Thyroid Function Test Abnormalities in Twin Pregnancies

Abstract

Background:

Compared with singletons, a twin pregnancy is associated with a larger thyroid hormone demand and an increased stimulation of gestational thyroid function due to higher concentrations of human chorionic gonadotropin. However, such effects have been sparsely quantified. The aim of this study was to evaluate thyroid function and thyroid function test abnormalities in twin pregnancies during early and late pregnancy compared with singletons.

Methods:

We included 1208 twin pregnancies and 46,834 singleton pregnancies with thyroid function tests available. Thyroid function test abnormalities were defined using population-based reference ranges. The analyses were adjusted for potential confounders including maternal age and body mass index.

Results:

Compared with singletons, a twin pregnancy was associated with a lower thyrotropin (TSH) (β = −0.46 [95% confidence interval, CI −0.49 to −0.44], p < 0.001) and a higher free thyroxine (fT4) (β = 0.91 [CI 0.69–1.16], p < 0.001) during early pregnancy. During late pregnancy, a twin pregnancy was associated with a higher TSH (β = 0.35 [CI 0.29–0.42], p < 0.001) while fT4 did not differ (β = −0.11 [CI −0.22 to 0.01], p = 0.065). During early pregnancy, a twin pregnancy was associated with a higher risk of overt hyperthyroidism (odds ratio, OR = 7.49 [CI 6.02–9.33], p < 0.001), subclinical hyperthyroidism (OR = 5.26 [CI 4.17–6.64], p < 0.001), and isolated hypothyroxinemia (OR = 1.89 [CI 1.43–2.49], p < 0.001), but with a lower risk of subclinical hypothyroidism (OR = 0.27 [CI 0.13–0.54], p < 0.001). In late pregnancy, a twin pregnancy was associated with a higher risk of subclinical hypothyroidism (OR = 4.05 [CI 3.21–5.11], p < 0.001), isolated hypothyroxinemia (OR = 1.48 [CI 1.04–2.10], p = 0.028), and subclinical hyperthyroidism (OR = 1.76 [CI 1.27–2.43], p < 0.001).

Conclusions:

During early pregnancy, a twin pregnancy was associated with a higher thyroid function and a higher risk of (subclinical) hyperthyroidism, as well as a higher risk of isolated hypothyroxinemia. During late pregnancy, a twin pregnancy was associated with a higher TSH concentration and a higher risk of subclinical hypothyroidism, as well as a persistently higher risk of isolated hypothyroxinemia and subclinical hyperthyroidism. The study was approved by Chinese Clinical Trial Registry (registration no. ChiCTR1800014394).

Introduction

Adequate thyroid hormone availability is crucial for the growth and development of the fetus, predominantly the fetal brain (1). During the first 18–20 weeks of pregnancy, the fetus predominantly depends on the placental transfer of maternal thyroid hormones. Some studies showed that thyroid dysfunction during pregnancy is associated with various adverse pregnancy and child outcomes such as spontaneous abortion, preterm birth, gestational hypertensive disorders, gestational diabetes, low birth weight, and suboptimal offspring neuropsychological development (2,3).

Physiological changes during pregnancy increase the demand for thyroid hormone production such as an increase in thyroxine binding proteins (mainly thyroxine binding globulin), placental type 3 deiodinase expression, and the consumption of thyroid hormone by the fetus (4,5). In parallel, thyroid hormone production is upregulated through additional stimulation of the thyroid gland by high concentrations of human chorionic gonadotropin (hCG). In a twin pregnancy, the demand for thyroid hormone could be higher due to more pronounced changes in the above-mentioned thyroid physiology.

It is generally believed that a failure to meet the increased thyroid hormone demand of pregnancy could expose women with a suboptimal thyroid functional capacity as they could present with (subclinical) hypothyroidism. However, in women with a normal thyroid function capacity, the increased thyroidal stimulation in twin pregnancies could be a risk factor for (subclinical) hyperthyroidism. For both sides of the spectrum, data on these potential risks remain sparse. Quantification of the risks of thyroid function test abnormalities in twin pregnancies is timely considering that the incidence of twin pregnancy is increasing due to rapid development and availability of assisted reproductive technology, and relevant as child health could be affected by thyroid function test abnormalities.

The aim of this study was to study thyroid function and thyroid function test abnormalities in twin pregnancies during early and late pregnancy compared with singleton pregnancies.

