Yuan et al.

BMC Pregnancy and Childbirth (2020) 20:491

https://doi.org/10.1186/s12884-020-03176-4

RESEARCH ARTICLE Open Access

Relationship between anti-thyroid

peroxidase antibody positivity and
pregnancy-related and fetal outcomes in
Euthyroid women: a single-center cohort
study
Ning Yuan1, Jianbin Sun2, Zhi Li3, Sanbao Chai2, Xiaomei Zhang2*† and Linong Ji1*†

Abstract
Background: Thyroid autoimmunity (TAI) and subclinical hypothyroidism (SCH) have been associated with poor
pregnancy and fetal outcomes. However, whether euthyroid women with anti-thyroid peroxidase antibody (TPOAb)
positivity have a higher risk of poor pregnancy and fetal outcomes is debatable. Therefore, this study aimed to
investigate the association between TPOAb positivity and pregnancy-related and fetal outcomes in euthyroid
women.
Methods: In total, 938 pregnant women participated in this prospective cohort study. The euthyroid group
included 837 pregnant women and the TPOAb-positive group included 101 euthyroid pregnant women. Serum
TPOAb, thyroglobulin antibody (TGAb), thyroid-stimulating hormone (TSH), and free thyroxine (FT4) levels were
assessed. Pregnancy and fetal outcomes included gestational diabetes mellitus, spontaneous abortion, premature
rupture of membranes, hypertensive disorders of pregnancy, preterm birth, fetal distress, low birth weight, fetal
macrosomia, and small for gestational age infant.
Results: Logistic regression analysis showed TPOAb positivity was not associated with an increased risk of poor
pregnancy or fetal outcomes in euthyroid women. However, TPOAb-positive euthyroid women pregnant with a
female fetus were independently associated with preterm births (OR: 4.511, 95% CI: 1.075–18.926) after adjustment
for potential confounding factors.
(Continued on next page)

* Correspondence: z.x.mei@163.com; jiln@bjmu.edu.cn

†
Xiaomei Zhang and Linong Ji contributed equally to this work and should
be considered co-corresponding authors.
2
Department of Endocrinology, Peking University International Hospital,
Beijing 102206, China
1
Department of Endocrinology, Peking University People’s Hospital, Beijing
100044, China
Full list of author information is available at the end of the article

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Yuan et al. BMC Pregnancy and Childbirth (2020) 20:491 Page 2 of 10

(Continued from previous page)

Conclusions: TPOAb positivity was not found to be associated with poor pregnancy-related or fetal outcomes in
euthyroid women. However, in euthyroid women with a female fetus, TPOAb positivity was strongly associated
with preterm births. The risk of preterm birth in the euthyroid women with TPOAb positivity should be emphasized
in clinical practice.
Trial registration: ClinicalTrials.gov Identifier: NCT02966405. Registered on October 24th 2016 - Retrospectively
registered.
Keywords: Thyroid peroxidase antibodies, Euthyroid, Pregnancy and fetal outcomes

Background period and human chorionic gonadotropin (HCG); (c)

