Thyroid cancer is one of the common malignancies in women of reproductive age, and there are many questions about its relationship with pregnancy. In this paper, we review the close and complex association between pregnancy and thyroid cancer from the perspectives of both “the effect of pregnancy on thyroid cancer” and “the effect of thyroid cancer on pregnancy”, and introduce the current recommendations in the relevant clinical guidelines for diagnosis and treatment in China.
Keywords: pregnancy; thyroid cancer
Thyroid cancer is one of the common malignancies in women of childbearing age, and its relationship with pregnancy has received much attention. In this article, we will summarize the relevant studies in the past 15 years in the form of question-answer format, and describe the close and complex association between pregnancy and thyroid cancer from two aspects: “the effect of pregnancy on thyroid cancer” and “the effect of thyroid cancer on pregnancy”. After that, we will list the recommended articles in our “Guidelines for the diagnosis and treatment of thyroid disorders in pregnancy and postpartum”.
I. Effect of pregnancy on thyroid cancer
During pregnancy, the body undergoes a series of physiological changes, including a significant increase in estrogen and human chorionic gonadotropin levels, and the development of a maternal “immune immune immune” status. Given that hormones and immunity are often associated with malignancy, it is interesting to know whether pregnancy affects the occurrence and development of thyroid cancer.
1. Does pregnancy increase the incidence of thyroid cancer?
Several case-control studies have investigated whether menstruation, childbirth and contraceptive use increase the incidence of thyroid cancer in women: Zivaljevic et al. analyzed data from 204 female thyroid cancer patients and 204 control women and found that pregnancy itself did not increase the risk of thyroid cancer, while a history of spontaneous abortion, use of oral contraceptives and an enlarged thyroid during pregnancy were A history of spontaneous abortion, use of oral contraceptives and an enlarged thyroid gland during pregnancy were risk factors for the development of thyroid cancer, with ratios (OR) of 2.22, 2.46 and 18.08, respectively.
Truong et al. conducted a study in NewCaledonia, France, a region with a high incidence of thyroid cancer, which included 293 and 354 women in the case and control groups, respectively, and showed that the number of pregnancies constituted a risk factor for the development of thyroid cancer only when the number of pregnancies was eight or more. Subsequently, French scholar Brindel et al. used 201 thyroid cancer patients and 324 control women as study subjects and observed a trend of increasing thyroid cancer risk with increasing number of pregnancies, while breastfeeding and abortion were not high risk factors for thyroid cancer.
In 2009, a cohort follow-up study by Japanese scholar Pham et al. provided evidence of a higher level of evidence. In this study, 379,281 women of childbearing age were followed up 379,281/year, during which the incidence of thyroid cancer was 22.7/100,000, and neither pregnancy and childbirth history, age at menarche, nor age at menopause affected the risk of thyroid cancer. 2012, Peterson et al. conducted a meta-analysis of the association between female reproductive factors and thyroid cancer risk, including 17 studies. The results showed that pregnancy, childbirth, oral contraceptives and estrogen did not increase the risk of thyroid cancer.
In conclusion, there is a general consensus on whether pregnancy affects the incidence of thyroid cancer, that is, pregnancy is not a risk factor for increased thyroid cancer incidence.
2. Does pregnancy affect the growth and malignancy of thyroid nodules?
At the end of last century, American scholar Marley et al. evaluated 97 nodules in 57 patients with thyroid nodules diagnosed during pregnancy and postpartum period by fine needle aspiration pathology, including 17 cases of suspected papillary thyroid cancer (PTC) and PTC; nodular lesions found during pregnancy (including PTC) did not change significantly during pregnancy.
In 2002, Kung et al. from Hong Kong, China, performed ultrasound screening of thyroid nodules (early pregnancy) and follow-up (mid and late pregnancy, 6 weeks and 3 months postpartum) in 221 pregnant women and showed that the prevalence of thyroid nodules (>2 mm) in early pregnancy was 15.4%, and 12 of 34 patients had a single nodule; of 187 individuals without thyroid nodules in early pregnancy 25 new nodules were diagnosed during follow-up; despite the increase in size and number of thyroid nodules during pregnancy, 21 nodules >5 mm were examined by fine needle aspiration at 3 months postpartum and no thyroid cancer was observed.