Materials and Methods

Patient enrollment

This study was performed in the International Peace Maternity and Child Health Hospital (IPMCH), a large community hospital providing secondary and tertiary care in Shanghai, China. All women presenting between January 2013 and December 2016 underwent first trimester screening as part of a standard work-up in the hospital. A total of 52,027 women were enrolled during early pregnancy. Women who used thyroid-interfering medication (levothyroxine, antithyroid drugs), who had pre-existing thyroid disease (Grave's disease, Hashimoto's thyroiditis, or other forms of hyper- or hypothyroidism), or for whom thyroid function test during early pregnancy (weeks 8–14) was missing were excluded. The study was approved by the Ethics Committee of IPMCH (No. GKLW2012-49). All participants signed the written informed consent.

Data collection

During hospital visits, all data were prospectively collected by nurses, residents, and gynecologists with the use of electronic patient files. Blood samples were drawn during early (weeks 8–14) and late (weeks 28–35) pregnancy from the median antecubital vein and were separated by centrifugation within six hours.

Thyrotropin (TSH), free thyroxine (fT4), and thyroid peroxidase antibody (TPOAb) concentrations were measured with Abbott kits (ARCHITECT i2000; Abbott, Chicago, IL) according to the manufacturer's protocol. The inter- and intra-assay variations were 3.6% and 1.6% for TSH and 4.0% and 1.9% for fT4, respectively. A cutoff value of 6 IU/mL was used to define TPOAb positivity, in line with recommendations by the assay manufacturer. hCG was measured in serum using a solid-phase two-site chemiluminescent immunometric assay on an Immulite 2000 XPi system (Siemens Healthcare Diagnostics, Deerfield, IL) from January 2015 to December 2016 and thus was only available in a subset of the study population.

Data on maternal age, method of conception, and parity were collected via interviews at the first clinical presentation, during which height and weight were measured to calculate body mass index (BMI). Gestational age at sampling was calculated based on the date of last menstrual period. Less than 0.1% of all women smoked or consumed alcohol at presentation to the hospital.

Definitions of thyroid function test abnormalities

Reference ranges for TSH and fT4 were defined by the 2.5th and 97.5th percentiles of the total population of women who received routine prenatal care at the hospital from January 2013 to December 2016 after exclusion of: twin pregnancies, women who conceived via in vitro fertilization (IVF), women who used thyroid-interfering medication, women who had pre-existing thyroid disease, or women who were TPOAb positive (2).

According to the above-mentioned reference ranges, we defined overt hypothyroidism as TSH >97.5th percentile with fT4 < 2.5th percentile, subclinical hypothyroidism as TSH >97.5th percentile with fT4 within the normal range, overt hyperthyroidism as TSH <2.5th percentile with fT4 > 97.5th percentile, subclinical hyperthyroidism as TSH <2.5th percentile with fT4 within the normal range, and isolated hypothyroxinemia as fT4 < 2.5th percentile with TSH within the normal range.

Statistical analyses

We used multiple linear regression models to study the association of twin pregnancy with TSH or fT4 concentrations as well as the effect of TPOAb status on TSH or fT4 in twin and singleton pregnancies by stratifying patients into four groups: Group 1: TPOAb negative and singleton; Group 2: TPOAb positive and singleton; Group 3: TPOAb negative and twin; Group 4: TPOAb positive and twin. With a skewed distribution, TSH and fT4 values were log-transformed as ln(TSH +1) and ln(fT4) for analyses and numbers shown are back-transformed values in mU/L and pmol/L, respectively. We used multiple logistic regression models to study the association of twin pregnancy with thyroid function test abnormalities. Model assumptions were checked with residual plots and outlier exclusions. All analyses were adjusted for potential confounders including maternal age, BMI, parity, and gestational age at sampling.

Comparisons of characteristics between twin and singleton pregnancies were assessed using the Mann–Whitney U-test for continuous variables and using chi-squared test or the Fisher test for categorical variables.

All statistical analyses were performed using R statistical software v3.03 (Statistical Computing, Vienna, Austria) or Statistical Package of Social Sciences for Windows (SPSS 22.0; IBM Corp., Armonk, NY). Statistical significance was defined as a p-value <0.05.

