REVIEW

CURRENT
OPINION Pregnancy as a risk factor for thyroid
cancer progression
Luba Rakhlin a and Stephanie Fish b

Purpose of review
The current review evaluates the impact of pregnancy on women with thyroid cancer in three different
clinical situations: those with newly diagnosed differentiated thyroid cancer (DTC), those under active
surveillance for papillary thyroid microcarcinomas (PMCs), and those with previously treated DTC.
Recent findings
Recent pregnancy is not associated with high-risk pathological features of DTC. In women with known
PMCs under active surveillance, pregnancy does not increase the risk of disease progression. Thus,
deferring surgery for newly diagnosed DTC or known PMCs until after delivery is safe for both mother and
the unborn child. If a woman with previously treated DTC is planning pregnancy, response-to-therapy status
is an excellent guide for predicting pregnancy-associated disease progression or recurrence.
Summary
Clinical studies consistently show that pregnancy is not associated with significant disease progression in
newly diagnosed thyroid cancer, PMCs under active surveillance, or previously treated DTC.
Keywords
differentiated thyroid cancer, papillary thyroid microcarcinoma, pregnancy, response to therapy

INTRODUCTION For many physicians, managing women of

The incidence of thyroid cancer has been increasing
over the last 40 years and is three times higher
in women than in men. More than one-third of
women with a diagnosis of thyroid cancer are
reproductive age with a diagnosis of thyroid cancer
is challenging. The timing of surgery, radioactive
iodine treatment, and routine surveillance needs
to be carefully planned taking into account the
&

of reproductive age [1]. Therefore, the impact of
pregnancy on thyroid cancer status is a pertinent
issue for women between the ages of 20 and
49 years old.
Over the last few decades, several studies raised
concern that the high serum levels of human chori-
onic gonadotropin and estrogen during pregnancy
may stimulate growth of thyroid cancer [2,3]. In
2010, Vannucchi et al. [4] noted that expression
of estrogen receptor a (ERa) was significantly higher
in tumors of women who were diagnosed with
differentiated thyroid cancer (DTC) during preg-
nancy or in the 1st year after delivery compared
with women diagnosed with DTC at least 1 year after
delivery or before pregnancy. Messuti et al. [5]
attempted to reproduce these results in 2014; how-
ever, they found no difference in ERa or estrogen
receptor ß expression between pregnant and non-
pregnant patients. At this time, there are no consis-
tent molecular data to explain a potential impact of
pregnancy on DTC.
patient’s plans for pregnancy [6 ]. In this review,
we focus on recent studies that clarify the manage-
ment recommendations for women with DTC who
are newly diagnosed during pregnancy and for
women with a history of previously treated DTC.
IMPACT OF PREGNANCY ON NEWLY
DIAGNOSED THYROID CARCINOMA
In 2017, Chen et al. published a matched-control
study that examined the impact of pregnancy on
a
Division of Endocrinology, Maimonides Medical Center, Brooklyn and
b
Department of Medicine, Memorial Sloan Kettering Cancer Center, New
York, New York, USA
Correspondence to Luba Rakhlin, MD, Division of Endocrinology,
Maimonides Medical Center, 984 50th Street, 2nd Floor, Brooklyn,
NY 11219, USA. Tel: +1 718 283 5923; fax: +1 718 635 7640;
e-mail: lrakhlin@maimonidesmed.org
Curr Opin Endocrinol Diabetes Obes 2018, 25:326–329
DOI:10.1097/MED.0000000000000424

