Abstract
Background
The effects of thyroid hormone replacement or suppression therapy in women with thyroid cancer on thyroid function during pregnancy and subsequent adverse fetal outcomes are still largely unknown. To compare thyroid function at 8 weeks of gestation and its changes during pregnancy between the survivors and controls, and to assess the association of these differences with adverse fetal outcomes.
Methods
This was a retrospective cohort-based parallel control study. A total of 140 survivors and 280 controls delivery time-matched controls were extracted from 46,610 singleton pregnant women who received prenatal examinations in a second-level specialized hospital between January 2019 and March 2024. The primary outcomes were birth defects, small for gestational age (SGA, defined as birth weight < 10th percentile by gestational week), preterm birth (< 37 weeks), and neonatal asphyxia (defined as fetuses with a 1 min-Apgar score of < 7). Apgar scores at 1 and 5 min and umbilical arterial blood gas (ABG) indexes were surrogate indicators of neonatal asphyxia.
Results
Compared to the control group, FT3 was lower in the survivors, while FT4 was higher. Change of FT3 between 8 and 16 weeks of gestation in survivors was significantly smaller than that in the controls (-0.08 vs. -0.30, P < 0.005). The survivors had an insignificant association with SGA/preterm birth (adjusted OR 2.06, 0.68–6.23, P = 0.20), a slightly higher risk of fetal asphyxia (Peto OR, 6.49; 95% CI: 0.81-52.0; P = 0.078), and a lower 1 min Apgar score (β, -0.10; 95% CI: -0.16 to -0.03;P = 0.004). Change in FT3 between 8 and 16 weeks was associated with SGA/preterm birth (adjusted OR, 4.42, 95%CI: 1.32–14.84, P = 0.016). FT3 at 8 weeks of gestation and its changes between 16 and 32 weeks of gestation were negatively correlated with the umbilical ABG index, with both β of -0.02(p = 0.015 and 0.019, respectively).
Conclusions
This study found differences in FT3 and FT4 levels and their changes during pregnancy between the survivors and controls. These differences, especially the changes in FT3 during pregnancy, might suggest a potential biological link, though further studies are needed to establish causality.
Keywords: Thyroid cancer survivors, Pregnancy, Thyroid function, Birth weight, Apgar scores, Umbilical arterial blood gas
Introduction
Thyroid cancer, a malignant tumor that originates from the follicular epithelium of the thyroid gland, is one of the most common malignant endocrine tumors among women of childbearing age and the incidence is currently increasing year by year [1]. In China, thyroid cancer ranks fourth among common cancers [2]. Despite the high burden, most pregnant women who are thyroid cancer survivors have a good prognosis, with a 5-year survival rate of > 98% [3].
Normal thyroid function is crucial for maintaining a smooth pregnancy and supporting normal fetal growth and development [4]. Maternal thyroid dysfunction is associated with an increased risk of adverse pregnancy outcomes, including miscarriage, preterm delivery, pre-eclampsia, gestational diabetes mellitus (GDM), postpartum hemorrhage, and abnormal fetal development [3–9]. Pregnant women with a history of thyroid cancer are an increasing concern due to the potential impact of the treatment on thyroid function. According to the management guidelines of the American Thyroid Association, thyroid hormone replacement or suppression therapy is typically prescribed for the affected women who have undergone thyroidectomy [10].
Adverse pregnancy outcomes may arise from hypothyroidism due to thyroidectomy and hyperthyroidism following thyroid stimulating hormone (TSH) suppressive therapy [4]. Numerous studies have investigated the association between pregnant women with a history of thyroid cancer and the risk of adverse pregnancy outcomes [4, 5, 9, 11]. Although there are inconsistencies regarding postpartum hemorrhage [5, 9], these studies generally conclude null associations for adverse fetal outcomes. However, few studies have examined the association of the changes in thyroid function during pregnancy in survivors with adverse fetal outcomes. Our previous studies have found that the impact of thyroid function during pregnancy on the fetus is specific to the gestational age [8, 12], with this specificity occurring around 18 weeks, close to the time when the fetal thyroid function matures. Therefore, we conducted a matched parallel case-control study within a retrospective cohort study to address the concerns. We hypothesized that changes in thyroid function in women with a history of thyroid cancer would be different from those in controls, and consequently have an impact on fetal outcomes.
Materials and methods
Study design
This was a retrospective cohort-based parallel control study. The cohort consisted of singleton pregnant women who received prenatal examinations at Tongren Hospital, Shanghai Jiao Tong University School of Medicine between January 2019 and March 2024. All pregnant women underwent routine prenatal examinations and were followed up until delivery. Pregnant women with a history of thyroid cancer were enrolled as the observed group. Inclusion criteria included: a histopathological diagnosis of thyroid cancer after thyroid surgery (total thyroidectomy or lobectomy), a singleton pregnancy, no mental illness, and age above 18 years old during pregnancy. During the period, each pregnant woman with a history of thyroid cancer was randomly matched with 2 controls from the 46,470 pregnant women without a history of thyroid cancer, using maternal age (± 3 years) and delivery time (± 2 days) as matching criteria. The study was approved and a waiver of informed consent was granted by the ethics committee of Tongren Hospital, Shanghai Jiao Tong University School of Medicine.