Results

The final study population comprised 1208 twin pregnancies and 46,834 singleton pregnancies (Fig. 1). Compared with singleton pregnancies, women with a twin pregnancy had a higher median age (31 years vs. 30 years, respectively; p < 0.05), a higher median BMI (21.1 kg/m² vs. 20.6 kg/m², respectively; p < 0.05), a higher hCG concentrations (50,030 IU/L vs. 35,060 IU/L, respectively; p < 0.05), were more often nulliparous (87.8% vs. 82.3%, respectively; p < 0.05), and were more likely to have conceived by IVF (54.6% vs. 3.1%, respectively; p < 0.05; Table 1). The reference ranges for TSH were 0.03 to 3.60 mU/L in early pregnancy and 0.39 to 3.69 mU/L in late pregnancy. The reference ranges for fT4 were 11.7 to 19.8 pmol/L in early pregnancy and 9.1 to 14.4 pmol/L in late pregnancy.

FIG. 1.

Flowchart of the study population. IPMCH, International Peace Maternity and Child Health Hospital.

Table 1.

Study Cohort Characteristics

Characteristic	Twin (n = 1208)		Singleton (n = 46,834)
Age, median (95% range), years	31 (25–39)		30 (24 –28)^*
Maternal pre-pregnancy BMI, median (95% range), kg/m²	21.1 (17.2–29.4)		20.6 (16.9–27.7)^*
Nulliparity, n (%)	775 (87.8)		35,790 (82.3)^*
Educational levels, n (%)
Bachelor degree or above	693 (67.4)		35,874 (76.6)^*
Conception by IVF, n (%)	659 (54.6)		1429 (3.1)^*
TPOAb positivity, n (%)	131 (10.8)		4819 (10.3)
Gestational age at thyroid function measurement, median (95% range), weeks
Early pregnancy	12.3 (10.3–14.0)		12.3 (10.4–14.0)
Late pregnancy^a	31.0 (29.2–33.1)		32.6 (30.0–34.6)^*
hCG during early pregnancy,^b median (95% range), IU/L	50,030 (11, 598–267,956)		35,060 (6360–164,845)^*
Child sex (girls), n (%)	550 (45.5)^c	557 (46.0)^d	22,462 (48.0)

Data available for 1030 twin pregnancies and 43,513 singleton pregnancies.

Measurement results available for 463 twin pregnancies and 28,821 singleton pregnancies.

The data represent the number and percentage of the girls in the elders of the twins.

The data represent the number and percentage of the girls in the youngers of the twins.

p < 0.05.

BMI, body mass index; IVF, in vitro fertilization; hCG, human chorionic gonadotropin; TPOAb, thyroid peroxidase antibody.

Twin pregnancy and thyroid function

Compared with singleton pregnancies, a twin pregnancy was associated with a lower TSH (median 0.64 mU/L vs. 1.17 mU/L, respectively; β = −0.46 [95% confidence interval, CI −0.49 to −0.44], p < 0.001) and a higher fT4 (median 15.4 pmol/L vs. 14.8 pmol/L, respectively; β = 0.91 [CI 0.69–1.16], p < 0.001; Table 2) during early pregnancy. During late pregnancy, a twin pregnancy was associated with a higher TSH (median 1.88 mU/L vs. 1.47 mU/L, respectively; β = 0.35 [CI 0.29–0.42], p < 0.001) while fT4 did not differ (median 11.3 pmol/L vs. 11.5 pmol/L, respectively; β = −0.11 [CI −0.22 to 0.01], p = 0.065; Table 2).

Table 2.

Association of Twin Pregnancy with Gestational Thyroid Function

	Twin, median (95% range)	Singleton, median (95% range)	Adjusted difference, β ^a [CI]	p^a
Early pregnancy
TSH, mU/L	0.64 (0.01–3.59)	1.17 (0.03–3.65)	−0.46 [−0.49 to −0.44]	<0.001
fT4, pmol/L	15.4 (9.0–25.8)	14.8 (11.7–19.7)	0.91 [0.69–1.16]	<0.001
Late pregnancy^b
TSH, mU/L	1.88 (0.22–4.96)	1.47 (0.38–3.69)	0.35 [0.29–0.42]	<0.001
fT4, pmol/L	11.3 (8.8–14.4)	11.5 (9.1–14.4)	−0.11 [−0.22 to 0.01]	0.065

TSH and fT4 values were log-transformed as ln(TSH +1) and ln(fT4) for analyses and numbers shown are back-transformed values in mU/L and pmol/L, respectively.

Analyses were adjusted for maternal age, BMI, parity, TPOAb positivity, and gestational age at thyroid function measurement.

Data available for 1030 twin pregnancies and 43,513 singleton pregnancies.