Recently, a similar study was conducted by Turkish scholars in a severe iodine deficiency area: in 83 pregnant women, a total of 26 thyroid nodules were found during pregnancy, of which 6.6% were confirmed to be malignant after delivery; the volume of nodules increased significantly during pregnancy, while the number increased, but the difference was not statistically significant.
In conclusion, the number of relevant studies on this issue is still small and the conclusions are not consistent. More studies are still needed on the changes of nodule size, number, benign and malignant ratio during pregnancy.
3. Does pregnancy accelerate the progression of thyroid cancer?
According to the time of thyroid cancer diagnosis and disease status, the studies in this area can be divided into 3 parts.
Leboeuf et al. followed 36 such patients during pregnancy and only 3 showed signs of recurrence after delivery; if the patient was treated before pregnancy and was in a disease-free survival state, pregnancy did not cause progression. In a case-control study conducted by Hirsch et al. in 63 patients with PTC who had their first pregnancy at (5.1 to 3.4) years after completion of treatment, nine patients had pregnancy-related PTC progression/recurrence; disease progression was not associated with tumor pathologic stage, time to diagnosis, TSH, or pre-pregnancy thyroglobulin, but was associated with residual pre-pregnancy cancer tissue and total dose of radioactive iodine 131 (RAI) therapy; pregnancy itself did not cause recurrence of thyroid cancer (in disease-free survival after treatment). A 2013 case-control study showed no significant difference in the rate of disease recurrence in patients with thyroid cancer who survived treatment without disease, with or without pregnancy.
(ii) Thyroid cancer was diagnosed before pregnancy and has not yet been treated.
Given the rarity of women who undergo pregnancy in such cases, it is difficult to study. The only report available is from Japan, where all women with papillary microcarcinoma of the thyroid (PMTC) who had not received surgical treatment were studied. The pregnancy group consisted of 9 women who had been pregnant after the diagnosis of PMTC and 27 women who were not pregnant as a control group, with a follow-up period of 16 to 175 months.
The results showed that the proportion of patients with enlarged PMTC lesions (increase in diameter equal to or greater than 3 mm) was 44.4% and 11.1% in the pregnancy group and the control group, respectively. The authors thus concluded that pregnancy may cause (untreated) PMTC growth.
(iii) Thyroid cancer is diagnosed during pregnancy.
Moosa et al. compared the long-term prognosis of 61 female PTC patients diagnosed during pregnancy and 528 female PTC patients not diagnosed during pregnancy (median follow-up of 22.4 and 19.5 years, respectively) and showed no significant differences in tumor recurrence, distant metastases, and thyroid cancer-related mortality between the 2 groups.
Eight years later, a large controlled study by Yasmeen et al. (595 diagnosed during pregnancy and 2270 age-matched, non-pregnant diagnoses) again reported that survival was not affected in women who developed thyroid cancer during pregnancy.
However, 2 Italian studies in 2010 and 2014 obtained inconsistent results with the previous ones – women with thyroid cancer diagnosed within 1 or 2 years after pregnancy or delivery had a significantly higher rate of persistent thyroid cancer lesions or The rate of recurrence was significantly higher in women diagnosed within 2 years of pregnancy compared to those diagnosed before pregnancy, those diagnosed longer after delivery, and those who had never been pregnant.
In conclusion, it is not possible to give a definitive answer as to whether pregnancy accelerates the progression of thyroid cancer. For those diagnosed before pregnancy and surviving in a disease-free state after treatment, there is more agreement that pregnancy has no effect on the disease. For those diagnosed before pregnancy but not treated, the only observation in a small sample suggests that pregnancy may cause further growth of PTMC. For patients with thyroid cancer diagnosed during pregnancy or within one to two years after delivery, it is controversial whether pregnancy affects long-term prognosis.
4. Does pregnancy affect the treatment plan of thyroid cancer?
Surgery is one of the most important treatments for thyroid cancer. Therefore, for thyroid cancer patients with disease progression during pregnancy, surgery can be performed in the fourth to sixth month of pregnancy, when complications are rare for both mother and fetus. RAI therapy, another treatment for thyroid cancer, cannot be used during pregnancy because pregnancy is an absolute contraindication to radionuclide screening and treatment.
