prognosis of suspected malignant thyroid nodules found during pregnancy can be deferred until postpartum for surgical treatment with no adverse effect on their prognosis. Unlike differentiated thyroid cancer, L-T4 suppressive therapy is not recommended for pregnant women with suspected malignant thyroid nodules.
Recommendation 9-7: FNA diagnosis of suspicious thyroid malignancy without rapid tumor growth or lymph node metastasis does not require the administration of L-T4 therapy. (Recommendation level B)
Question 59: What is the management of benign thyroid nodules in pregnancy?
Pregnancy is known to be a risk factor for thyroid nodule progression, but there is no evidence that L-T4 prevents thyroid nodule growth. Therefore, L-T4 supplementation is not recommended for the treatment of thyroid nodules during pregnancy, but surgery may be considered for nodules that have been confirmed as benign by FNA but are growing rapidly or are suspicious for malignant lesions on ultrasound. Surgical treatment is not required in cases of nodules that do not grow significantly during pregnancy, when the nodule pathology is benign or when there is uncertainty about the benignity or malignancy of the nodule. Surgery should be considered in cases where benign nodules are compressing the trachea or esophagus.
Question 60: What is the goal of TSH control during pregnancy in patients with thyroid cancer who have already undergone surgery? How to give L-T4 therapy?
According to ATA and ETA guidelines on DTC, serum TSH should be kept below 0.1 mIU/L in patients with incomplete control of thyroid cancer, and should be suppressed to 0.1-0.5 mIU/L in patients with controlled but still high-risk thyroid cancer. In patients with controlled thyroid cancer and low-risk thyroid cancer, TSH should be kept in the low normal range (0.3 to 1.5 mIU/L).
In patients with surgically treated thyroid cancer, the main difficulty after pregnancy is to maintain the pre-pregnancy suppression levels and prevent the development of hypothyroidism. For most patients with surgically treated thyroid cancer, the L-T4 dose is gradually increased by 9% during the first trimester, 21% during the fourth to sixth months of pregnancy, and 26% during the seventh to ninth months of pregnancy, and thyroid function should be tested as soon as pregnancy is confirmed. Thyroid function should be tested every 4 weeks and the dose of L-T4 should be adjusted. The above tests should be measured in the same laboratory to ensure the accuracy and comparability of the results.
Recommendation 9-8: Maintain established TSH suppression goals in patients with DTC after pregnancy. Monitor serum TSH regularly, every 4 weeks, until 20 weeks of gestation. (Recommendation level B)
Question 61: What is the impact of having received radioactive iodine for thyroid cancer on subsequent pregnancies?
No side effects of radioiodine nail ablation treatment have been found to cause infertility, miscarriage, stillbirth, neonatal death, congenital malformations, preterm birth, low birth weight, or neonatal death [122,123]. The increased risk of miscarriage in patients receiving radioactive iodine nail ablation may stem from a decrease in thyroid hormones. Therefore, L-T4 replacement therapy should be given after 131 iodine nail elimination therapy to maintain a stable thyroid hormone status for at least 6 months before pregnancy.
Recommendation 9-9: Radioiodine therapy before pregnancy in patients with DTC is not dangerous for pregnancy outcome or offspring. The timing of pregnancy should be chosen after 6 months of radioiodine therapy, when the L-T4 replacement dose has stabilized. (Recommendation level B)
Question 62: Does pregnancy increase the risk of recurrence of differentiated thyroid cancer (DTC)?
There is no evidence that pregnancy increases the risk of recurrence of differentiated thyroid cancer. 60 pregnant women with a history of DTC were evaluated by Rosvol and Winship. Of these, 38 were free of other disease for 2 to 15 years and did not see tumor recurrence. in 22 patients with stable or slowly progressive DCT, pregnancy did not promote accelerated tumor growth. hill et al. reported no difference in the recurrence rate of thyroid cancer in 70 patients with single or multiple pregnancies with established DTC compared to 109 without pregnancy. leeboef et al. reported that in Rosario et al. reported that in 64 pregnant women treated with DTC, pregnancy did not lead to cancer recurrence. Hirsch evaluated 63 pregnant women treated with DTC.
X. Congenital hypothyroidism
Question 63: Etiology and screening for congenital hypothyroidism in newborns
The prevalence of congenital hypothyroidism (CH) is about 1/3000-4000, and the causes of CH include hypothyroidism (75%), impaired thyroid hormone synthesis (10%), central hypothyroidism (5%), and transient hypothyroidism in newborns (10%). Screening for congenital hypothyroidism in newborns has been performed in China since 1981, and the national screening coverage has now exceeded 60%, with a prevalence of about 1/2050 [131].