CI, 95% confidence interval; fT4, free thyroxine; TSH, thyrotropin.

In addition, we evaluated if the effects of TPOAb status on thyroid function would differ between twin and singleton pregnancies. For singleton pregnancies, TPOAb-positive women had a higher TSH and a lower fT4 compared with TPOAb-negative women during early pregnancy, but not during late pregnancy (Table 3). However, TPOAb-positive women with a twin pregnancy had a similar TSH concentration as TPOAb-negative women with a singleton pregnancy during early pregnancy (Table 3). Interestingly, during late pregnancy, the TSH concentration did not differ between TPOAb-positive and TPOAb-negative women in either the twin or the singleton pregnancies (Table 3). Yet during late pregnancy, the TSH concentration was higher in twin pregnancies than in singleton pregnancies (Table 3).

Table 3.

Thyroid Function According to Thyroid Peroxidase Antibody Status in Singleton and Twin Pregnancies

	TSH, mU/L, median (β ^a )		fT4, pmol/L, median (β ^a )
	Early pregnancy	Late pregnancy^b	Early pregnancy	Late pregnancy^b
Singleton with TPOAb(−)	1.14 (ref)	1.47 (ref)	14.8 (ref)	11.5 (ref)
Singleton with TPOAb(+)	1.54 (0.40^*)	1.49 (−0.01)	14.6 (−0.20^*)	11.6 (0.24^*)
Twin with TPOAb(−)	0.58 (−0.49^*)	1.89 (0.37^*)	15.5 (1.26^*)	11.3 (−0.18^*)
Twin with TPOAb(+)	1.12 (0.08)	1.80 (0.19^*)	14.1 (−0.13)	11.1 (−0.35^*)

Multiple linear regression models were used for analyses. TSH and fT4 values were log-transformed as ln(TSH +1) and ln(fT4) for analyses and numbers shown are back-transformed values in mU/L and pmol/L, respectively.

Analyses were adjusted for maternal age, BMI, parity, and gestational age at thyroid function measurement.

Data available for 1030 twin pregnancies and 43,513 singleton pregnancies.

p-value for β value, p < 0.05. Singleton with TPOAb(−) group was used as the reference group to calculate the β value.

ref: reference group; TPOAb(+), thyroid peroxidase antibody positive; TPOAb(−), thyroid peroxidase antibody negative.

Twin pregnancy and thyroid function test abnormalities

During early pregnancy, a twin pregnancy was associated with a higher risk of overt hyperthyroidism (8.5% vs. 1.3%, respectively; odds ratio, OR = 7.49 [CI 6.02–9.33], p < 0.001), subclinical hyperthyroidism (7.2% vs. 1.4%, respectively; OR = 5.26 [CI 4.17–6.64], p < 0.001), and isolated hypothyroxinemia (4.7% vs. 2.2%, respectively; OR = 1.89 [CI 1.43–2.49], p < 0.001), but with a lower risk of subclinical hypothyroidism (0.7% vs. 2.5%, respectively; OR = 0.27 [CI 0.13–0.54], p < 0.001; Table 4).

Table 4.

Association of Twin Pregnancy with Thyroid Function Test Abnormalities

	Twin (%)	Singleton (%)	OR ^a [CI]	p^a
Early pregnancy
Overt hypothyroidism^b	22 (1.8)	130 (0.3)	1.95 [0.70–5.42]	0.200
Subclinical hypothyroidism	8 (0.7)	1173 (2.5)	0.27 [0.13–0.54]	<0.001
Isolated hypothyroxinemia	57 (4.7)	1020 (2.2)	1.89 [1.43–2.49]	<0.001
Overt hyperthyroidism	103 (8.5)	605 (1.3)	7.49 [6.02–9.33]	<0.001
Subclinical hyperthyroidism	87 (7.2)	663 (1.4)	5.26 [4.17–6.64]	<0.001
Late pregnancy^c
Overt hypothyroidism	13 (1.3)	71 (0.2)	2.83 [0.67–11.94]	0.157
Subclinical hypothyroidism	84 (8.2)	988 (2.2)	4.05 [3.21–5.11]	<0.001
Isolated hypothyroxinemia	34 (3.3)	854 (2.0)	1.48 [1.04–2.10]	0.028
Overt hyperthyroidism	5 (0.5)	125 (0.3)	1.66 [0.68–4.08]	0.269
Subclinical hyperthyroidism	40 (3.9)	965 (2.2)	1.76 [1.27–2.43]	<0.001

Analyses were adjusted for maternal age, BMI, parity, TPOAb positivity, and gestational age at thyroid function measurement.