www.co-endocrinology.com Volume 25  Number 5  October 2018

Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

 Pregnancy as a risk factor for thyroid cancer progression Rakhlin and Fish
KEY POINTS
 Recent pregnancy is not associated with high-risk
pathological features of DTC.
 Pregnancy is not associated with an increased risk of
progression of PMCs and active surveillance can be
safely continued during pregnancy.
 In patients with newly diagnosed DTC during
pregnancy, deferring surgery until after delivery is not
associated with a worse prognosis. If aggressive
features of DTC are present, surgery should be
considered during the second trimester.
 Response-to-therapy status is an excellent guide for
predicting pregnancy-associated disease progression in
women previously treated for DTC.
DTC histopathologic characteristics including
tumor size, extrathyroidal extension, and nodal
metastases. Three hundred and one recently preg-
nant women, defined as pregnancy within 5 years
before and 9 months after the diagnosis of DTC,
were compared with 903 nonpregnant controls. No
significant difference was observed between the
groups in terms of tumor size, extrathyroidal exten-
sion, distant metastases, or disease-specific survival.
The data are reassuring that recent pregnancy is not
associated with high-risk pathological features in
&&
DTC [7 ].
With newly diagnosed DTC during pregnancy,
studies consistently show that pregnancy has no
&
impact on overall survival (OS) [6 ]. In the landmark
retrospective study by Moosa et al., 61 pregnant
women with newly diagnosed DTC were compared
with 528 age-matched nonpregnant controls. No
difference in OS or risk of recurrence was noted
between the two groups in up to 40 years of
follow-up. However, the contemporary tools of dis-
ease detection, such as thyroglobulin levels and
neck ultrasonography, were not used to monitor
for recurrence of disease in this study [8].
In two recent studies, higher rates of recurrent/
persistent disease were noted when thyroglobulin
and neck ultrasonography were used for surveil-
lance. Vanucchi et al. reported an increase in recur-
rent/persistent disease in patients who were
diagnosed with thyroid cancer during pregnancy
or within 1-year postpartum (60%) as compared
with patients who were diagnosed more than a year
after delivery (4%) or were nulliparous at the time of
diagnosis (13%). This rate of recurrent/persistent
disease is higher than expected for patients with
Stage I disease. Of note, 60% of the patients consid-
ered to have recurrent disease only had biochemical
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evidence of disease [4]. The study by Mesutti et al.
attempted to reproduce the data from Vanucchi
et al. Again, higher rates of recurrent/persistent dis-
ease were noted in patients diagnosed with thyroid
cancer during pregnancy. However, this study did
not comment if the recurrent or persistent disease
was biochemical or structural [5].
A recent study by Oh et al. retrospectively
reviewed serial neck ultrasonography of 19 women
(median age 33 years old) who were diagnosed with
DTC just before or during pregnancy. Thirteen of
these patients had papillary thyroid microcarcino-
mas (PMCs). At follow-up (median 9.5 months),
minimal increase in tumor size was observed. Three
of the women had cervical lymph node metastasis at
diagnosis. None of the remaining 16 women devel-
oped cervical lymph node disease during follow-up.
After delivery, 16 of the 19 patients underwent
thyroid surgery, and nine patients were noted to
have small lymph node metastasis. Yet, with the use
of contemporary tools of detection, no persistent or
recurrent disease was noted in follow-up (median
&
53.8 months) [9 ]. These results may be due to the
fact that this was a small cohort with low-risk thy-
roid cancer. Larger prospective studies using con-
temporary tools of detection are needed to better
understand if there is an increased risk of biochemi-
cal or structural recurrence in patients with newly
diagnosed DTC during pregnancy, specifically
focusing on those with tumor size greater than 1 cm.
PAPILLARY THYROID
MICROCARCINOMAS UNDER ACTIVE
SURVEILLANCE DURING PREGNANCY
Since 1993, Kuma Hospital in Japan has had an
active surveillance program for patients with low-
risk PMCs. In the last 20 years, 50 of 1549 women in
the active surveillance group became pregnant
&&
[10 ]. In 2013, a report from Kuma Hospital com-
pared nine women who became pregnant during
active surveillance with 27 nonpregnant women
matched by age. It was noted that PMC enlarged
significantly more in pregnant patients compared
with controls [11].
However, in a follow-up publication, 50 women
(median age 33 years; range 28–41 years old) who
became pregnant during active surveillance were
included and significant progression was seen in
only 8% (4/51 cases). Two of the four patients with
structural progression (1.7 and 1.8-cm tumors)
underwent thyroidectomy with central lymph
node dissection after pregnancy. One of these two
patients had lymph node involvement. The other
two patients who remained under surveillance as
&&
PMC were 1.0 and 1.1 cm, respectively [10 ].
www.co-endocrinology.com 327
Thyroid
It is important to note that in the prospective
cohort from the same institution, 9.5% of younger
patients (age less than 40 years) had progression
of PMCs in 5 years of follow-up. In contrast,
progression of PMCs was seen in only 4% of patients
age 40–59 years and in 2.2% of patients age greater
