Research

JAMA Internal Medicine | Original Investigation

Association Between Pregnancy Outcomes and Radioactive Iodine

Treatment After Thyroidectomy Among Women With Thyroid Cancer
Hye Ok Kim, MD, PhD; Kyungjong Lee, MD; Sang Moo Lee, MD, PhD; Gi Hyeon Seo, MD

IMPORTANCE Current guidelines recommend that women delay pregnancy for 6 to 12 months
after the receipt of radioactive iodine treatment (RAIT) following thyroidectomy for
differentiated thyroid carcinoma. Although concerns exist regarding the risks associated with
pregnancy after RAIT, no large-scale study, to date, has investigated the association between
RAIT and pregnancy outcomes.

OBJECTIVE To investigate whether RAIT was associated with increases in adverse pregnancy
outcomes among South Korean women who received RAIT after thyroidectomy for thyroid
cancer and to evaluate the appropriate interval between RAIT and conception.

DESIGN, SETTING, AND PARTICIPANTS This population-based cohort study used the Health
Insurance Review and Assessment database of South Korea to identify a total of 111 459
women of childbearing age (20-49 years) who underwent thyroidectomy for the treatment
of differentiated thyroid carcinoma between January 1, 2008, and December 31, 2015.
Participants were allocated to 2 cohorts: those who underwent surgery alone (n = 59 483
[53.4%]) and those who underwent surgery followed by RAIT (n = 51 976 [46.6%]). The
pregnancy outcomes data were collected from January 1, 2008, to December 31, 2017.

MAIN OUTCOMES AND MEASURES The rates of abortion (both spontaneous and induced),
preterm delivery, and congenital malformation were assessed. Multivariate logistic regression
models were used to control for confounding variables.

RESULTS Among the 111 459 women of childbearing age who underwent thyroidectomy with
or without RAIT for the treatment of thyroid cancer, the mean (SD) age at surgery or RAIT was
39.8 (6.7) years. Of those, 10 842 women (9.7%) became pregnant, and the mean (SD) age at
conception was 33.3 (4.4) years. The rates of abortion, preterm delivery, and congenital
malformation among patients who underwent surgery alone compared with patients who
underwent surgery followed by RAIT were 30.7% vs 32.1% for abortion, 12.8% vs 12.9% for
preterm delivery, and 8.9% vs 9.0% for congenital malformation, respectively (P > .05). A
subgroup analysis based on the interval between RAIT and conception indicated congenital
malformation rates of 13.3% for the interval of 0 to 5 months, 7.9% for 6 to 11 months, 8.3%
for 12 to 23 months, and 9.6% for 24 months or more. The adjusted odds ratio of congenital
malformation was 1.74 (95% CI, 1.01-2.97; P = .04) in conceptions that occurred 0 to 5
months after RAIT compared with conceptions that occurred 12 to 23 months after RAIT. The
abortion rates based on the interval between RAIT and conception were 60.6% for the
interval of 0 to 5 months, 30.1% for 6 to 11 months, 27.4% for 12 to 23 months, and 31.9% for
24 months or more.

CONCLUSIONS AND RELEVANCE These large-scale real-world data indicate that receipt of RAIT
Author Affiliations: Health Insurance
before pregnancy does not appear to be associated with increases in adverse pregnancy
Review and Assessment Service,
outcomes when conception occurs 6 months or more after treatment. Seoul, South Korea (Kim, S. M. Lee,
Seo); Department of Nuclear
Medicine, College of Medicine, Ewha
Womans University, Seoul, South
Korea (Kim); Department of Internal
Medicine, Samsung Medical Center,
Sungkyunkwan University School of
Medicine, Seoul, South Korea (K. Lee)
.
Corresponding Author: Gi Hyeon
Seo, MD, Health Insurance Review
and Assessment Service, 267,
Hyoryeong-ro, Seocho-gu, Seoul
JAMA Intern Med. doi:10.1001/jamainternmed.2019.4644 06653, South Korea
Published online October 21, 2019. (seogihyeon@hira.or.kr).