Analyses did not remain statistically significant after adjustment for maternal BMI.

Data available for 1030 twin pregnancies and 43,513 singleton pregnancies.

OR, odds ratio.

During late pregnancy, a twin pregnancy remained associated with a persistently higher risk of subclinical hyperthyroidism (3.9% vs. 2.2%, respectively; OR = 1.76 [CI 1.27–2.43], p < 0.001) and isolated hypothyroxinemia (3.3% vs. 2.0%, respectively; OR = 1.48 [CI 1.04–2.10], p = 0.028; Table 4). Furthermore, a twin pregnancy was associated with a higher risk of subclinical hypothyroidism (8.2% vs. 2.2%, respectively; OR = 4.05 [CI 3.21–5.11], p < 0.001; Table 4).

hCG concentrations according to thyroid function test abnormalities are shown in Supplementary Table S1. In twin pregnancies, those with subclinical hyperthyroidism during late pregnancy had considerably higher hCG concentrations in early pregnancy (Supplementary Table S1). Furthermore, women with isolated hypothyroxinemia during either early or late pregnancy had lower hCG concentrations compared with euthyroid women (Supplementary Table S1). The numbers of women with thyroid disease entities that persisted from early to late pregnancy are shown in Supplementary Table S2. Stratification of the results according to the IVF status revealed similar results (data not shown).

Discussion

The current study shows that a twin pregnancy is associated with a higher risk of (subclinical) hyperthyroidism and isolated hypothyroxinemia during early pregnancy while it was protective of subclinical hypothyroidism. Yet during late pregnancy, a twin pregnancy was associated with a persistently higher risk of subclinical hyperthyroidism and isolated hypothyroxinemia while it was also associated with a higher risk of subclinical hypothyroidism. Moreover, TPOAb-positive twin pregnancies had a similar TSH concentration as TPOAb-negative singleton pregnancies during early pregnancy indicating that the higher hCG concentrations in twin pregnancies could overcome the impaired thyroidal stimulation due to thyroid autoimmunity.

Compared with singleton pregnancies, a twin pregnancy was associated with a lower TSH and a higher fT4 during early pregnancy. This result is similar to previous studies (6 –9) and could be explained by the fact that hCG concentrations are higher in twin pregnancies (Table 1) (10,11), leading to more stimulation of the TSH receptor on the thyroid gland. In the current study, we were also able to investigate these associations during late pregnancy, and we identified that the TSH concentrations were higher, but the fT4 concentrations were similar in twin pregnancies compared with singleton pregnancies. One possible explanation for these differences is the decline in hCG concentrations toward later pregnancy. A time-dependent differential effect of hCG on thyroid function is also supported by recent findings showing that the impaired thyroidal stimulation by hCG in TPOAb-positive women can be identified during early pregnancy, but not late pregnancy (12).

Another possible explanation might be that there are more pronounced thyroid physiological changes that would lead to lower thyroid hormone availability in twin pregnancies than in singleton pregnancies. For example, physiological changes that would decrease thyroid hormone availability such as the estrogen-mediated increase in thyroxine binding globulin, increased iodine excretion and turnover, a higher absolute deiodinase type 3 activity (due to a larger placenta), as well as a 10% larger increment in blood volume could all be more pronounced in twin pregnancies than in singleton pregnancies (13). This could lead to differences in thyroid function between singleton and twin pregnancies even more so toward late pregnancy as these factors are no longer compensated for by higher thyroid hormone production due to hCG stimulation. More studies are needed to further elucidate the extent and clinical consequences of thyroid physiological changes in twin pregnancies.

In the current study, we tried to further translate the potential clinical consequences of the differences in thyroid physiology and function by studying the risk of thyroid function test abnormalities in twin pregnancies. During early pregnancy, a twin pregnancy was associated with roughly seven times higher risk of overt hyperthyroidism and a five times higher risk of subclinical hyperthyroidism compared with singleton pregnancies. In studies that included singleton pregnancies, subclinical hyperthyroidism has not been associated with adverse pregnancy outcomes (14,15). However, some but not all studies showed that overt hyperthyroidism is associated with a higher risk of hypertensive disorders (16 –22). Furthermore, recent studies have indicated that a higher fT4 concentration or a lower TSH is associated with lower birth weight and lower cerebral gray matter in the offspring (23 –26). However, it remains unknown whether such results can be generalized to twin pregnancies as studies to date have only included singleton pregnancies. It is important to weigh the potential harms associated with the use of antithyroid drugs in early pregnancy (mainly the higher risk of fetal birth defects and neonatal/maternal hypothyroidism) and the potential benefits of restoring euthyroidism (27,28).

