The Impact of Pregnancy on Disease Progression in Females with Differentiated Thyroid Cancer

The worldwide incidence of differentiated thyroid cancer (DTC), the most common endocrine cancer, has steadily increased over the last two decades. ¹ DTC comprises of two major subtypes, papillary and follicular thyroid carcinomas (PTC, FTC); these together account for 80%–85% of all thyroid carcinomas. Thyroid cancer occurs more frequently in females than it does in males and is one of the most common cancers diagnosed in women of reproductive age ^{2 –4} and is estimated to make up 20% of all diagnosed cancers in the perinatal period. ^5,6 The vast majority of the patients with DTC have an excellent 10-year disease-specific survival of more than 90%, which approaches 100% in stage I disease, ^7,8 especially in patients of reproductive age. However, the remaining reproductive time window for many patients, even among younger individuals, is often limited. Therefore, it is important to understand the effects of pregnancy on treated and/or persistent DTC to be able to determine the need for and optimal timing of specific treatments, as well as supporting plans for subsequent pregnancy, if desired, in those who already received initial treatment for DTC. ^9,10

Clinical data seem primarily to refute the theoretical concept that various pregnancy-specific physiological changes could promote thyroid cancer (remnant) growth to a clinically meaningful extent (e.g., increase in estrogen, placental growth hormone and human chorionic gonadotrophin) as of all studies, the majority showed no significant disease recurrence or worsening of structural disease during pregnancy. ^{11 –19} However, the interpretation of most of these studies is limited by the lack of a control group and/or the omission of adjusting for important confounders, and therefore, clinical controversy exists in the management of DTC during pregnancy.

Recently, Li et al. published the results of a propensity score matched (PSM) analysis of the association between pregnancy and disease progression in females with DTC. ²⁰ In this study, 1505 female patients after treatment with total thyroidectomy or lobectomy were enrolled retrospectively, of which 129 became pregnant and 1376 did not. Patients were matched using PSM, and those who became pregnant were compared with those who did not regarding disease progression/recurrence (biochemical or structural), including the time interval between treatment and pregnancy, and including prepregnancy response to therapy. A total of 405 patients could be matched (107 pregnancy and 298 nonpregnancy group) having a median follow-up of 4.5 years. Disease progression was seen in 12.1% (13/107) in the pregnant and 14.4% (43/298) in the nonpregnant group (p = 0.373), while these were 9.3% and 10.4% with respect to structural progression (p = 0.499), and 2.8% and 4.0% with respect to biochemical progression (p = 0.473). Further analyses showed that those that were treated <1 year before their pregnancy had a higher risk of progression than those who became pregnant >2 years after treatment (odds ratio [OR] 20.6 [95% confidence interval; CI 4.38–96.81; p < 0.001]), while no significant differences with respect to progression between more than two years and within one to two years after treatment were observed (OR 3.75 [95% CI 0.85–16.64; p = 0.082]). Lastly, patients who had a structural incomplete response to therapy before pregnancy had a higher risk (33%; 3/9) of structural and biochemical progression compared to these with an excellent response to therapy before pregnancy (9.6%; 5/52). The authors therefore justifiably conclude that in pregnant women, the risk of DTC progression is not higher compared to nonpregnant women, and that, after treatment, it seems safer, with respect to disease progression, to wait at least one year before becoming pregnant.

The main limitations of this study include the comparability between the pregnant and nonpregnant groups, even though PSM was used to overcome this problem. In relation to this, 16 women (13%) in the pregnancy group could not be matched, while these initially showed a higher proportion of extra-thyroidal extension (ETE) and lymph node metastases, and were treated with radioiodine (RAI). Consequently, those included in the current study have mainly low-risk disease (91%–92%), and therefore, this potentially hampers generalizability to intermediate and high-risk patients, and to those treated with RAI therapy. Further, it is a single-center study from a single country, which potentially hampers generalizability to other parts of the world with a different health care systems as well potentially different baseline population genetic risk profiles. ²¹

The study of Li et al. adds another study in confirmation that pregnancy is not associated with significant disease progression in females with DTC. Although retrospective in design, one of the strong points of this study is the use of PSM to maximize comparability of groups. However, a consequence of this matching is that those with more advanced disease were underrepresented in the current study, limiting the conclusions for these groups of patients. Another interesting result is that after treatment, it seems safer, with respect to disease progression, to wait at least 1 year before becoming pregnant. Thus far, a clear explanation for this phenomenon eludes us, and the data in the study by Li et al. cannot provide a clear hypothesis. Potentially, the observed higher rate of progression may be related to unsatisfactory thyroid stimulating hormone suppression in the first year after treatment when no clear treatment result has yet been established—as this is conventionally only determined 6–12 months after therapy. ²² It is also conceivable that pregnant women are followed up more intensively, increasing the chance of early detection of disease progression which otherwise would have only occurred at later follow-up checks. However, as the data yield no clear answer, further research is needed on this topic. Lastly, this study is another study that shows that the American Thyroid Association (ATA) thyroid cancer dynamic risk stratification (DRS) system ²² can help to predict disease progression in pregnant women previously treated for DTC. Moreover, in correspondence with the latest ATA guidelines, ²³ this study suggests that in women with an excellent response, no additional monitoring is needed during pregnancy, while in those with biochemically or structurally incomplete responses, additional monitoring is needed with both serum Tg levels and surveillance neck ultrasound. However, further studies in specific, currently underrepresented, high-risk subgroups, such as patients with distant metastases and/or ETE, or persistent disease during pregnancy following history of initial therapy are needed.

Notwithstanding the limitations and needs for further research, for clinical practice the study of Li et al. yet again highlights a comforting message which is becoming more and more evident as the body of evidence on various subtopics on the relationship between DTC and pregnancy increases: pregnancy does not, in essence, adversely affect DTC and its outcome.