The commonly used screening index internationally is heel blood TSH (filter paper dried blood spot specimen). Blood is collected from 48 hours to 4 days postnatally in full-term newborns. If the specimen is taken 1~48 hours after birth, it may be affected by the pulsatile secretion of TSH after birth and produce false positive results. The Chinese Ministry of Health Technical Specification for Newborn Disease Screening (2010 version) states that specimens should be taken within 72 hours to 7 days of birth for full-term newborns. The cut point value of positive TSH concentration depends on the laboratory and the kit, generally >10-20mIU/L is considered as positive screening.
Question 64: Diagnosis of congenital hypothyroidism in newborns
If the heel blood TSH screen is positive, the child needs to be recalled immediately for serum thyroid function index testing. （The reference criteria for the serologic diagnosis of primary hypothyroidism, primary subclinical hypothyroidism, TBG deficiency, and central hypothyroidism are shown in Table 3. These criteria are based on reference values for newborns around 2 weeks of age, and clinicians should take full account of the range of normal values for each age and the influence of different laboratory assay reagents and their methods when making their judgments. Statistics of confirmed CH cases show that 90% of CH patients have TSH >90 mIU/L and at least >30 mIU/L; 75% of CH patients have TT4 <6.5 μg/dL (84 nmol/L) and FT4 <10 pmol/L.
After the diagnosis of CH is established, further examination of the etiology is required, such as thyroid ultrasound, thyroid 99Tc (or 123 iodine scan), serum Tg and thyroid stimulating blocking antibody (TSBAb) assay for primary hypothyroidism; TSHβ gene analysis, TRH receptor gene analysis, other pituitary hormone assays, MRI of optic nerve and hypothalamus-pituitary for central hypothyroidism.
Recommendation 10-1: Newborn screening for congenital hypothyroidism should be performed 48 hours to 7 days after birth and is best if performed within 2 days to 4 days after birth. Heel blood TSH (DBS specimen) Cut point value is 10~20mIU/L. (Recommendation level A)
Recommendation 10-2: Immediate re-testing of serum TSH and TT4 in those who screen positive. diagnostic criteria are determined by local laboratories based on their own laboratory reference values. Recently Lafranchi in JCEM proposed serum TSH>9mIU/L and FT4<0.6ng/dL as diagnostic criteria for CH can be referred. It remains to be combined with the results of CH etiology tests. (Recommendation level A)
Question 65: Treatment of congenital hypothyroidism in newborns
Treatment with levothyroxine (L-T4) should be started as soon as possible once congenital hypothyroidism is diagnosed, so that the child’s serum T4 returns to normal levels within 1 to 2 weeks and serum TSH returns to normal levels within 2 to 4 weeks. The literature reports that the age of starting treatment for CH is significantly correlated with the intellectual development of the child, with no significant difference in IQ between those starting treatment within 2 months of birth and the average child; 89 for those starting treatment at 3 months; 71 for those starting treatment between 3 and 6 months; and 54 for those starting treatment after 6 months.
The goals of CH treatment are 1) serum FT4: within the upper 50% of the reference value; 2) serum TT4: 10-16 μg/dL for 1-2 years, >2 years within the upper 50% of the reference value; 3) serum TSH: <5.0 mIU/L, with an optimal range of 0.5-2.0 mIU/L.
The starting dose of levothyroxine (L-T4) is 10 to 15 μg/kg/d taken once daily. Recommended doses of L-T4 for various etiologies: 15 μg/kg/d for thyroid development deficiency, 12 μg/kg/d for ectopic thyroid, and 10 μg/kg/d for thyroid hormone synthesis disorder.
Regular monitoring of serum TSH and TT4: every 2-4 weeks for the first 6 months of treatment, every 1-2 months from 6 months to 1 year, every 3-4 months from 6 months to 3 years, and every 6 months from 3 years to the end of the growth period. L-T4 should not be mixed with other foods; soy protein, iron concentrate and calcium supplements can affect the absorption of the drug. It is best to take the drug on an empty stomach for 30-60 minutes before taking it.