Recent studies have reported that thyroid autoimmunity euthyroid women (TSH > 0.12 and ≤ 2.5 uIU/mL) in the
(TAI) and subclinical hypothyroidism (SCH) are associ- first trimester of pregnancy. The exclusion criteria were
ated with an increased risk of poor pregnancy and fetal (a) diagnosis of hereditary disease, tumors, autoimmune
outcomes, such as spontaneous abortion, preterm birth, disease (e.g., systemic lupus erythematosus, Sjogren syn-
and lower offspring motor and intelligence quotients [1, drome, or antiphospholipid antibody syndrome), heart
2]. TAI is characterized by anti-thyroid peroxidase anti- disease, liver disease, renal disease, or chronic hyperten-
body (TPOAb) and/or thyroglobulin antibody (TGAb) sion; (b) consumption of medication that could affect
positivity. Guidelines published by the American Thy- thyroid function. In total, 1428 pregnant women who
roid Association (ATA) in 2017 [3] recommended estab- presented at the Department of Gynaecology and
lishing population-based trimester-specific reference Obstetrics of Peking University International Hospital
ranges for serum thyroid-stimulating hormone (TSH) volunteered to participate in this study from October
levels. If information is unavailable, the recommended 2016 to April 2018. In total, twenty six women with twin
upper normal limit cutoff for TSH is 4.0 mU/L. Mean- pregnancies, 38 pregnant women with subclinical hyper-
while, 2.5 mU/L can be used as the cutoff for SCH com- thyroidism or hyperthyroidism, 223 pregnant women
bined with TPOAb positivity. Levothyroxine (LT4) with a TSH concentration of > 2.5 and ≤ 4.16 uIU/mL,
replacement therapy may be considered for TPOAb- and normal FT4, 105 pregnant women with SCH or
positive women with TSH concentrations > 2.5 mU/L hypothyroidism, 24 pregnant women with hypothyroxi-
and below the upper limit of the pregnancy-specific ref- nemia, 59 euthyroid women with only TGAb positivity,
erence range [3]. However, whether TPOAb positivity is and 15 pregnant women with other thyroid dysfunctions
associated with poor pregnancy and fetal outcomes in were excluded. Ultimately, 938 subjects participated in
euthyroid women is debatable. It is known that the this study. The euthyroid group included 837 pregnant
prevalence of TPOAb varies with ethnicity, gender, and women with a TSH concentration of > 0.12 and ≤ 2.5
iodine intake [3–5]. A recent meta-analysis [6] showed uIU/mL, normal FT4, and TPOAb and TGAb negativity.
the presence of TAI was associated with an increased The TPOAb-positive group included 101 TPOAb-
risk of spontaneous miscarriage. A separate meta- positive with or without TGAb positivity euthyroid
analysis [7] found TPOAb-positive women had a higher women (Fig. 1). Written informed consents were ob-
risk of preterm birth than TPOAb-negative women. Sev- tained from all study participants. This study was regis-
eral studies have examined the associations between ma- tered on ClinicalTrials.gov (Identifier: NCT02966405).
ternal TAI and child autism spectrum [8] and lower All pregnant women completed the questionnaire
motor and intellectual development [9]. TPOAb positiv- about the history of thyroid or autoimmune disease,
ity has been associated with poor pregnancy and fetal family health history of thyroid disorders, and previous
outcomes in euthyroid women in some but not all stud- abortion. The height, weight, blood pressure, and gesta-
ies [10, 11]. Therefore, the aim of the present study was tional age of the participants were recorded. The body-
to investigate the impact of TPOAb positivity on the mass index (BMI) was calculated as weight in kilograms
pregnancy-related and fetal outcomes in euthyroid divided by height in meters squared. The serum blood
women. glucose (GS), glycosylated hemoglobin (HbA1c), low-
density lipoprotein cholesterol (LDL-C), uric acid (UA),
Methods homocysteine (Hcy) and ferritin tests were analyzed and
Study population recorded. The participants were followed up through the
This was a prospective cohort study conducted at a sin- second and third trimesters of pregnancy until delivery.
gle site. The inclusion criteria were (a) single birth; (b) The pregnancy status of participants was recorded, in-
fetus at 4–8 weeks’ gestation diagnosed by last menstrual cluding the mode of birth, delivery time, neonatal
Yuan et al. BMC Pregnancy and Childbirth (2020) 20:491 Page 3 of 10