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 Research Original Investigation Association Between Pregnancy Outcomes and Radioactive Iodine Treatment for Thyroid Cancer
R
adioactive iodine treatment (RAIT) after thyroidec-
tomy for differentiated thyroid carcinoma is com-
monly used for remnant ablation and adjuvant therapy
and is intended to improve disease-specific and disease-free
survival.1 Radioactive iodine (RAI; sodium iodide I 131, or Na131I)
affects ovarian tissue, and common adverse effects of RAIT in-
clude oligomenorrhea, temporary secondary amenorrhea,
and/or an earlier onset of menopause.2-4 Radiation exposure
is also a risk factor for mutagenic abnormalities.
In 2015, the American Thyroid Association released guide-
lines that strongly recommended women of childbearing age
who are scheduled to receive RAIT should have a negative
screening result for pregnancy before RAI administration and
should avoid pregnancy for 6 to 12 months after receiving RAIT.1
In its 2017 guidelines, the American Thyroid Association up-
dated its recommendation for deferring pregnancy, reducing
the interval to 6 months after RAIT; however, the quality of
the evidence supporting this recommendation remains rela-
tively low.5 Guidelines from the European Association of
Nuclear Medicine Therapy Committee recommend that preg-
nancy should be avoided and effective contraception should
be used for 6 to 12 months after receiving RAIT.6
A study from 20152 reported that RAIT is associated with
a substantial delay in the median time between treatment and
first live birth across most reproductive age groups and with
a significantly decreased birth rate among women of ad-
vanced maternal age (35-39 years). Although concerns exist re-
garding the risks associated with pregnancy after RAIT, no
large-scale study, to our knowledge, has investigated the as-
sociation between RAIT and pregnancy outcomes.
This study used the Health Insurance Review and Assess-
ment (HIRA) database of South Korea to investigate whether
RAIT was associated with an increase in adverse pregnancy out-
comes, such as spontaneous and induced abortions, preterm
deliveries, and congenital malformations, among South Ko-
rean women of childbearing age (20-49 years) and to evalu-
ate the appropriate interval between the receipt of RAIT and
conception.
Methods
Data for this study were collected using the HIRA database of
South Korea, which includes the health insurance claims of the
country’s entire population. The HIRA database includes pa-
tient demographics, records of diagnoses as determined by the
International Classification of Diseases, Tenth Revision (ICD-
10), procedure codes, and prescription records. Identifying data
were removed from the HIRA patient records in accordance
with South Korea’s Personal Information Protection Act, which
is maintained by public agencies. This study was conducted
in accordance with the Declaration of Helsinki7 and approved
by the institutional review board of the Health Insurance Re-
view and Assessment Service of South Korea with a waiver of
informed consent.
The database search identified 255 245 women who un-
derwent thyroidectomy (HIRA procedure codes P4561, P4552,
P4554, P4551, and P4553) between January 1, 2008, and
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Key Points
Question What is the appropriate interval between treatment
and pregnancy among women who receive radioactive iodine
treatment after thyroidectomy for thyroid cancer?
Findings In this population-based cohort study of 111 459 South
Korean women of childbearing age (20-49 years) who underwent
thyroidectomy for differentiated thyroid carcinoma, the receipt of
radioactive iodine treatment after surgery was not associated with
an increase in the rates of abortion, preterm delivery, or congenital
malformation when conception occurred 6 months or more after
treatment compared with surgery alone.
Meaning These large-scale real-world data suggest that
radioactive iodine treatment after thyroidectomy is not associated
with an increase in adverse pregnancy outcomes when conception
occurs after a 6-month waiting period.
December 31, 2015. This sample was narrowed to 215 515
women who underwent thyroidectomy for the treatment of a
thyroid malignancy (ICD-10 code C73); of those, 111 459 women
of childbearing age (20-49 years) were selected for inclusion
in the study. The HIRA prescription claims code 3684 was used
to identify women who received RAIT, which was defined as
the administration of an RAI dose greater than 0.925 GBq. The
study population was then allocated to 2 groups: a surgery co-
hort composed of women who underwent thyroidectomy alone
(n = 59 483 [53.4%]) and a RAIT cohort composed of women
who underwent thyroidectomy followed by RAIT (n = 51 976
[46.6%]). Women who conceived before December 31, 2016,
were included. A total of 10 842 pregnancies, with 5958 in the
surgery cohort and 4884 in the RAIT cohort, occurred during
the study period. The linked records of infants delivered were
also obtained from the HIRA database. Of the 7445 deliveries
in both cohorts, 7096 records were matched as mother-
infant pairs, accounting for 95.3% of all deliveries within the
study period (Figure).
The date of conception was defined as the earliest of 38
weeks (266 days) before the date of delivery (HIRA procedure
codes R3131-R3148, R4351-R4362, R4380, R4501-R4520, R5001-
R5002, RA311-RA318, and RA361-RA362), 14 days before a clinic
visit with an ICD-10 code for abortion (ICD-10 codes O00-
O08), or 14 days before a clinic visit with an ICD-10 code for preg-
nancy (ICD-10 codes Z321 and Z33-Z35), in which only patients
who had revisited the clinic within 90 days with an ICD-10 code
for pregnancy were enrolled. Data were further analyzed based
on the cumulative RAI dose and the interval between RAIT and
conception; intervals were categorized as 0 to 5 months (0-179
days), 6 to 11 months (180-359 days), 12 to 23 months (360-719
days), and 24 months or more (≥720 days). The conception in-
terval after treatment was calculated from the date of thyroid-
ectomy in the surgery cohort and from the date of RAI admin-
istration in the RAIT cohort. Among patients who received RAIT