Data collection
The basic information was extracted from medical records, including maternal age, parity, mode of conception, miscarriage history, pre-pregnancy weight and height, weight gain during pregnancy, and maternal complications during pregnancy (gestational hypertension, gestational diabetes, etc.). Fetal outcomes and delivery information were recorded after delivery.
Adverse fetal outcomes
In the present study, we focused on adverse fetal outcomes, including birth defects (BD), small for gestational age (SGA, defined as birth weight < 10th percentile by gestational week), preterm birth (< 37 weeks of gestation), and neonatal asphyxia (defined as neonates with a 1 min-Apgar score of < 7) [2, 4]. Considering the small number of neonatal asphyxia (4 cases), we combined SGA (17 cases) and preterm births (7 cases) into a composite outcome. We used three measures, 1-minute and 5-minute Apgar scores and umbilical arterial blood gas (ABG) index, to assess the risk of neonatal asphyxia.
Thyroid function measurement
Maternal serum samples were collected at the prenatal visits to the hospital. Thyroid hormones, including TSH, free-triiodothyronine (FT3), free-thyroxine (FT4), were measured at tested at 8, 16, and 32 weeks of gestation. Thyroid hormone concentrations were measured with an electro-chemiluminescence immunoassay (BECKMAM COULTER DXI800, USA).
According to relevant Chinese guidelines [13, 14], levothyroxine is the first choice for thyroid replacement therapy in pregnant women who have undergone thyroid cancer surgery. During pregnancy, the patient’s TSH level was monitored to adjust the levothyroxine dosage accordingly, aiming to keep TSH within the target range.
Covariates
We collected the following covariates that were included in the adjusted model, including maternal age at pregnancy (years), pre-pregnancy body mass index (BMI) (< 18.5, 18.5–24.0 or > 24 kg/m2), gestational weight gain (kg), natural conception (yes or no), history of miscarriage (yes or no), parity (0 or ≥ 1), gestational diabetes mellitus (yes or no) and pre-eclampsia (yes or no).
Data analysis
Differences between the observed and control groups were compared using t-tests for continuous variables and chi-squared tests or Fisher’s exact tests for categorical variables. The data analysis consisted of 3 parts. First, differences in thyroid function at 8 weeks of gestation and the changes during pregnancy (e.g., changes between 8 and 16 or 16 and 32 weeks of gestation) between the observed pregnant women with a history of thyroid cancer and controls were assessed using GEE model.
Second, associations of survivors, early pregnancy thyroid function, and their changes during pregnancy with risk of adverse fetal outcomes were estimated by logistic regression. Odds ratio (OR) and 95% confidence interval (CI) were presented. The covariates collected were controlled for in the adjusted models. Peto’s OR was calculated for the association with neonatal asphyxia due to the rare cases (4 cases). Association of survivors and thyroid function during pregnancy with Apgar scores at 1 and 5 min and umbilical ABG index were estimated using linear regression.
Third, the potential non-linear association between changes in FT3 between 8 and 16 weeks and SGA was estimated using a restricted cubic spline curve based on the logistic regression model (four knots at the 20th, 40th, 60th, and 80th percentiles). The cutoff of changes in FT3 between 8 and 16 weeks of gestation was determined using ROC method, along with sensitivity and specificity. We also fitted the relationship between early pregnancy FT3 and its changes during pregnancy with umbilical ABG indices.
All analyses were conducted by SPSS version 20 and the Stata 12.0 software package. A two-sided P < 0.05 was considered statistically significant.
Results
Basic characteristics
After matching for maternal age and delivery time, 280 controls were confirmed, along with 140 survivors, a total of 420 pregnant women were included in the analysis (Fig. 1). The mean age of the study population was 32.54 years (SD, 3.27), with predominantly natural conception (94.3%). A total of 144 participants (34.3%) reported a history of miscarriage. The incidence rates of gestational diabetes mellitus and preeclampsia were 6.4% and 3.8%, respectively. A total of 52 fetuses (with one fetus experiencing two adverse outcomes) were identified with adverse outcomes, including 25 BD, 24 SGA/preterm birth, and 4 cases of neonatal asphyxia. No statistically significant differences in variables or outcomes between the observed and control groups were found, except for a difference in 1-minute Apgar scores (8.91 vs. 8.98, P = 0.04; Table 1).
Fig. 1.
Study flow chart
Table 1.