Fig. 1 Flow chart of patient selection. TSH, thyroid-stimulating hormone; FT4, free thyroxine; SCH, subclinical hypothyroidism; TGAb, thyroglobulin
antibody; TPOAb, thyroid peroxidase antibody

gender, weight and height, and other pregnancy-related a fetus suffering from insufficient oxygen supply, based
data. The pregnancy-related and fetal outcomes included on abnormal fetal heart rate and movements, or acidosis
gestational diabetes mellitus (GDM), spontaneous abor- (fetal scalp blood sample showing pH < 7.20) [16]. Low
tion, premature rupture of membranes (PROM), hyper- birth weight was defined as a live birth smaller than
tensive disorders of pregnancy (HDP), preterm birth, 2500 g. Fetal macrosomia was defined as a live birth of
fetal distress, low birth weight, fetal macrosomia, and more than 4000 g. SGA infant was defined by a birth
small for gestational age (SGA) infant. weight below the 10th percentile of normative birth
weights for singletons [17].
Definitions
GDM was diagnosed if one or more of the following
plasma GS levels were met or exceeded following the 75 Thyroid function tests
g oral glucose tolerance test: at fasting ≥92 mg/dL, at 1 TSH, FT4, TGAb, and TPOAb from collected serum
h ≥ 180 mg/dL, and at 2 h ≥ 153 mg/dL, according to the samples were assessed using a COBAS Elesys 601 im-
guidelines of the International Association of Diabetes munoassay analyzer (Roche Diagnostics, Switzerland).
and Pregnancy Study Groups [12]. Spontaneous abortion The intraassay coefficient of variability (CV) for serum
was defined as a spontaneous loss of a pregnancy before TSH, FT4 and TPOAb were 1.1–3.0%, 1.5–4.3% and
the 20th week of gestation [13]. PROM was defined as 2.7–6.3% respectively, and the interassay CVs were 3.2–
the rupture of the amniotic sac before the onset of labor. 7.2%, 3.3–8.4% and 4.2–9.5%, respectively. According to
HDP included gestational hypertension, preeclampsia- pregnancy-specific thyroid function guidelines estab-
eclampsia, chronic hypertension (of any cause diagnosed lished in Peking University International Hospital, the
before 20 weeks of gestation), and chronic hypertension reference range of thyroid indicators for the 2.5th to
with preeclampsia superimposed [14, 15]. Preterm birth 97.5th percentile for TSH level was 0.12 uIU/mL to 4.16
was defined as the birth of a baby at fewer than 37 uIU/mL and for the FT4 level, it was 13.36 pmol/L to
weeks’ gestation excluding iatrogenic preterm birth 23.55 pmol/L. A TPOAb titer of 34 IU/mL or more and
caused by preeclampsia, placenta previa, fetal growth re- a TGAb titer of 115 IU/mL or more were classified as
striction, and other factors. Fetal distress was defined as positivity (in non-pregnant women).
Yuan et al. BMC Pregnancy and Childbirth (2020) 20:491 Page 4 of 10

Outcome parameters between the euthyroid group and the TPOAb-positive

The primary aim of the present study was to investigate euthyroid group were analyzed by a t-test or Mann-
the impact of TPOAb positivity on preterm birth in Whitney U test for continuous data and by a Fisher’s
euthyroid women. The secondary objectives were to exact test for categorical data. Univariable logistic re-
explore the role of TPOAb positivity on other gression analysis was used to assess the association be-
pregnancy-related and fetal outcomes, and to compare tween demographic parameters and pregnancy and fetal
the effect of TPOAb positivity on pregnancy-related and outcomes. A multivariate logistic regression model was
fetal outcomes according to fetal gender. used to assess the association between TPOAb-positive
euthyroid women and pregnancy and fetal outcomes. In
Sample size calculation the model, the confounding factors for adjustment in-
According to previous studies [7], it was assumed for the cluded TSH and HbA1c, as well as demographic param-
sample size calculation that the rate of preterm births in eters such as age, BMI, parity, and history of
the TPOAb-positive group were 6.6 and 4.9% in the eu- spontaneous abortion. A P-value < 0.05 was considered
thyroid group resulting in a minimum sample size of statistically significant.
803 pregnant women for a two-sided chi-square test
with a power of 0.80 and a two-sided t-test with a sig- Results
nificance level of 5%. The rate of non-response in this Characteristics of participants
study was estimated to be 10%, therefore, requiring a The characteristics of the pregnant women in this study
sample size at least 892 cases. are listed in Table 1. There were 837 pregnant women
in the euthyroid group and 101 pregnant women in the
Statistical analysis TPOAb-positive euthyroid group. The serum TSH levels
We used SPSS version 17.0 (SPSS, IBM, USA) for all were higher in the TPOAb-positive euthyroid group
statistical analyses. Continuous data conforming to the than in the euthyroid group (median TSH 1.51 uIU/ml,
normal distribution were expressed as number ± stand- IQR [1.14–2.08] uIU/ml vs. 1.31 uIU/ml, IQR [0.826–
ard deviation; otherwise, they were expressed as median 1.80] uIU/ml, P < 0.001). No significant differences were
(interquartile range [IQR]). Categorical data were observed between the two groups regarding maternal
expressed as numbers (percentages) of cases. Differences age, BMI, the rate of parity and history of spontaneous