more than once, the conception interval was calculated from
the date of the last RAIT before pregnancy.
We analyzed both spontaneous and induced abortions
(defined as conception without delivery within 280 days),
preterm deliveries (ICD-10 codes O60, O601, and O603 at
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 Association Between Pregnancy Outcomes and Radioactive Iodine Treatment for Thyroid Cancer
0-90 days before delivery), and the presence of congenital
malformations at birth or during the first year of life. All con-
genital malformations were categorized into 10 groups that
were identified using ICD-10 codes: nervous system (ICD-10
codes Q00-Q07); eye, ear, face, and neck (ICD-10 codes Q10-
Q18); circulatory system (ICD-10 codes Q20-Q28); respira-
tory system (ICD-10 codes Q30-Q34); cleft lip and cleft palate
(ICD-10 codes Q35-Q37); other digestive system (ICD-10
codes Q38-Q45); genital organs (ICD-10 codes Q50-Q56); uri-
nary system (ICD-10 codes Q60-Q64); musculoskeletal sys-
tem (ICD-10 codes Q65-Q79); and other congenital malfor-
mations (ICD-10 codes Q80-Q99). Congenital stenosis and
stricture of lacrimal duct (ICD-10 code Q10.5) and ankylo-
glossia (ICD-10 code Q38.1) were excluded from analysis
because clinical diagnosis of these conditions is inconsis-
tent, and the conditions are often resolved without medical
treatment. The pregnancy outcomes data were collected
from January 1, 2008, to December 31, 2017.
Descriptive statistical analyses were performed for all
women included in the study. A χ2 test was used to evaluate
the associations between pregnancy outcomes and RAIT. A
multivariate logistic regression analysis was conducted to cal-
culate adjusted odds ratios (AORs) and 95% CIs for risk fac-
tors associated with adverse pregnancy outcomes among
women who received RAIT. All statistical tests were 2-sided
with a significance threshold of P < .05. Data analyses were per-
formed using R software, version 3.4.0 (R Foundation for Sta-
tistical Analysis).
Results
Among the 111 459 women who underwent thyroidectomy
for the treatment of thyroid cancer, the mean (SD) age at
treatment with surgery or RAIT was 39.8 (6.7) years
(Table 1). Of those, 10 842 women (9.7%) became pregnant
(10.0% of women in the surgery cohort compared with 9.4%
of women in the RAIT cohort; P < .001), and the mean (SD)
age at conception for both cohorts was 33.3 (4.4) years. In
the RAIT cohort, the mean (SD) cumulative RAI dose was
4.44 (3.17) GBq; 10 367 patients (19.9%) received RAIT more
than 2 times. Significant differences were noted in the time
between treatment and conception in the surgery and RAIT
cohorts (mean [SD], 22.0 [19.1] months vs 25.3 [17.4]
months, respectively; P < .001). The conception rates in the
RAIT cohort were significantly lower than those of the sur-
gery cohort for the intervals of 0 to 5 months and 6 to 11
months after treatment (0.7% vs 2.0% and 1.4% vs 1.9%,
respectively; P < .001). The conception rates in the 12- to
23-month interval were 3.5% in the RAIT cohort and 2.6% in
the surgery cohort.
No statistically significant differences were observed in the
rates of abortion (both spontaneous and induced) between the
surgery and RAIT cohorts (30.7% vs 32.1%, respectively; P = .12;
Table 2). A total of 956 preterm deliveries (12.8%) were ob-
served in both cohorts, with no significant difference be-
tween the surgery and RAIT cohorts (12.8% vs 12.9%, respec-
tively; P = .96). In total, 634 cases of congenital malformation
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Original Investigation Research
Figure. Flow Diagram of Study Cohort Selection
255 245 Women who underwent thyroidectomy
assessed for eligibilty
39 730 Excluded who did not have
thyroid cancer
215 515 Underwent thyroidectomy for thyroid cancer
104 056 Excluded who were not of
childbearing age
(<20 or >49 years)
111 459 Were of childbearing age (20-49 years)
59 483 Included in surgery cohort 51 976 Included in RAIT cohort
(underwent surgery alone) (underwent surgery
plus RAIT)
59 483 Included in analysis 51 976 Included in analysis
5958 Pregnancies after 4884 Pregnancies after RAIT
surgery 3316 Deliveries
4129 Deliveries 3166 Mother-infant
3930 Mother-infant pairs
pairs
RAIT indicates radioactive iodine treatment.
(8.9%) were observed in both cohorts, with 349 cases (8.9%)
in the surgery cohort and 285 cases (9.0%) in the RAIT cohort
(P = .89).
In a preplanned subgroup analysis based on the interval
between RAIT and conception, 18 cases of congenital mal-
formation (13.3%) were observed in the 0- to 5-month inter-
val, 37 cases (7.9%) in the 6- to 11-month interval, 105 cases
(8.3%) in the 12- to 23-month interval, and 125 cases (9.6%)
in the 24-month or more interval (Table 3). Eighteen cases
of congenital malformation were observed among women
who became pregnant less than 6 months after RAIT,
including 6 cases of malformation in the circulatory system,
4 in the musculoskeletal system, and 3 in the urinary sys-
tem, with rare cases of malformation in the nervous system,
respiratory system, lip and palate, and genital organs. The
OR of congenital malformation after adjusting for age at
conception and cumulative RAI dose was 1.74 (95% CI, 1.01-
2.97; P = .04) for the 0- to 5-month interval after RAIT com-
pared with the 12- to 23-month interval after RAIT (Table 4).
In the surgery cohort, the interval between surgery and con-
ception was not associated with a risk of congenital malfor-
mation.
The rates of abortion (both spontaneous and induced)
based on the interval between RAIT and conception in the RAIT
cohort were 60.6% for the 0- to 5-month interval, 30.1% for
the 6- to 11-month interval, 27.4% for the 12- to 23-month in-
terval, and 31.9% for the 24-month or more interval. Early con-
ception (less than 6 months) after RAIT was associated with
an increased abortion rate (AOR, 4.08; 95% CI, 3.19-5.22;
P < .001). The abortion rate for the 6- to 11-month interval be-
tween RAIT and conception did not differ significantly from
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 Research Original Investigation Association Between Pregnancy Outcomes and Radioactive Iodine Treatment for Thyroid Cancer