Basic characteristics and fetal outcomes between case and control group
| Characteristics and fetal outcomes | Control (N = 280) | Case (N = 140) | P value | Total sample (N = 420) | |||
|---|---|---|---|---|---|---|---|
| Mean | SD | Mean | SD | Mean | SD | ||
| Maternal age, years, mean, SD | 32.39 | 3.09 | 32.84 | 3.60 | 0.21 | 32.54 | 3.27 |
| Gestational weight gain, kg; mean, SD | 12.42 | 3.88 | 12.75 | 4.61 | 0.43 | 12.53 | 4.14 |
| Apgar, 1 min | 8.98 | 0.17 | 8.91 | 0.41 | 0.04 | 8.96 | 0.27 |
| Apgar, 5 min | 9.38 | 0.50 | 9.41 | 0.54 | 0.64 | 9.39 | 0.51 |
| Umbilical arterial blood gas index | 7.31 | 0.06 | 7.30 | 0.07 | 0.23 | 7.31 | 0.07 |
| Parity (0)* | 193 | 68.9% | 98 | 70.0% | 0.82 | 291 | 69.3% |
| Natural conception* | 267 | 95.4% | 129 | 92.1% | 0.18 | 396 | 94.3% |
| History of miscarriage* | 98 | 35.0% | 46 | 32.9% | 0.66 | 144 | 34.3% |
| Gestational diabetes mellitus* | 49 | 17.5% | 20 | 14.3% | 0.40 | 69 | 16.4% |
| Preeclampsia* | 10 | 3.6% | 6 | 4.3% | 0.72 | 16 | 3.8% |
| Pre-pregnancy body mass indes (kg/m2)* | 0.24 | ||||||
| 18.5–24 | 223 | 79.6% | 112 | 80.0% | 335 | 79.8% | |
| < 18.5 | 25 | 8.9% | 7 | 5.0% | 32 | 7.6% | |
| > 24 | 32 | 11.4% | 21 | 15.0% | 53 | 12.6% | |
| Fetal outcomes* | |||||||
| Total | 34 | 12.1% | 18 | 12.9% | > 0.99 | 52 | 12.4% |
| Birth defects | 20 | 7.1% | 5 | 3.6% | 0.17 | 25 | 6.0% |
| Small for gestational age/preterm birth | 13 | 4.6% | 11 | 7.9% | 0.20 | 24 | 5.7% |
| Neonatal asphyxia | 1 | 0.4% | 3 | 2.1% | 0.11# | 4 | 1.0% |
*Present as number and %. # P for Fisher’s exact test
Differences in thyroid function between survivors and controls
The GEE model showed that both FT3 and FT4 decreased significantly with gestational week (P < 0.001). Compared to the control group, FT3 was lower in the observed group, while FT4 was higher, and there was no significant difference in TSH (Table 2; Fig. 2). Compared with measurements at 8 weeks of gestation, FT3, FT4, and TSH all showed significant decreases at 16 weeks (all P < 0.001). At 32 weeks, the declines in FT3 and FT4 remained significant, but the change in TSH did not reach statistical significance (Table 2). The change of FT3 between 8 and 16 weeks of gestation for the observed pregnant women with a history of thyroid cancer was significantly smaller than that in the controls (-0.08 vs. -0.30, P < 0.005; Fig. 2).
Table 2.
Changes in thyroid function during pregnancy and case-control group differences
| Free-triiodothyronine | Free-thyroxine | Thyroid stimulating hormone | |||||||
|---|---|---|---|---|---|---|---|---|---|
| β | 95% confidence interval | P | β | 95% confidence interval | P | β | 95% confidence interval | P | |
| Subjects | |||||||||
| Control | Reference | Reference | Reference | ||||||
| Case | -0.19 | -0.26 to -0.11 | < 0.001 | 0.90 | 0.55 to 1.24 | < 0.001 | 0.01 | -0.18 to 0.19 | 0.95 |
| Gestational weeks at test | |||||||||
| 8 | Reference | Reference | Reference | ||||||
| 16 | -0.23 | -0.30 to -0.16 | < 0.001 | -2.11 | -2.68 to -1.55 | < 0.001 | -0.40 | -0.56 to -0.25 | < 0.001 |
| 32 | -0.47 | -0.54 to -0.41 | < 0.001 | -3.58 | -4.14 to -3.02 | < 0.001 | 0.002 | -0.16 to 0.17 | 0.98 |
Controlling for maternal age (years), parity (0 or ≥ 1), natural conception (yes or no), history of miscarriage (yes or no), gestational diabetes mellitus (yes or no), preeclampsia (yes or no), pre-pregnancy BMI (< 18.5, 18.5–24.0 or > 24 kg/m2) and gestational weight gain (kg)
Fig. 2.
Thyroid function change during pregnancy and its difference between cases and controls. Red (women with thyroid cancer) and blue line (controls). * P < 0.05. Abbreviation: FT3 Free-triiodothyronine, FT4 Free-thyroxine, TSH Thyroid stimulating hormone
Association of thyroid cancer and function with adverse fetal outcomes
Logistic regression analysis showed that no significant associations were observed for adverse fetal outcomes (Table 3). However, changes in FT3 levels between 8 and 16 weeks of gestation were significantly associated with SGA/preterm birth (OR, 4.42; 95% CI: 1.32–14.84; P = 0.016). Observed survivors showed a higher risk of having neonatal asphyxia, although not reaching statistical significance (Peto OR, 6.49; 95% CI: 0.81-52.0; P = 0.078).
Table 3.