Table 1 Subject’s characteristics in Euthyroid group and Euthyroid women with TPOAb positivity group
Euthyroid group (n = 837) Euthyroid women with TPOAb Statistics P
positivity group (n = 101)
Maternal age (years) 30 (28,34) 31 (29,34) −1.660 0.097
Age ≥ 35 years (%) 157 (18.8%) 21 (20.8%) 0.243 0.622
BMI (kg/m ) 2
21.48 (19.81,23.43) 21.35 (20.07,23.19) −0.149 0.881
BMI ≥ 24 kg/m2 (%) 174 (20.8%) 19 (18.8%) 0.215 0.643
Parity (%)
primipara 519 (62.0%) 60 (59.4%) 0.258 0.611
multipara 318 (38.0%) 41 (40.6%)
History of spontaneous abortion (%) 114 (13.6%) 11 (10.9%) 0.581 0.446
HbA1c (%) 5.1 (4.9,5.3) 5.1 (5.0,5.3) −1.174 0.240
GS (mmol/L) 4.88 (4.65,5.14) 4.85 (4.65,5.15) −0.175 0.861
TSH (uIU/ml) 1.31 (0.826,1.80) 1.51 (1.14,2.08) −3.793 0.000*
FT4 (pmol/L) 17.20 (15.80,18.50) 16.9 (15.80,18.80) −0.318 0.751
LDL (mmol/L) 2.02 (1.69,2.37) 1.98 (1.77,2.28) −0.426 0.670
UA (μmol/L) 209 (181,236) 215 (189,239) −0.841 0.401
Hcy (μmol/L) 6.40 (5.70,7.20) 6.1 (5.70,7.38) −0.224 0.823
Ferritin (ng/ml) 53.1 (33.03,80.95) 48.75 (29.95,69.30) −1.426 0.154
*P < 0.05
Statistics: Maternal age, BMI, FT4, TSH, GS, HbA1c, LDL, UA, Hcy and Ferritin for Mann-Whitney U test; Age<35 years, BMI<24 kg/m2, parity, and history of
spontaneous abortion for chi-square test or Fisher test
Continuous data are expressed as median (interquartile range). Categorical data are expressed as numbers (percentages) of cases
BMI body-mass index, TSH thyroid-stimulating hormone, FT4 free thyroxine, HbA1c glycated hemoglobin, GS blood glucose, LDL low density lipoprotein
cholesterol, UA uric acid, Hcy homocysteine
Yuan et al. BMC Pregnancy and Childbirth (2020) 20:491 Page 5 of 10