Table 1. Characteristics of the Study Population

No. (%)
Total Population Surgery Cohort RAIT Cohort
Characteristic (N = 111 459) (n = 59 483) (n = 51 976) P Value
Age at thyroidectomy 39.8 (6.7) 39.8 (6.6) 39.8 (6.9) .70
or RAIT, mean (SD), y
Pregnancies 10 842 (9.7) 5958 (10.0) 4884 (9.4) <.001
Age at thyroidectomy, mean (SD), y 31.2 (4.5) 31.5 (4.4) 30.7 (4.5) <.001
Age at RAIT, mean (SD), y NA NA 31.2 (4.5) NA
Age at conception, y
.39
Mean (SD) 33.3 (4.4) 33.3 (4.3) 33.2 (4.4)
20-29 2003 (18.5) 1078 (18.1) 925 (18.9)
30-34 5063 (46.7) 2801 (47.0) 2262 (46.3)
.25
35-39 2810 (25.9) 1525 (25.6) 1285 (26.3)
≥40 966 (8.9) 554 (9.3) 412 (8.4)
Conception interval, mo
0-5 1545 (1.4) 1187 (2.0) 358 (0.7)
6-11 1860 (1.7) 1150 (1.9) 710 (1.4) <.001
12-23 3378 (3.0) 1559 (2.6) 1819 (3.5)
≥24 4059 (3.6) 2062 (3.5) 1997 (3.8)
Deliveries, No. (% of pregnancies) 7445 (68.7) 4129 (69.3) 3316 (67.9) .12
Mother-infant pairs 7096 3930 3166 .59
Infant status .33
Male, single birth 3510 (49.5) 1914 (48.7) 1596 (50.4)
Female, single birth 3416 (48.1) 1923 (48.9) 1493 (47.2)
Abbreviation: RAIT, radioactive iodine
Multiple birth 170 (2.4) 93 (2.4) 77 (2.4)
treatment.