Association of thyroid cancer and thyroid function with small for gestational age/preterm birth and birth defects
| Thyroid cancer and function during pregnancy | Small for gestational age/preterm birth | Birth defects | ||||
|---|---|---|---|---|---|---|
| Adjusted odds ratios | 95% Confidence interval | P value | Adjusted odds ratios | 95% Confidence interval | P value | |
| Subjects | ||||||
| Control | 1.00 | 1.00 | ||||
| Case | 2.06 | 0.68–6.23 | 0.20 | 0.62 | 0.18–2.08 | 0.44 |
| Free-triiodothyronine | ||||||
| At 8 weeks | 2.65 | 0.81–8.66 | 0.107 | 1.51 | 0.49–4.60 | 0.47 |
| Change between 16 − 8 | 4.42 | 1.32–14.84 | 0.016 | 0.97 | 0.29–3.20 | 0.96 |
| Change between 32 − 16 | 2.23 | 0.87–5.72 | 0.096 | 1.46 | 0.54–3.96 | 0.45 |
| Free-thyroxine | ||||||
| At 8 weeks | 0.79 | 0.48–1.29 | 0.34 | 0.88 | 0.55–1.41 | 0.91 |
| Change between 16 − 8 | 0.92 | 0.58–1.47 | 0.73 | 0.97 | 0.60–1.58 | 0.91 |
| Change between 32 − 16 | 1.1 | 0.75–1.60 | 0.63 | 0.97 | 0.62–1.52 | 0.99 |
| Thyroid stimulating hormone | ||||||
| At 8 weeks | 0.78 | 0.43–1.42 | 0.42 | 1 | 0.53–1.86 | 0.99 |
| Change between 16 − 8 | 0.67 | 0.37–1.22 | 0.19 | 0.92 | 0.50–1.70 | 0.79 |
| Change between 32 − 16 | 0.85 | 0.51–1.42 | 0.53 | 0.87 | 0.51–1.49 | 0.61 |
Controlling for maternal age (years), parity (0 or ≥ 1), natural conception (yes or no), history of miscarriage (yes or no), gestational diabetes mellitus (yes or no), pre-eclampsia (yes or no), pre-pregnancy BMI (< 18.5, 18.5–24.0 or > 24 kg/m2) and gestational weight gain (kg)
Bold denotes statistical significance (P < 0.05)
FT3 at 8 weeks of gestation and the changes in FT3 between 8 and 16 weeks and between 16 and 32 weeks were positively associated with SGA/preterm birth (OR ranged from 2.23 to 4.42). The association between the change in FT3 between 8 and 16 weeks and SGA was statistically significant (adjusted OR, 4.42, 95% CI: 1.32–14.84, P = 0.016; Table 3). Null associations of FT4 and TSH levels at 8 weeks of gestation and their changes during pregnancy with adverse fetal outcomes were found.
Association of pregnant women with a history of thyroid cancer and thyroid function with Apgar score and umbilical ABG indexes
Compared with the controls, the observed pregnant women with a history of thyroid cancer had a decrease in neonatal 1-minute and 5-minute Apgar scores and umbilical ABG index. However, a significant association was only observed for the 1-minute Apgar score (β = -0.10; 95% CI: -0.16 to -0.03; P = 0.004; Table 4). FT3 at 8 weeks of gestation and its changes between 16 and 32 weeks of gestation were negatively correlated with the umbilical ABG index, with β of -0.02(P = 0.015 and P = 0.019, respectively). FT4 and TSH and their changes during pregnancy were not associated with Apgar scores and umbilical ABG indexes (Table 4).
Table 4.
Association of thyroid cancer and thyroid function with apgar score and umbilical arterial blood gas indices
| Apgar scores at 1 min | Apgar scores at 5 min | Umbilical arterial blood gas indices | |||||||
|---|---|---|---|---|---|---|---|---|---|
| β | 95% confidence interval | P | β | 95% confidence interval | P | β | 95% confidence interval | P | |
| Subjects | |||||||||
| Control | 1.00 | 1.00 | 1.00 | ||||||
| Case | -0.10 | -0.16 -0.03 | 0.004 | -0.01 | -0.13 0.12 | 0.89 | -0.01 | -0.03 0.01 | 0.24 |
| Free-triiodothyronine value | |||||||||
| At 8 weeks | -0.03 | -0.10 0.05 | 0.47 | -0.11 | -0.24 0.03 | 0.12 | -0.02 | -0.04 -0.01 | 0.015 |
| Change between 16 − 8 | -0.01 | -0.08 0.06 | 0.72 | -0.07 | -0.20 -0.07 | 0.32 | -0.02 | -0.04 0.002 | 0.086 |
| Change between 32 − 16 | -0.003 | -0.06 0.05 | 0.92 | -0.08 | -0.19 0.03 | 0.14 | -0.02 | -0.03 -0.003 | 0.019 |
| Free-thyroxine value | |||||||||
| At 8 weeks | 0.01 | -0.01 0.04 | 0.34 | 0.004 | -0.05 0.05 | 0.88 | -0.001 | -0.01 0.01 | 0.98 |
| Change between 16 − 8 | 0.01 | -0.01 0.04 | 0.30 | -0.002 | -0.05 0.05 | 0.84 | -0.001 | -0.01 0.01 | 0.86 |
| Change between 32 − 16 | 0.001 | -0.02 0.02 | 0.99 | -0.007 | -0.05 0.04 | 0.76 | -0.01 | -0.01 0.001 | 0.11 |
| Thyroid stimulating hormone | |||||||||
| At 8 weeks | 0.01 | -0.03 0.04 | 0.66 | -0.02 | -0.08 0.04 | 0.56 | -0.001 | -0.01 0.01 | 0.76 |
| Change between 16 − 8 | -0.002 | -0.04 0.03 | 0.90 | -0.02 | -0.09 0.04 | 0.47 | 0.001 | -0.01 0.01 | 0.83 |
| Change between 32 − 16 | -0.02 | -0.05 0.01 | 0.13 | -0.007 | -0.06 0.05 | 0.80 | 0.003 | -0.01 0.01 | 0.53 |
Controlling for maternal age (years), parity (0 or ≥ 1), natural conception (yes or no), history of miscarriage (yes or no), gestational diabetes mellitus (yes or no), preeclampsia (yes or no), pre-pregnancy BMI (< 18.5, 18.5–24.0 or > 24 kg/m2) and gestational weight gain (kg)