than 60 years [12]. These data suggest that age,
rather than pregnancy, is a major risk factor for
disease progression. Therefore, Ito et al. conclude
that patients of child-bearing age should be
included in the active surveillance program even
if there is a possibility of pregnancy in the future
[12,13].
The current American Thyroid Association
(ATA) guidelines recommend monitoring PMCs
with neck ultrasonography during each trimester
&
of pregnancy [6 ]. However, the guidelines were
published prior to the most recent report by Ito
et al. Therefore, it is likely that less stringent moni-
toring may be recommended in the future.
TIMING OF SURGERY IN PATIENTS WITH
NEWLY DIAGNOSED THYROID CANCER
In patients with newly diagnosed DTC during preg-
nancy, it can be difficult to determine the best time
for surgery. Current studies show that thyroid sur-
gery has no impact on pregnancy outcome if per-
formed by an experienced surgeon. In addition,
deferring thyroid surgery until after delivery is not
associated with a worse prognosis from the thyroid
&
cancer [6 ]. Boucek et al. recently published a study
in which 29 out of 35 patients diagnosed with DTC
during pregnancy underwent surgery during the
pregnancy. All patients delivered at full-term with
neonatal and maternal outcomes similar to the
&
general population [14 ].
Another recent study by Uruno et al. compared
24 patients who underwent thyroidectomy during
pregnancy with 21 patients who completed thyroid-
ectomy after delivery. The majority of the surgeries
occurred during the second trimester. In both the
groups, there were no pregnancy losses or birth
defects. The recurrence rate of DTC was similar
between the two groups during follow-up [15].
Based on these data, the current ATA guidelines
recommend monitoring DTC detected during preg-
nancy with neck ultrasonography and considering
surgery only if aggressive features are present, such
as a significant growth of the tumor or the presence
of abnormal cervical lymph nodes. If surgery is
recommended during pregnancy, the second tri-
mester is considered the safest time due to the risk
of altered organogenesis or spontaneous abortion in
the first trimester and preterm labor in the third
& &&
trimester [6 ].
328 www.co-endocrinology.com
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RESPONSE-TO-THERAPY STATUS
AS A GUIDE FOR PROGNOSIS AND
MANAGEMENT OF PREVIOUSLY TREATED
DIFFERENTIATED THYROID CANCER
DURING AND IMMEDIATELY FOLLOWING
PREGNANCY
Several studies have shown that pregnancy has min-
imal impact on the progression or recurrence of
previously treated DTC in women who are dis-
ease-free [16–18]. Yet, minor biochemical or struc-
tural disease progression has been observed in
patients with evidence of disease prior to pregnancy
[16,17]. The 2015 ATA guidelines recommend
applying response-to-therapy restaging assessments
during follow-up [19]. We recently completed a
retrospective review evaluating the risk of preg-
nancy-associated recurrence or progression within
the four established prepregnancy response-to-ther-
apy categories: excellent, indeterminate, biochemi-
&&
cal incomplete, and structural incomplete [20 ].
In our study, we reviewed 235 women followed
at Memorial Sloan Kettering Cancer Center for DTC
between 1997 and 2015 who had a full-term preg-
nancy. The median age of our cohort was 34 years,
and the pregnancy occurred at a median of 3 years
after initial treatment for DTC. The majority of
women had a total thyroidectomy (89%) and
received radioactive iodine ablation (61%). Sev-
enty-eight percent of the women were classified as
having intermediate risk of recurrence based on the
&&
initial DTC lesion [20 ].
None of the women with excellent, indetermi-
nate, or biochemical incomplete response to ther-
apy developed identifiable structural disease during
pregnancy or after delivery. In the group of patients
with a structurally incomplete response to therapy,
29% had structural progression of disease during
pregnancy, which was defined as an increase in
known lymph node disease by at least 3 mm, devel-
opment of new abnormal lymph nodes, or evidence
of structural progression of distant metastasis. How-
ever, only 8% of these patients had clinically signif-
icant disease progression that required additional
therapy in the 1st year of follow-up after pregnancy
&&
[20 ].
Although the study had several limitations,
including a follow-up of only 3–12 months after
delivery, it confirms that response-to-therapy status
is an excellent guide for predicting pregnancy-
associated disease progression in women previously
treated for DTC. These data are reassuring for
women with a history of DTC and no evidence of
structural disease. For patients with evidence of
structural disease, these data indicate that the risk
of clinically significant disease progression during
pregnancy is very low [20 ].
Volume 25  Number 5  October 2018
 Pregnancy as a risk factor for thyroid cancer progression Rakhlin and Fish
As recommended by the ATA guidelines, close
monitoring with neck ultrasonography and thyro-
globulin should be performed during pregnancy
in all DTC patients with a structural incomplete
response to therapy to identify those few patients
with clinically significant pregnancy-associated
structural disease progression [19].
CONCLUSION
Thyroid cancer is highly prevalent in women of
reproductive age and is one of the most common
cancers diagnosed during pregnancy. Clinical