abortion, or the serum levels of HbA1c, GS, LDL, UA, Incidences of fetal distress were associated with multip-
Hcy, ferritin, and FT4. ara (OR: 0.323, 95% CI: 0.161–0.649). There was no cor-
relation between spontaneous abortion, PROM, HDP,
Pregnancy and fetal outcomes preterm birth, low birth weight, SGA infant and the
The pregnancy-related and fetal outcomes in the two demographic parameters (Table 3).
groups are summarized in Table 2 and Fig. 2. The inci-
dences of spontaneous abortion and preterm births were Multivariate logistic regression analysis
higher in the TPOAb-positive euthyroid women than in Logistic regression analysis with poor pregnancy and
the euthyroid group; however, the difference was not sig- fetal outcomes as the categorical dependent variables
nificant (5.9% vs 3.5%, P = 0.215; 6.9% vs 4.1%. P = 0.183, showed that euthyroid women with TPOAb positivity
respectively). In this study, four iatrogenic preterm birth did not have a higher risk of poor pregnancy or fetal
were excluded (2 cases of placenta previa, 1 case of fetal outcomes, including GDM, spontaneous abortion,
brain edema, and 1 case of severe eclampsia). In the eu- PROM, preterm birth, fetal distress, low birth weight,
thyroid group, the incidence of HDP and SGA were 2.1 and fetal macrosomia. However, in euthyroid women
and 1.8% respectively. In the TPOAb-positive euthyroid with a female fetus, TPOAb positivity was independently
group, there were no pregnant women with HDP and no associated with preterm birth (OR: 4.511, 95% CI:
SGA infants. No significant differences were found in 1.075–18.926) after adjustment for demographic param-
the incidence of GDM, PROM, fetal distress, low birth eters, HbA1c, and TSH. No significant relationship was
weight, fetal macrosomia, female/male infant ratio, birth- found between TPOAb positivity and preterm birth
weight, or gestational age at birth between the two among euthyroid women with a male fetus (Table 4).
groups.
Discussion
Univariable logistic regression analysis This study aimed to investigate the association between
Results from the univariable logistic regression analysis TPOAb positivity and pregnancy-related and fetal out-
performed with demographic parameters as independent comes in euthyroid women. The primary finding is that
variables and poor pregnancy and fetal outcomes as cat- TPOAb positivity was not associated with an increased
egorical dependent variables showed that GDM was as- risk of poor pregnancy or fetal outcomes, including pre-
sociated with maternal age ≥ 35 years (OR: 2.055, 95% term birth, GDM, spontaneous abortion, PROM, fetal
CI: 1.418–2.978) and BMI ≥ 24 kg/m2 (OR: 2.284, 95% distress, low birth weight, and fetal macrosomia in eu-
CI: 1.568–3.327). Fetal macrosomia was associated with thyroid women. However, in euthyroid pregnant women
BMI ≥ 24 kg/m2 (OR: 2.543, 95% CI: 1.359–4.761). with a female fetus, TPOAb positivity was independently

Table 2 Subject’s pregnancy and fetal outcomes in Euthyroid group and Euthyroid women with TPOAb positivity group
Euthyroid group (n = 837) Euthyroid women with TPOAb Statistics P
positivity group (n = 101)
GDM (%) 174 (20.8%) 21 (20.8%) 0.000 0.999
Spontaneous abortion (%) 29 (3.5%) 6 (5.9%) 1.538 0.215
PROM (%) 137 (16.4%) 14 (13.9%) 0.419 0.517
HDP(%) 18 (2.1%) NA
Preterm Birth (%) 34 (4.1%) 7 (6.9%) 1.774 0.183
Fetal distress (%) 51 (6.1%) 7 (6.9%) 0.109 0.741
Low Birth weight (%) 29 (3.5%) 4 (4.0%) 0.063 0.802
Fetal macrosomia (%) 49 (5.9%) 8 (7.9%) 0.674 0.412
SGA (%) 15 (1.8%) NA
Infant
Female infant (%) 399 (49.7%) 46 (48.9%) 0.019 0.890
Male infant (%) 404 (50.3%) 48 (51.1%)
Birthweight (Kg) 3.35 (3.08,3.61) 3.32 (3.02,3.60) −0.856 0.392
Gestational age at birth (weeks) 39 (38,40) 39 (38,40) −0.760 0.447
Statistics: Birthweight and gestational age at birth for Mann-Whitney U test; pregnancy and fetal outcomes for chi-square test or Fisher test
Continuous data are expressed as median (interquartile range). Categorical data are expressed as numbers (percentages) of cases
GDM gestational diabetes, PROM premature rupture of membranes, HDP hypertensive disorders of pregnancy, SGA small for gestational age
Yuan et al. BMC Pregnancy and Childbirth (2020) 20:491 Page 6 of 10