Abbreviation: ABG Arterial blood gas, CI Confidence interval, FT3 Free-triiodothyronine, FT4 Free-thyroxine, TSH Thyroid stimulating hormone
Bold denotes statistical significance (P < 0.05)
Non-linear associations and thresholds of FT3 and its changes with SGA/preterm birth and umbilical ABG index
Restricted cubic spline curve analysis showed that the change in FT3 between 8 and 16 weeks of gestation was associated with SGA in a J-shape manner. Compared with women with a 1%-10% decrease in FT3 from 8 to 16 weeks, a significantly higher risk of SGA/preterm birth was observed in women with an increase in FT3 at 16 weeks of gestation. The higher the FT3 increase, the higher the risk of SGA/preterm birth. The ROC curve showed that the cut-off value for the change in FT3 from 8 to 16 weeks was − 0.008 (a decrease of 0.8%, Fig. 3). The corresponding sensitivity and specificity were 72.7% and 69.7%, respectively. FT3 in early pregnancy and its changes during pregnancy were negatively correlated with the umbilical ABG index, and the umbilical ABG indexes were significantly decreased in neonates whose mothers had an FT3 ≥ 5.30 at 8 weeks or in those with a 10% increase in FT3 from 16 to 32 weeks (Fig. 4).
Fig. 3.
Restricted cubic spline regression analysis of the change in free triiodothyronine between 8 and 16 weeks of gestation with small for gestational age (a) and its screening value (b). In panel (a), the group with a 10% to 1% decrease (-0.10 to -0.01) in free triiodothyronine was selected as the reference level. The continuous lines indicate estimated odds ratios, and the dotted lines represent 95% confidence intervals
Fig. 4.
Correlation of FT3 and its changes during pregnancy with neonatal arterial indices. Values in red boxes are significantly lower than values in blue boxes (P < 0.05)
Discussion
Main findings
In the present study, we had three main findings. First, significant differences in FT3 and FT4 during pregnancy were found between the pregnant women with a history of thyroid cancer and the control group. The decrease in FT3 levels in the survivors from 8 to 16 weeks was smaller than that in the control group. Second, a non-significant higher risk of SGA/preterm birth and a lower Apgar score at 1 min were observed in the pregnant women with a history of thyroid cancer relative to those in the controls. Third, changes in FT3 from 8 to 16 weeks were positively associated with the risk of SGA/preterm birth, while an inverse correlation were identified between FT3 concentration and its change during pregnancy with umbilical ABG indexes.
Context with previous literatures
Our research found that the levels of FT3 and FT4 in survivors were different from those in the control group, which is consistent with previous studies [2, 4, 9, 11, 12, 15, 16]. We found that the level of FT4 in the observed group was higher than that in the control group, but FT3 was lower than that in the control group, indicating that the conversion of FT4 to FT3 in survivors may be affected. 80% of the active FT3 required by the normal human body is produced by the conversion of FT4 via deiodinase, which is mostly present in thyroid tissue [17]. Although congenital deficiency of deiodinase is not known to exist, the expression polymorphism of this enzyme gene can affect its function [18]. Furthermore, some authors have found that the expression of deiodinase in thyroid tumor tissues is significantly reduced compared to that in surrounding normal tissues [19–21].
Scores on risk indicators of neonatal asphyxia decreased in the pregnant women with a history of thyroid cancer, particularly the 1-minute Apgar score showed a significant decrease. This is consistent with the results of previous studies [21, 22]. Abnormal Apgar score at 1–5 min at birth and umbilical ABG indices often indicate that the fetus is in poor intrauterine condition, and the respiratory function and metabolic status of the newborn are abnormal at birth [4, 15, 22]. Various growth factors and pro- and anti-angiogenic factors may influence perinatal outcome via thyroid function [22]. Beksaç et al. demonstrated that 1-minute and 5-minute Apgar scores were lower in the pregnant women with a history of thyroid cancer compared with the control group [23]. Immune and metabolic alterations due to thyroid cancer may cause inflammation at the materno-fetal interface, potentially leading to impaired fetal perfusion and an increased risk of low Apgar scores [9, 23].