Table 2. Frequency of Adverse Pregnancy Outcomes

No. (%)
Total Population Surgery Cohort RAIT Cohort
Outcome (N = 111 459) (n = 59 483) (n = 51 976) P Value
Pregnancies 10 842 (9.7) 5958 (10.0) 4884 (9.4) <.001
Abortions, No. (% of pregnancies) 3397 (31.3) 1829 (30.7) 1568 (32.1) .12
Preterm deliveries, No. (% of 956 (12.8) 529 (12.8) 427 (12.9) .96
deliveries)
Deliveries, No. (% of pregnancies) 7445 (68.7) 4129 (69.3) 3316 (67.9) .12
Mother-infant pairs 7096 3930 3166
Congenital malformations, No. 634 (8.9) 349 (8.9) 285 (9.0)
.89
(% of mother-infant pairs)
Nervous system 22 (0.3) 9 (0.2) 13 (0.4)
Eye, ear, face and neck 31 (0.4) 14 (0.4) 17 (0.5)
Circulatory system 225 (3.2) 124 (3.2) 101 (3.2)
Respiratory system 18 (0.3) 13 (0.3) 5 (0.2)
Cleft lip and cleft palate 12 (0.2) 6 (0.2) 6 (0.2)
NA
Other digestive system 27 (0.4) 13 (0.3) 14 (0.4)
Genital organs 46 (0.6) 20 (0.5) 26 (0.8)
Urinary system 61 (0.9) 36 (0.9) 25 (0.8)
Musculoskeletal system 198 (2.8) 110 (2.8) 88 (2.8)
Abbreviation: RAIT, radioactive iodine
Other malformation 45 (0.6) 25 (0.6) 20 (0.6)
treatment.

that of the 12- to 23-month interval (AOR, 1.16; 95% CI, 0.95-
1.42; P = .14). Increased maternal age (40 years or older) at
conception was associated with an increased risk of abortion
(AOR, 10.61; 95% CI, 8.05-13.96; P < .001). The number of
preterm births in the surgery cohort was 79 (9.5%) in the 0-
to 5-month interval, 93 (11.6%) in the 6- to 11-month interval,
133 (12.2%) in the 12- to 23-month interval, and 224 (16.0%)
in the 24-month or more interval (P < .001). In the RAIT
cohort, the number of preterm births was 15 (10.6%) for the
0- to 5-month interval, 61 (12.3%) for the 6- to 11-month
interval, 149 (11.3%) for the 12- to 23-month interval, and
202 (14.9%) for the 24-month or more interval (P = .04). The
cumulative dose of RAI was not associated with the risk of
congenital malformation.

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 Table 3. Pregnancy Outcomes Based on Conception Interval After Surgery or RAIT and Cumulative RAI Dose

Surgery Cohort, No. (%) RAIT Cohort, No. (%)

Conception Interval After Surgery, mo Conception Interval After RAIT, mo Cumulative RAI Dose, GBq
P P ≤1.11 1.12-3.7 ≥3.8 P
Pregnancy Outcome 0-5 6-11 12-23 ≥24 Value 0-5 6-11 12-23 ≥24 Value (n = 10 315) (n = 16 477) (n = 25 184) Value
Pregnancies 1187 1150 1559 2062 NA 358 710 1819 1997 NA 807 1325 2752 NA