Recommendation 10-3: Treatment for CH should be started within 2 months of birth, and the earlier the prognosis the better. The goal of treatment is to maintain serum TSH <5mIU/L and TT4 and FT4 at 50% of the upper reference level. (Recommendation level A)
Table 4 Management of congenital hypothyroidism
First examination of the condition
Detailed history and physical examination
Referral to a pediatric endocrinologist
Repeat serum TSH and serum FT4
Thyroid ultrasound and/or thyroid scan
Medication.
L-T4: 10-15 μg/kg/day once daily on an empty stomach in the early morning
Monitoring of condition.
Repeat FT4, TSH
Start 2~4 weeks after first treatment
Infants within 6 months of age: recheck every 1~2 months
Children from 6 months to 3 weeks of age: review every 3-4 months
3 years old ~ growth arrest: review every 6~12 months
Treatment goals.
Normalize TSH and maintain FT4 and T4 in the upper 1/2 range of the reference value.
Assess if hypothyroidism is permanent
Permanent hypothyroidism is diagnosed if the initial thyroid scan suggests ectopic or absent thyroid.
If the initial TSH is <50 mU/L and the TSH is not elevated after the neonatal period, treatment may be discontinued experimentally at 3 years of age. If TSH rises after stopping treatment, permanent hypothyroidism is considered.
XI. Screening for thyroid disease in pregnancy
Question 66: Which method is effective in screening for thyroid disease in pregnancy?
Vaidya et al. evaluated the effectiveness of a targeted case-finding strategy and a universal screening strategy. 30% of women with hypothyroidism and 69% of women with hyperthyroidism were missed when applying the targeted case-finding approach. In an analysis of 4800 pregnant women screened by Weiwei Wang at the China Medical University, it was found that 81.6% of hypothyroid women and 80.4% of hyperthyroid women were missed by the targeted case-finding approach. The current study concluded that screening for target cases only does not achieve the screening goal.
Question 67: Who are at high risk for thyroid disease in pregnancy?
1. history of thyroid disease and/or history of thyroid surgery/ or 131 iodine treatment
2. Family history of thyroid disease
3. Goiter
4. Women with positive thyroid antibodies
5. Symptoms or clinical manifestations of hypothyroidism
6. Type 1 diabetes mellitus
7, other autoimmune diseases: including vitiligo, hypoadrenalism, hyperparathyroidism, atrophic gastritis, pernicious anemia, systemic sclerosis, systemic lupus erythematosus, dry syndrome, etc.
8.Infertile women
9, had head and neck radiation therapy
10, obesity (BMI>40kg/m2 )
11.Women over 30 years old
12.Take amiodarone
13.Taking lithium treatment
14.Women exposed to iodine radiography
Recommendation 11-1: Screening in a high-risk pregnancy population with 30 to 80% of missed cases of hyperthyroidism, subclinical hyperthyroidism or hypothyroidism or subclinical hypothyroidism. (Recommendation level A)
Recommendation 11-2: Cost-effectiveness analysis shows that screening the entire gestational population is preferable to no screening. (Recommendation level B)
Question 68: What is the attitude of this Guideline toward screening for thyroid disease in pregnancy?
This guideline supports screening for thyroid indicators before pregnancy and in early pregnancy for the following reasons: 1. Thyroid disease is one of the common diseases in women of childbearing age in China. According to the recently completed “Survey on thyroid disease and iodine nutrition in ten cities in China” by the Chinese Medical Association Endocrine Society, the prevalence of clinical hypothyroidism, subclinical hypothyroidism and positive TPOAb among women of childbearing age (n=4438) were 0.77%, 5.32% and 12.96%, respectively. 2. The prevalence of screening for clinical hypothyroidism, subclinical hypothyroidism and TPOAb among women in the first half of pregnancy in China The prevalence of clinical hypothyroidism, subclinical hypothyroidism and TPOAb among women in the first half of pregnancy in China is 0.6%, 5.27% and 8.6% respectively; 3. Several studies in the field of thyroid disorders in pregnancy at home and abroad in recent years have shown that positive clinical hypothyroidism, subclinical hypothyroidism and TPOAb in pregnant women have different degrees of negative effects on pregnancy outcome and neurointellectual development of offspring; 4.
Recommendation 11-3: According to China’s national situation, this guideline supports the screening of thyroid disease for women in early pregnancy in hospitals and maternal and child health care departments in China that are in a position to do so. The screening indexes are serum TSH, FT4 and TPOAb. The timing of screening is chosen before 8 weeks of gestation. Preferably, screening should be done before pregnancy. (Recommendation level B)