Thyroid hormone receptors were expressed in the nuclei of human placental extravillous trophoblasts (EVT), suggesting that EVT-derived cells respond to triiodothyronine (T3) [24]. EVTs are cells detached from the placental villi that mediate villous invasion into the decidua [25]. Furthermore, T3 can inhibit the apoptosis of EVTs through suppressing the Fas-Fas ligand system in vitro [11]. However, there are few studies investigating the association between abnormal invasive placental formation and early pregnancy thyroid function. A previous study suggested that overt hyperthyroidism may increase the risk of placenta previa (OR 4.19, 95% CI 1.22–14.38) [26], and Liu et al. [27] provided evidence to support the effect of thyroid hormones on placental disease. Therefore, the formation of the placenta might be affected by abnormal thyroid function in early pregnancy for the pregnant women with a history of thyroid cancer. Abnormal placental formation or placental disease may lead to slow fetal growth and even a decrease in Apgar score at birth.
Our study identified that FT3 and its changes during pregnancy are associated with SGA/preterm birth and ABG indices. Thyroid hormones play an important role in regulating the metabolism in carbohydrates, lipids, and proteins, influencing various metabolic pathways [2]. They are also vital for cell differentiation and development in tissues [28, 29], as well as for maintaining glucose metabolism and homeostasis [29]. Among these hormones, FT3, which is converted from FT4 or directly produced by the thyroid [17], is the main biologically active hormone involved in glucose homeostasis and responsible for stimulating endogenous glucose production [30].
The gestational age specificity of the association between the change in FT3 and SGA/preterm birth may be attributed to fetal thyroid gland development. The thyroid gland of the fetus begins to function at 14 weeks of pregnancy and matures at 18 to 20 weeks of pregnancy. Prior to this, the thyroid hormone required for fetal growth and development comes from maternal thyroid hormone transmitted through the placenta. Therefore, at this time, the maternal thyroid function level is within the normal range is crucial for the optimal growth of the fetus [15, 16]. The reduction in FT3 levels in early pregnancy in pregnant women with a history of thyroid cancer was less pronounced than in the controls, suggesting that the affected conversion of FT4 to FT3 potentially leads to an insufficient supply of FT3 to meet the fetal needs. The lack of FT3 during this critical window period may impact fetal development. Investigations on the impact of thyroid cancer on the changes in FT3 levels in early pregnancy are warranted.
Clinical significance
Although the mechanisms or reasons for the association of a history of thyroid cancer and changes in FT3 with risk of SGA and indicators of fetal asphyxia are unknown, our study findings provide preliminary insights into the potential effects of thyroid cancer and FT3 on the fetal outcomes. We also established thresholds for FT3 changes in early pregnancy, which may warrant further investigation as a basis for clinical screening in future studies.
Dynamic monitoring of thyroid function during pregnancy, especially for those undergoing thyroid hormone suppression therapies, is generally recommended, ideally with a monthly check-up [8]. Our findings suggest that changes in FT3 between 8 and 16 weeks of pregnancy might be associated with fetal growth and development. The use of changes in FT3 during pregnancy to estimate SGA/preterm birth and neonatal asphyxia appears promising based on our data, but these findings should be considered exploratory and require validation in larger, prospective studies. If confirmed, monitoring these indicators might help clinicians design a patient-specific antenatal care programs and perinatal surveillance, as well as prepare in advance the personnel and materials needed for neonatal resuscitation at delivery if applicable.
Strengths and limitations
We preformed comprehensive thyroid function tests on all enrolled pregnant women. Thyroid function was assessed at different stages of pregnancy. These strengths help to understand the change in thyroid function at different stages of pregnancy and its impact on fetal outcomes. We used a study design with randomly matched controls, which ensures balanced comparability between groups, avoided selection bias, and thus provides a true and robust estimation of the associations. However, due to the insufficient sample size, we had to combine some outcomes (e.g., SGA and preterm birth) and were unable to use a categorical approach to define asphyxia (e.g., Apgar score < 7). Instead, we used continuous data (e.g., Apgar score and ABG index) to assess asphyxia risk. Although this approach increased the statistical power to detect associations, it may obviously affect the accuracy of the relationship between thyroid function indicators and specific outcomes. Additionally, the representativeness of the single-center sample may affect the generalizability of the results. Critically, the observed associations should be interpreted as preliminary evidence rather than definitive causal relationships. Future large-scale prospective studies are warranted to validate these relationships and establish potential causal mechanisms.