studies consistently show that pregnancy is not
associated with significant progression of newly
diagnosed thyroid cancer, previously treated DTC
or PMCs under active surveillance. Unless DTC is
exhibiting aggressive features during pregnancy,
thyroid surgery should be deferred until after deliv-
ery. Yet, if surgery is recommended during preg-
nancy, it should be performed during the second
trimester by an experienced surgeon. In those DTC
patients with a structurally incomplete response to
treatment, close monitoring during pregnancy is
recommended due to the small risk of clinically
significant disease progression.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED
READING
Papers of particular interest, published within the annual period of review, have
been highlighted as:
& of special interest
&& of outstanding interest
1. National Cancer Institute. Surveillance, epidemiology, and end results pro-
gram. 2017. Available at: www.seer.cancer.gov. [Accessed 5 November
2017].
2. Yoshimura M, Hershman JM. Thyrotropic action of human chorionic gonado-
tropin. Thyroid 1995; 5:425–434.
1752-296X Copyright ß 2018 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
3. Dalla Valle L, Ramina A, Vianello S, et al. Potential for estrogen synthesis and
action in human normal and neoplastic thyroid tissues. J Clin Endocrinol
Metab 1998; 83:3702–3709.
4. Vannucchi G, Perrino M, Rossi S, et al. Clinical and molecular features of
differentiated thyroid cancer diagnosed during pregnancy. Eur J Endocrinol
2010; 162:145–151.
5. Messuti I, Corvisieri S, Bardesono F, et al. Impact of pregnancy on prognosis
of differentiated thyroid cancer: clinical and molecular features. Eur J En-
docrinol 2014; 170:659–666.
6. Alexander EK, Pearce EN, Brent GA, et al. 2017 Guidelines of the American
& Thyroid Association for the diagnosis and management of thyroid disease
during pregnancy and the postpartum. Thyroid 2017; 27:315–389.
These are the most recent guidelines on the management of thyroid disease during
pregnancy, which include a comprehensive section on management of women
with thyroid nodules and thyroid cancer.
7. Chen AJ, Livhits MJ, Du L, et al. Recent pregnancy is not associated with high-
&& risk pathological features of well differentiated thyroid cancer. Thyroid 2018;
28:68–71.
This is a matched-control study that compares histopathologic disease character-
istics of differentiated thyroid cancer (DTC) in women with recent pregnancy with
nonpregnant controls. The findings of this study reassure that pregnancy is not
associated with high-risk pathological features of DTC.
8. Moosa M, Mazzaferri EL. Outcome of differentiated thyroid cancer diagnosed
in pregnant women. J Clin Endocrinol Metab 1997; 82:2862–2866.
9. Oh HS, Kim WG, Park S, et al. Serial neck ultrasonographic evaluation of
& changes in papillary thyroid carcinoma during pregnancy. Thyroid 2017;
27:773–777.
The study examines the behavior of DTC diagnosed during pregnancy through
serial neck ultrasonography evaluations.
10. Ito Y, Miyauchi A, Kudo T, et al. Effects of pregnancy on papillary micro-
carcinomas of the thyroid re-evaluated in the entire patient series at Kuma
&&
Hospital. Thyroid 2016; 26:156–160.
The study examines the effects of pregnancy on papillary thyroid microcarcinomas
in women who are enrolled in active surveillance clinical trial.
11. Shindo H, Amino N, Ito Y, et al. Papillary thyroid microcarcinoma might
progress during pregnancy. Thyroid 2014; 24:840–844.
12. Ito Y, Miyauchi A, Kihara M, et al. Patient age is significantly related to the
progression of papillary microcarcinoma of the thyroid under observation.
Thyroid 2014; 24:27–34.
13. Hershman JM. Pregnancy does not increase the size of papillary thyroid
microcarcinomas. Clin Thyroidol 2016; 28:39–40.
14. Boucek J, de Haan J, Halaska MJ, et al. Maternal and obstetrical outcome in 35
& cases of well differentiated thyroid carcinoma during pregnancy. Laryngo-
scope 2018; 128:1493–1500.
The study examines the impact of thyroid surgery for DTC during pregnancy on
fetal and maternal outcomes.
15. Uruno T, Shibuya H, Kitagawa W, et al. Optimal timing of surgery for
differentiated thyroid cancer in pregnant women. World J Surg 2014;
38:704–708.
16. Leboeuf R, Emerick LE, Martorella AJ, et al. Impact of pregnancy on serum
thyroglobulin and detection of recurrent disease shortly after delivery in
thyroid cancer survivors. Thyroid 2007; 17:543–547.
17. Hirsch D, Levy S, Tsvetov G, et al. Impact of pregnancy on outcome
and prognosis of survivors of papillary thyroid cancer. Thyroid 2010;
20:1179–1185.
18. Rosário PW, Barroso AL, Purisch S. The effect of subsequent pregnancy on
patients with thyroid carcinoma apparently free of the disease. Thyroid 2007;
17:1175–1176.
19. Haugen BR, Alexander EK, Bible KC, et al. American Thyroid Association
management guidelines for adult patients with thyroid nodules and differen-
tiated thyroid cancer: the American Thyroid Association guidelines task force on
thyroid nodules and differentiated thyroid cancer. Thyroid 2016; 26:1–133.
20. Rakhlin L, Fish S, Tuttle RM. Response to therapy status is an excellent
&& predictor of pregnancy-associated structural disease progression in patients
previously treated for differentiated thyroid cancer. Thyroid 2017; 27:
396–401.
The study investigates the risk of recurrence/progression of DTC in patients who
were previously treated for DTC by applying response-to-therapy assessments to
prepregnancy status.
www.co-endocrinology.com 329