jamainternalmedicine.com
Abortions, No. (% of pregnancies) 355 (29.9) 345 (30.0) 468 (30.0) 661 (32.1) .43 217 (60.6) 214 (30.1) 499 (27.4) 638 (31.9) <.001 260 (32.2) 443 (33.4) 865 (31.4) .44
Preterm deliveries, No. 79 (9.5) 93 (11.6) 133 (12.2) 224 (16.0) <.001 15 (10.6) 61 (12.3) 149 (11.3) 202(14.9) .04 82 (15.0) 107 (12.1) 238 (12.6) .26
(% of deliveries)
Deliveries 832 (70.1) 805 (70.0) 1091 (70.0) 1401 (67.9) .43 141 (39.4) 496 (69.9) 1320 (72.6) 1359 (68.1) <.001 547 (67.8) 882 (66.6) 1887 (68.6) .44
Mother-infant pairs 792 762 1030 1346 .23 135 471 1264 1296 .89 525 846 1795 .53
Congenital malformations, No. 67 (8.5) 58 (7.6) 103 (10.0) 121 (9.0) .35 18 (13.3) 37 (7.9) 105 (8.3) 125 (9.6) .16 45 (8.6) 76 (9.0) 164 (9.1) .92
(% of mother-infant pairs)
Nervous system 2 (0.3) 0 4 (0.4) 3 (0.2) 1 (0.7) 2 (0.4) 3 (0.2) 7 (0.5) 5 (1.0) 0 8 (0.4)
Eye, ear, face and neck 3 (0.4) 3 (0.4) 4 (0.4) 4 (0.3) 0 5 (1.1) 7 (0.6) 5 (0.4) 7 (1.3) 1 (0.1) 9 (0.5)
Circulatory system 23 (2.9) 18 (2.4) 40 (3.9) 43 (3.2) 6 (4.4) 12 (2.5) 40 (3.2) 43 (3.3) 14 (2.7) 32 (3.8) 55 (3.1)
Respiratory system 3 (0.4) 3 (0.4) 5 (0.5) 2 (0.1) 1 (0.7) 0 3 (0.2) 1 (0.1) 1 (0.2) 2 (0.2) 2 (0.1)
Cleft lip and cleft palate 0 0 3 (0.3) 3 (0.2) 1 (0.7) 0 3 (0.2) 2 (0.2) 0 3 (0.4) 3 (0.2)
NA NA NA
Other digestive system 6 (0.8) 2 (0.3) 2 (0.2) 3 (0.2) 0 3 (0.6) 4 (0.3) 7 (0.5) 2 (0.4) 2 (0.2) 10 (0.6)
Genital organs 2 (0.3) 6 (0.8) 6 (0.6) 6 (0.4) 1 (0.7) 3 (0.6) 10 (0.8) 12 (0.9) 3 (0.6) 6 (0.7) 17 (0.9)
Urinary system 6 (0.8) 5 (0.7) 11 (1.1) 14 (1.0) 3 (2.2) 2 (0 .4) 5 (0.4) 15 (1.2) 5 (1.0) 5 (0.6) 15 (0.8)
Musculoskeletal system 20 (2.5) 20 (2.6) 27 (2.6) 43 (3.2) 4 (3.0) 13 (2.8) 36 (2.8) 35 (2.7) 14 (2.7) 25 (3.0) 49 (2.7)
Other malformation 3 (0.4) 3 (0.4) 5 (0.5) 14 (1.0) 2 (1.5) 3 (0.6) 6 (0.5) 9 (0.7) 2 (0.4) 4 (0.5) 14 (0.8)
Association Between Pregnancy Outcomes and Radioactive Iodine Treatment for Thyroid Cancer

Abbreviations: RAI, radioactive iodine (sodium iodide I 131, or Na131I); RAIT, radioactive iodine treatment.

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Original Investigation Research

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 Research Original Investigation Association Between Pregnancy Outcomes and Radioactive Iodine Treatment for Thyroid Cancer

Table 4. Multivariate Analysis of Risk Factors Associated With Adverse Pregnancy Outcomes in Women Receiving RAIT

Abortion Preterm Delivery Congenital Malformation

Risk Factor OR (95% CI) P Value OR (95% CI) P Value OR (95% CI) P Value
Cumulative RAI dose, GBq
≤1.11 [Reference] NA NA NA NA NA NA
1.12-3.7 1.11 (0.91-1.36) .30 0.79 (0.58-1.08) .14 1.06 (0.72-1.56) .76
≥3.8 1.02 (0.85-1.22) .81 0.82 (0.63-1.08) .16 1.08 (0.76-1.52) .68
Conception interval after RAIT, mo
0-5 4.08 (3.19-5.22) <.001 0.92 (0.53-1.62) .78 1.74 (1.01-2.97) .04
6-11 1.16 (0.95-1.42) .14 1.10 (0.80-1.51) .57 0.95 (0.64-1.41) .80
12-23 [Reference] NA NA NA NA NA NA
≥24 1.08 (0.93-1.25) .31 1.34 (1.07-1.69) .01 1.17 (0.89-1.54) .26
Age at conception, y
20-29 [Reference] NA NA NA NA NA NA
30-34 1.17 (0.97-1.40) .10 0.97 (0.74-1.27) .83 1.27 (0.91-1.76) .16
35-39 2.11 (1.73-2.56) <.001 1.22 (0.90-1.64) .20 1.28 (0.88-1.86) .19
≥40 10.61 (8.05-13.96) <.001 1.22 (0.68-2.17) .51 1.39 (0.60-3.22) .44
131
Abbreviations: NA, not applicable; OR, odds ratio; RAI, radioactive iodine (sodium iodide I 131, or Na I); RAIT, radioactive iodine treatment.