Conclusions
This study identified significant differences in FT3 and FT4 levels between the observed and control groups, with survivors exhibiting a reduced decline in FT3 and a lower 1-minute Apgar scores. In addition, FT3 changes during pregnancy in pregnant women with a history of thyroid cancer were linked to SGA/preterm birth risk and inversely correlated with umbilical ABG indexes. Future research is warranted to investigate the underlying mechanisms of thyroid cancer and treatment on FT3 changes and subsequent fetal growth and neonatal outcomes.
Acknowledgements
We appreciate the participants of the study.
Abbreviations
- ABG
Arterial blood gas
- BD
Birth defects
- BMI
Body mass index
- CI
Confidence interval
- EVT
Extravillous trophoblasts
- FT3
Free-triiodothyronine
- FT4
Free-thyroxine
- GDM
Gestational diabetes mellitus
- OR
Odds ratio
- SGA
Small for gestational age
- TSH
Thyroid stimulating hormone
- T3
Triiodothyronine
Authors’ contributions
T.P. provided the research direction and focus of the article, Z.H. and J.C. reviewed literature and collected cases, JN.W. conducted statistical analysis on various data and prepared figures and tables. Everyone shared the responsibility of writing the main content of the article. All authors reviewed the manuscript.
Funding
No funding.
Data availability
No datasets were generated or analysed during the current study.
Declarations
Ethics approval and consent to participate
The study was approved and a waiver of informed consent was granted by the ethics committee of Tongren Hospital, Shanghai Jiao Tong University, School of Medicine.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Zhi-Fen Hua and Juan Chen contributed equally to this work and are co-first authors.
Contributor Information
Jiang-Nan Wu, Email: wjnhmm@126.com.
Ting Peng, Email: qch1868@163.com.
References
- 1.Lim H, Devesa SS, Sosa JA, Check D, Kitahara CM. Trends in Thyroid Cancer Incidence and Mortality in the United States, 1974–2013. JAMA. 2017;317(13):1338–48. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Yuan X, Zhao J, Wang J, Zheng W, Kong Y, Li G. Pregnancy outcomes and neonatal thyroid function in women with thyroid cancer: a retrospective study. BMC Pregnancy Childbirth. 2023;23(1):383. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Moon S, Yi KH, Park YJ. Risk of Adverse Pregnancy Outcomes in Young Women with Thyroid Cancer: A Systematic Review and Meta-Analysis. Thyroid. 2019;29(6):879–85. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Cao Q, Zhu H, Zhang J, Li Y, Huang W. Pregnancy Outcomes in Thyroid Cancer Survivors: A Propensity Score-Matched Cohort Study. Front Endrocrinol. 2022;13:816132. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Spiegel E, Spence AR, Czuzoj-Shulman N, Abenhaim HA. Pregnancy Outcomes After Thyroid Cancer. J Perinat Med. 2019;47(7):710–6. [DOI] [PubMed] [Google Scholar]
- 6.Blackburn BE, Ganz PA, Rowe K, Snyder J, Wan Y, Deshmukh V, Newman M, Fraser A, Smith K, Herget K, Kim J, Kirchhoff AC, Porucznik C, Hanson H, Abraham D, Monroe M, Hashibe M. Reproductive and gynecological complication risks among thyroid cancer survivors. J cancer Surviv. 2018;12(5):702–11. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.WuJN, Pérez-López FR, Peng T, Xie F, Li MQ. Association Early Pregnancy Free Total Triiodothyronine Withthe Subsequent Risk Gestation Diabetes Mellitus Endocr Pract. 2023;29(1):40–7. [DOI] [PubMed] [Google Scholar]
- 8.Wu JN, Peng T, Xie F, Li MQ. Association of thyroid dysfunction and autoantibody positivity with the risk of preterm birth: a hospital-based cohort study. BMC Pregnancy Childbirth. 2022;22(1):473. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Cho GJ, Kim SY, Lee HC, Lee KM, Han SW, Oh MJ, et al. Risk of Adverse Obstetric Outcomes and the Abnormal Growth of Offspring in Women With a History of Thyroid Cancer. Thyroid. 2019;29(6):879–85. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, Pacini F, Randolph GW, Sawka AM, Schlumberger M, et al. 2015 american thyroid Association Management Guidelines for adult patients with thyroid nodules and differentiated thyroid Cancer: the american thyroid Association Guidelines Task Force on thyroid nodules and differentiated thyroid Cancer. Thyroid. 2016;26(1):1–133. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Laoag-Fernandez JB, Matsuo H, Murakoshi H, Hamada AL, Tsang BK, Maruo T. 3,5,3’-Triiodothyronine down-regulates Fas and Fas ligand expression and suppresses caspase-3 and poly (adenosine 5’-diphosphate-ribose) polymerase cleavage and apoptosis in early placental extravillous trophoblasts in vitro. J Clin Endocrinol Metab. 2004;89(8):4069–77. [DOI] [PubMed] [Google Scholar]
- 12.Dong J, Peng T, Li MQ, Xie F, Wu JN. Association between Maternal Thyroxine and Risk of Fetal Congenital Heart Defects: A Hospital-Based Cohort Study. Int J Endocrinol, 2022; 3859388. [DOI] [PMC free article] [PubMed]
- 13.Ad Hoc writing committee for Guidelines on diagnosis and management of thyroid diseases during pregnancy and postpartum; Chinese society of endocrinology, Chinese medical association, Chinese society of perinatology, Chinese medical association. Guideline on diagnosis and management of thyroid diseases during pregnancy and postpartum (2nd edition). Chin J Endocrinol Metab. 2019; 35(8):636 – 65.