Fig. 2 Subject’s pregnancy and fetal outcomes in the Euthyroid group and the Euthyroid women with TPOAb positivity group. GDM, gestational
diabetes; PROM, premature rupture of membranes; HDP, hypertensive disorders of pregnancy; SGA, small for gestational age

associated with preterm birth after adjustment for demo- that investigated outcomes such as spontaneous abor-
graphic parameters, HbA1c, and TSH. tions, GDM, and preterm births and other rarer out-
TPOAb positivity is present in 6 to 8.8% of pregnant comes such as PROM, fetal distress, low birth weight,
women [7, 18], and TAI and SCH during pregnancy are fetal macrosomia, and SGA infant, were inconclusive [7,
associated with poor pregnancy and fetal outcomes [19, 21]. Since it may play a role in maternal physiological
20]. The upper normal cutoff limit for TSH was set at processes during pregnancy, the secondary objective in
4.0 mU/L during pregnancy instead of 2.5 mU/L as per the present study was to compare the effect of TPOAb
the 2017 ATA guidelines [3]. However, LT4 replacement positivity on pregnancy and fetal outcomes according to
therapy may be considered for TPOAb-positive women the sex of the fetus. The results indicate that TPOAb
with TSH > 2.5 mU/L and below the upper limit of the positivity was independently associated with preterm
pregnancy-specific reference range [3]. The association birth in euthyroid pregnant women with a female fetus.
between TPOAb positivity and poor pregnancy and fetal Preterm birth complicates 5 to 15% of births world-
outcomes in euthyroid women remains controversial wide and is the leading cause of morbidity and mortality
because evidence from several prospective cohort studies in children younger than 5 years [7, 22]. Thus, it is very

Table 3 Univariable logistic regression analysis with demographic parameters as independent variables and pregnancy and fetal
outcomes as categorical dependent variables
pregnancy and fetal outcomes Age ≥ 35 years BMI ≥ 24 kg/m2 Multipara History of spontaneous
abortion
Independent variables OR (95% CI) p OR (95% CI) p OR (95% CI) p OR (95% CI) p
GDM 2.055 (1.418–2.978) 0.000* 2.284 (1.568–3.327) 0.000* 1.317 (0.948–1.830) 0.101 0.922 (0.571–1.490) 0.740
Spontaneous abortion 1.937 (0.934–4.014) 0.076 0.853 (0.320–2.276) 0.751 1.108 (0.540–2.273) 0.785 1.604 (0.687–3.744) 0.275
PROM 0.648 (0.396–1.061) 0.085 0.816 (0.512–1.303) 0.395 0.737 (0.507–1.072) 0.737 0.568 (0.311–1.037) 0.066
HDP 1.661 (0.584–4.720) 0.341 2.572 (0.982–6.733) 0.054 0.803 (0.299–2.160) 0.664 1.877 (0.611–5.826) 0.270
Preterm Birth 0.874 (0.381–2.005) 0.751 1.236 (0.574–2.661) 0.588 1.128 (0.587–2.167) 0.718 0.889 (0.346–2.337) 0.828
Fetal distress 0.756 (0.365–1.568) 0.453 0.912 (0.449–1.853) 0.799 0.323 (0.161–0.649) 0.001* 1.105 (0.891–3.362) 0.105
Low Birth weight 0.947 (0.385–2.329) 0.906 1.108 (0.471–2.606) 0.813 0.621 (0.284–1.359) 0.233 0.894 (0.309–2.587) 0.836
Fetal macrosomia 0.906 (0.512–2.126) 0.906 2.543 (1.359–4.761) 0.004* 1.060 (0.585–1.922) 0.848 1.637 (0.798–3.359) 0.179
SGA 1.095 (0.305,3.923) 0.890 1.598 (0.495,5.158) 0.433 0.243 (0.054,1.082) 0.063 1.468 (0.468,6.06) 0.425
*P < 0.05
GDM gestational diabetes, PROM premature rupture of membranes, HDP hypertensive disorders of pregnancy, SGA small for gestational age
Yuan et al. BMC Pregnancy and Childbirth (2020) 20:491 Page 7 of 10