Discussion
In this population-based cohort study, the rates of adverse preg-
nancy outcomes, including spontaneous and induced abor-
tions, preterm deliveries, and congenital malformations, did
not differ between the surgery and RAIT cohorts. However, a
subgroup analysis that examined the interval between RAIT
and conception found that, after adjusting for age at concep-
tion and cumulative RAI dose, the congenital malformation rate
was higher when conception occurred early (less than 6
months) after RAIT. Early conception after RAIT was also as-
sociated with an increased abortion rate; however, this asso-
ciation was not observed in the 6- to 11-month interval group.
Adverse pregnancy outcomes were not associated with the cu-
mulative RAI dose.
The oncologic complications of RAIT associated with an
increased risk of developing solid cancers and leukemia have
been relatively well documented in studies of large
populations.8-12 Small studies have reported the pregnancy out-
comes of women who received RAIT before conception.13-21 To
our knowledge, this study is the first large-scale, nationwide
cohort study to examine the associations between RAIT and
pregnancy outcomes.
Previous studies that examined congenital malformation
rates among women who received RAIT before conception did
not report any significant associations; however, these stud-
ies were limited owing to the small number of patients who
h a d re c e ive d R A I T a n d t h e r a r it y o f c o nge n it a l
malformations.19,20 Those data could therefore not be strati-
fied based on the cumulative RAI dose and the interval be-
tween RAIT and conception. After RAI administration, the pri-
mary sources of radiation to the ovaries are the blood, bladder,
and gut, along with iodine uptake in metastases close to the
ovaries.16 Although a radiation dose of 140 mGy has been re-
ported to be damaging to the ovaries, when an RAI dose of 3.7
GBq was administered,20 the specific dose absorbed in the
ovaries after RAIT was only weakly associated with the RAI
dose administered owing to multiple anatomic, physiologic,
and pathophysiologic factors.19 Furthermore, the patient’s hy-
pothyroid status at the time of RAI administration can affect
the renal clearance of iodine, thereby increasing radiation ex-
posure to the ovaries. In this study, even groups that received
a cumulative RAI dose of more than 3.7 GBq did not exhibit
increased congenital malformations, although conception less
than 6 months after RAIT was associated with an increased risk
of congenital malformation. The possibility that a substantial
percentage of the induced abortions among early concep-
tions may have masked an increased incidence of congenital
malformation remains to be evaluated. However, based on
these real-world observational data, a waiting period after RAIT,
as current clinical practice guidelines recommend, appears to
be a reasonable approach.
Substantial differences were observed in preterm births
based on the interval between RAIT and conception; how-
ever, the frequency of preterm births was higher in those who
became pregnant years after RAIT compared with those who
became pregnant within the first few months. In the surgery
cohort, the preterm birth rates after surgery also increased over
time. Considering these data, preterm birth rates do not ap-
pear to be associated with RAIT.
The increase in abortion rates among patients who con-
ceived early after RAIT is consistent with a previous system-
atic review, which reported that the rates of spontaneous and
induced abortion increased in the first year after RAIT.3 Our
study was able to further categorize the interval between RAIT
and conception into 6-month periods owing to its large sample.
The results indicated that the abortion rate in the RAIT co-
hort was higher among women who became pregnant less than
6 months after RAIT compared with those who became preg-
nant 6 months or more after RAIT. However, among concep-
tions that occurred 6 to 11 months after RAIT, we did not ob-
serve a statistically higher rate of abortion compared with
conceptions that occurred 12 to 23 months after RAIT. In the

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 Association Between Pregnancy Outcomes and Radioactive Iodine Treatment for Thyroid Cancer Original Investigation Research