Interestingly, we also identified that twin pregnancies have a higher risk of isolated hypothyroxinemia. A single underlying cause of isolated hypothyroxinemia typically cannot be identified and isolated hypothyroxinemia most likely reflects a multifactorial pathophysiology that may involve iodine deficiency, iron deficiency, antiangiogenic factors and characteristics such as a high BMI (29 –32). It was shown previously that women with isolated hypothyroxinemia have a similar thyroidal response to hCG as euthyroid women, but also that lower hCG concentrations at the time of measurement were associated with a higher risk of isolated hypothyroxinemia (33). However, considering that hCG concentrations are higher in twin pregnancies than in singleton pregnancies, a difference in hCG concentrations cannot explain the higher risk of isolated hypothyroxinemia in twin pregnancies as shown in the current study. Alternatively, this novel finding could suggest that other physiological changes such as the placental and fetal consumption of thyroxine could play a role in the underlying mechanism of isolated hypothyroxinemia.

We also show that a twin pregnancy is associated with a lower risk of subclinical hypothyroidism during early pregnancy. This may suggest that the high hCG concentrations in twin pregnancies during early pregnancy could be a protective factor for developing subclinical hypothyroidism. However, we did identify a higher risk of overt hypothyroidism during early pregnancy, although this did not reach statistical significance due to the low number of affected pregnancies and after additional adjustment for BMI. It is likely that this probable association reflects the heterogeneity within the group of women with overt hypothyroidism. This group consists of a group of women with true thyroid failure in which higher hCG concentrations cannot overcome the underlying mechanisms leading to overt hypothyroidism such as severely diminished thyroidal functional capacity due to autoimmune disease or iodine deficiency. But also of a group of women who meet the biochemical definition of high TSH with a low fT4 that still have residual thyroid function, of which the thyroid gland could still partially respond to the hCG-mediated stimulation. During late pregnancy, a twin pregnancy was associated with roughly four times higher risk of subclinical hypothyroidism; although some studies indicate that subclinical hypothyroidism during late pregnancy is not associated with preterm birth or birth weight, more studies are needed to identify the clinical relevance of late pregnancy thyroid function test abnormalities (3,26).

To the best of our knowledge, this is the first adequately powered study to investigate whether a twin pregnancy is a risk factor for thyroid function test abnormalities at two time points. We were able to use a large data set of prospectively collected data on thyroid function at two time points in pregnancy with detailed data on covariates. However, one of the limitations of this study is that not all women had data available at both time points in pregnancy, and the proportion of twin pregnant women without available data was higher than that of singletons (14.7% vs. 7.1%), mainly due to the higher rate of preterm birth. In addition, some women were excluded from the analyses because they were treated with thyroid (interfering) drugs during pregnancy. Another potential limitation is that we did not assess iodine or iron status, which could affect the physiological mechanisms that underlie the differences between twin and singleton pregnancies shown in this study. Finally, it is important to note that the observational nature of this study limits any causal inference, and the results cannot be extrapolated to potential treatment effects.

In conclusion, we show that a twin pregnancy was associated with a higher thyroid function and a higher risk of (subclinical) hyperthyroidism and isolated hypothyroxinemia during early pregnancy, but a higher TSH concentration and a higher risk of subclinical hypothyroidism during late pregnancy. This study provides new insights in the extent of thyroid physiological changes in twin pregnancies and its potential consequences on developing thyroid function test abnormalities.

Footnotes

Acknowledgments

We gratefully acknowledge the contributions and efforts of all pregnant women who participated in this study and the doctors and nurses involved in data collection and patient care.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This work was supported by grants from the National Key Research and Development Program of China (2018YFC1004602) and the National Natural Science Foundation of China (81974235, 81501274). The study is also supported by Chinese Academy of Medical Sciences Research Unit (No. 2019RU056), Shanghai Jiao Tong University, CAMS Innovation Fund for Medical Sciences (CIFMS) (No. 2019-I2M-5-064), and Shanghai Municipal Key Clinical Specialty, Shanghai, China.

Supplementary Material

Supplementary Table S1

Supplementary Table S2

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