TSH suppressive therapy for thyroid cancer can still be administered during pregnancy. The levothyroxine T4 (LT4) used for TSH suppression therapy is identical to the physiologically synthesized T4 and is therefore safe for both mother and fetus. The target for TSH suppression during pregnancy in women with thyroid cancer is 0.1 to 1.5 mU/L, which varies compared to non-pregnancy periods. Because maternal T4 during pregnancy (especially before 20 weeks) is the source of all or important supplementation of thyroid hormones needed for fetal development, the dose of LT4 taken for TSH suppression therapy increases by an average of 9% to 26%. In conclusion, pregnancy affects the timing of surgery for thyroid cancer, contraindicates the application of RAI, and requires adjustment of the target and LT4 dose of TSH suppressive therapy.
II. Effect of thyroid cancer on pregnancy
The impact of the disease on pregnancy can be manifested in various aspects such as pregnancy rate, pregnancy outcome, maternal-fetal complications and offspring growth and development. These effects may be related to the disease itself or to the subsequent response associated with treatment. As thyroid cancer is a disease whose treatment may involve thyroid surgery, RAI and LT4 (TSH suppression), and changes in thyroid function associated with treatment are common [e.g., hypothyroidism (hypothyroidism) after surgery and RAI, subclinical hyperthyroidism (hyperthyroidism) during TSH suppression], it is indeed reasonable to wonder whether thyroid cancer may have an impact on The following are some of the most important factors that may affect pregnancy
1. Does thyroid cancer reduce pregnancy rates?
In 2011, Stensheim et al. reported on pregnancy status after cancer in Norwegian adolescents and adults. This was a population-based, matched cohort study and the only large sample study in the last 15 years to answer the question of the effect of thyroid cancer on pregnancy rates. The results showed that between 1967 and 2004, 947 women of childbearing age diagnosed with thyroid cancer did not have a lower pregnancy rate compared to those of healthy childbearing age.
Does treatment of thyroid cancer affect pregnancy and offspring?
In 2008, Sawka et al. systematically reviewed the results of 16 previous observational studies (totaling 3,023 female patients): within 1 year after RAI treatment, 8% to 27% experienced transient menopause; RAI treated patients had an earlier age of menopause; a few studies reported an increased proportion of miscarriages within 1 year of RAI treatment; overall, RAI treatment had no long-term effects on gonadal function, infertility, miscarriage, fetal arrest, neonatal mortality, or congenital defects.
In the same year, JNuclMed, a leading journal in nuclear medicine, published the results of a large sample (2673 pregnancies after RAI treatment): RAI treatment did not increase the rate of miscarriage, had no effect on fetal arrest, preterm birth, low birth weight, neonatal, congenital defects or death within 1 year of birth, and did not increase the incidence of thyroid cancer or other malignancies in offspring, confirming that RAI treatment In 2009, a case-control study by Fard-Esfahani et al [29] reaffirmed that RAI does not increase the rate of spontaneous abortion and congenital malformations in offspring.
On the other hand, abnormal states of thyroid function such as hypothyroidism, subclinical hypothyroidism, hyperthyroidism or subclinical hyperthyroidism may occur during surgery, RAI and TSH suppression therapy for thyroid cancer. Studies have shown that all of these thyroid dysfunctional states (except subclinical hyperthyroidism) have the potential to affect pregnancy and offspring.
Hypothyroidism can affect menstruation and ovulation, reduce pregnancy rates, increase the incidence of pregnancy and perinatal complications, and lead to impaired growth and development of the offspring; subclinical hypothyroidism is also associated with increased miscarriage rates, increased risk of pregnancy and perinatal complications, and impaired mental development of the offspring; hyperthyroidism can lead to abnormal menstruation, increased miscarriage rates and pregnancy and perinatal complications, as well as high T4 levels in late pregnancy Hyperthyroidism can also affect the normal feedback function of the pituitary-thyroid axis in the fetus due to high T4 levels in late pregnancy.
In conclusion, RAI treatment for thyroid cancer does not affect pregnancy and offspring; uncorrected thyroid dysfunction (except subclinical hyperthyroidism) during the treatment of thyroid cancer may have adverse effects on pregnancy and offspring.