- 14.Guidelines Working Committee of Chinese Society of Clinical Oncology. Guidelines of Chinese Society of Clinical Oncology (CSCO) Differentiated Thyroid Cancer. J Cancer Control Treat. 2021;34(12):1164–201. [Google Scholar]
- 15.Ding Z, Guo F, Zhou Y, Huang X, Liu Z, Fan J. Thyroxine Supplementation in Pregnant Women After Thyroidectomy for Thyroid Cancer and Neonatal Birth Weight. Front Endocrinol. 2021;12:728199. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Su PY, Huang K, Hao JH, Xu YQ, Yan SQ, Li T, et al. Maternal Thyroid Function in the First Twenty Weeks of Pregnancy and Subsequent Fetal and Infant Development: A Prospective Population-Based Cohort Study in China. J Clin Endocrinol Metab. 2011;96(10):3234–41. [DOI] [PubMed] [Google Scholar]
- 17.Maia AL, Goemann IM, Meyer EL, Wajner SM. Deiodinases: the balance of thyroid hormone: type 1 iodothyronine deiodinase in human physiology and disease. J Endocrinol. 2011;209(3):283–97. [DOI] [PubMed] [Google Scholar]
- 18.Cooper-Kazaz R, van der Deure W, Medici M, Visser TJ, Alkelai A, Glaser B, Peeters RP. Lerer B Preliminary evidence that a functional polymorphism in type 1 deiodinase is associated with enhanced potentiation of the antidepressant effect of sertraline by triiodothyronine. J Affect Disord. 2009;116(1–2):113–6. [DOI] [PubMed] [Google Scholar]
- 19.Meyer EL, Wagner MS, Maia AL. Iodothyronine deiodinases expression in thyroid neoplasias. Arq Bras Endocrinol Metabol. 2007;51:690–700. [DOI] [PubMed] [Google Scholar]
- 20.Dentice M, Ambrosio R, Salvatore D. Role of type 3 deiodinase in cancer. Expert Opin Ther Targets. 2009;13:1363–73. [DOI] [PubMed] [Google Scholar]
- 21.Arnaldi LA, Borra RC, Maciel RM, Cerutti JM. Gene expression profiles reveal that DCN, DIO1, and DIO2 are underexpressed in benign and malignant thyroid tumors. Thyroid,205, 15:210–21. [DOI] [PubMed]
- 22.Korevaar TI, Steegers EA, de Rijke YB, Visser WE, Jaddoe VW, Visser TJ, et al. Placental Angiogenic Factors Are Associated With Maternal Thyroid Function and Modify hCG-Mediated FT4 Stimulation. J Clin Endocrinol Metab. 2015;100:1328–34. [DOI] [PubMed] [Google Scholar]
- 23.Beksaç K, Aktoz F, Örgül G, Çelik HT, Özgü-Erdinç. AS,Beksaç MS. Pregnancy in papillary thyroid cancer survivors. J Turk Ger Gynecol Assoc. 2018;19(2):94–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Barber KJ, Franklyn JA, McCabe CJ, et al. The in vitro effects of triiodothyronine on epidermal growth factor-induced trophoblast function. J Clin Endocrinol Metab. 2005;90(3):1655–61. [DOI] [PubMed] [Google Scholar]
- 25.Mueller UW, Hawes CS, Jones WR. Identification of extra-villous trophoblast cells in human decidua using an apparently unique murine monoclonal antibody to trophoblast. Histochem J. 1987;19(5):288–96. [DOI] [PubMed] [Google Scholar]
- 26.Zhang Y, Li Y, Shan Z, et al. Association of overt and subclinical hyperthyroidism during weeks 4–8 with adverse pregnancy outcomes. J Womens Health. 2019;28(6):842–8. [DOI] [PubMed] [Google Scholar]
- 27.Liu D, We Yi, Zhao Y, Li R, Yan J. Obstetric outcomes in thyroid cancer survivors: A retrospective cohort study. Int J Gynaecol Obstet. 2021;155(1):119–24. [DOI] [PubMed] [Google Scholar]
- 28.Opazo MC, Haensgen H, Bohmwald K, et al. Imprinting of maternal thyroid hormones in the offspring. Int Rev Immunol. 2017;36(4):240–55. [DOI] [PubMed] [Google Scholar]
- 29.Rawal S, Tsai MY, Hinkle SN, et al. A longitudinal study of thyroid markers across pregnancy and the risk of gestational diabetes. J Clin Endocrinol Metab. 2018;103(7):2447–56. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Crunkhorn S, Patti ME. Links between thyroid hormone action, oxidative metabolism, and diabetes risk? Thyroid. 2008;18(2):227e237. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
No datasets were generated or analysed during the current study.