surgery cohort, no difference was observed in the abortion rate
relative to the interval between surgery and conception.
Although this study was not able to differentiate be-
tween spontaneous and induced abortions owing to limita-
tions in the HIRA claims database, a high rate of induced abor-
tions may have been likely during the early conception stage
after RAIT. The induced abortion rate among patients who re-
ceived RAIT has been reported in previous studies.16,17 A study
by Chow et al17 noted that 8 of 15 patients (53.3%) chose to ter-
minate a pregnancy if conception occurred within 1 year after
RAIT. Schlumberger et al16 also reported a significant in-
crease in induced abortions among women who received RAIT
the year before conception (10 of 20 [50%]) compared with
those who did not (45 of 247 [18%]; P < .001). Given that cur-
rent guidelines advise women to defer pregnancy for 6 to 12
months after RAIT, women who became pregnant early after
RAIT may have feared adverse effects on their fetuses or may
have been advised by their physicians to undergo a therapeu-
tic abortion. Thousands of induced abortions were reported
after the Chernobyl accident.22,23 Nevertheless, in real-world
practice, spontaneous and induced abortion rates did not con-
tinue to increase beyond 6 months after RAIT.
Although current guidelines recommend that women de-
lay pregnancy for 6 to 12 months after RAIT,1,5,6 in clinical prac-
tice, many clinicians may recommend extending the waiting
period to 12 months. A previous study reported that the me-
dian time to first birth was 34.5 months among women who
received RAIT compared with 26.1 months among women who
did not.2 Our data also demonstrated that the RAIT cohort ex-
perienced a longer interval between RAIT and conception com-
pared with the surgery cohort. This finding is likely to be an
example of delayed childbearing behavior among women who
received RAIT; however, the possibility that women experi-
enced increased infertility within the first 6 months after RAIT
cannot be excluded. In either case, given the increased ob-
stetric and perinatal complications associated with delayed
pregnancy owing to increased maternal age,24-26 accurate in-
formation about the recommended interval between RAIT and
conception is critical for women of childbearing age and their
treating physicians.
Limitations
This study had several limitations. Disease diagnoses may have
been miscoded in the claims data. Our findings were based on
ICD-10 diagnosis codes, and these codes are primarily in-
tended to be used for reimbursement purposes. Despite any
potential misclassifications, ICD-10 codes are a critical tool for
large-scale population studies. This study used operational
definitions to identify the date of conception because the HIRA
claims data did not provide detailed information about exact
gestational age at birth. Therefore, for the start date of preg-
nancy, we used 38 weeks (266 days) before delivery, which is
the typical duration of a full-term human pregnancy, as noted
in previous studies.27,28 However, if a delivery was notably pre-
term, the start date of pregnancy may have been set at a date
before actual conception because our start date was assumed
to be 38 weeks before delivery. In this case, the calculated in-
terval between RAIT and conception would have been shorter
than the actual interval, which may have resulted in overes-
timation of preterm birth rates in the 0- to 5-month interval.
However, even if some of these values were overestimated, the
association between a higher frequency of preterm births
among those who became pregnant years after RAIT com-
pared with those who became pregnant less than 6 months af-
ter RAIT would remain. On the other hand, in cases of con-
ception without delivery, in which the start date of pregnancy
was assumed to be 14 days before the first clinic visit, the cal-
culated conception date may have been set later than actual
conception date. In this case, abortions in the 0- to 5-month
interval would have been underestimated because the calcu-
lated interval may have been longer than the actual interval.
Factors other than RAIT history, including stage of mater-
nal thyroid cancer, history of smoking, alcohol intake, preex-
isting ovarian dysfunction, and partner’s genetic disease, which
may have influenced the results, were not considered. Pa-
tients who received RAIT were given maintenance treatment
with suppressive levothyroxine therapy, even during preg-
nancy, and suppression of thyrotropin levels may have af-
fected the study’s results. Furthermore, we were not able to
assess maternal hypothyroidism caused by medication non-
compliance or inadequately titrated thyroid hormone replace-
ment therapy owing to the absence of data about maternal thy-
roid function. Previous data have consistently indicated that
maternal thyroid hormone status is associated with preg-
nancy complications and adverse effects in fetuses and
infants.20,29 This study included a surgery cohort that re-
ceived maintenance treatment with suppressive levothyrox-
ine therapy without RAIT, but the possibility that abnormal thy-
roid hormone status affected the study’s results cannot be
excluded. We did not examine studies of radiographic imaging,
such as pelvic computed tomography or diagnostic radioio-
dine scans. Although the effects of radiographic imaging ex-
amined in these studies may have affected our results, the
number of imaging studies conducted among pregnant women
is low; therefore, their influence was considered to be mini-
mal to the study’s results.
Conclusions
These large-scale real-world data suggest that RAIT after thy-
roidectomy is not associated with an increase in adverse preg-
nancy outcomes when conception occurs 6 months or more
after treatment compared with thyroidectomy alone.

ARTICLE INFORMATION
Accepted for Publication: August 22, 2019.
Published Online: October 21, 2019.
doi:10.1001/jamainternmed.2019.4644
Author Contributions: Dr Kim and Dr K. Lee
contributed equally to the study. Dr Seo had full
access to all of the data in the study and takes
responsibility for the integrity of the data and the
accuracy of the data analysis.
Concept and design: Kim, K. Lee.
Acquisition, analysis, or interpretation of data: All
authors.
Drafting of the manuscript: Kim.
Critical revision of the manuscript for important

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 Research Original Investigation
intellectual content: K. Lee, S. Lee, Seo.
Statistical analysis: Seo.
Supervision: K. Lee, S. Lee, Seo.
Conflict of Interest Disclosures: None reported.
Additional Contributions: Professional editing
services were provided by Textcheck, a scientific
and technical editing company, which was
compensated for its work.
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