Table 4 Logistic regression analysis with euthyroid women with TPOAb positivity as independent variables and poor pregnancy and
fetal outcomes as categorical dependent variables
GDM Total Pregnant women with a female fetus Pregnant women with a male fetus
OR (95% CI) P OR (95% CI) P OR (95% CI) p
Model 1 0.991 (0.558–1.760) 0.975 0.596 (0.239–1.483) 0.239 1.696 (0.801–3.591) 0.168
Model 2 1.282 (0.610–2.694) 0.512 0.690 (0.215–2.218) 0.534 2.349 (0.831–6.638) 0.107
Spontaneous abortion
Model 1 1.925 (0.709–5.222) 0.199
Model 2 1.083 (0.227–5.171) 0.920
PROM
Model 1 0.757 (0.399–1.436) 0.383 0.641 (0.239–1.717) 0.197 0.914 (0.386–2.168) 0.914
Model 2 0.476 (0.181–1.250) 0.132 0.835 (0.264–2.640) 0.758 0.391 (0.084–1.831) 0.233
Preterm Birth
Model 1 1.765 (0.713–4.370) 0.219 3.650 (1.195–11.154) 0.023* 1.487 (0.415–5.328) 0.543
Model 2 2.202 (0.699–6.937) 0.178 4.511 (1.075–18.926) 0.04* 0.856 (0.103–7.116) 0.886
Fetal distress
Model 1 1.680 (0.755–3.736) 0.204 2.669 (0.999–7.129) 0.05 0.826 (0.183–3.734) 0.804
Model 2 1.084 (0.307–3.820) 0.900 1.902 (0.371–9.472) 0.440 0.769 (0.091–6.487) 0.809
Low Birth weight
Model 1 1.233 (0.480–3.171) 0.663 1.117 (0.246–5.074) 0.886 1.887 (0.394–9.023) 0.427
Model 2 1.128 (0.251–5.073) 0.875 0.617 (0.072–5.314) 0.661 2.467 (0.486–12.532) 0.276
Fetal macrosomia
Model 1 0.413 (0.098,1.745) 0.229 0.54 (0.069–4.218) 0.557 0.385 (0.050–2.944) 0.358
Model 2 0.401 (0.094–1.707) 0.216 0.504 (0.63–4.030) 0.518 0.375 (0.049–2.893) 0.347
*P < 0.05
Model 1: Adjusted for age, BMI, parity, and history of spontaneous abortion
Model 2: Additionally, adjusted for HbA1c and TSH
BMI body-mass index, TSH thyroid-stimulating hormone, HbA1c glycated hemoglobin, GDM gestational diabetes, PROM premature rupture of membranes

important to identify its risk factors. Hypothyroidism had a higher risk of preterm birth than TPOAb-negative
and SCH were found to be associated with preterm women (6.6% vs 4.9%, respectively; OR, 1.33 [95% CI,
births in previous studies [7, 23, 24]. However, it re- 1.15–1.56]) [7]. The two meta-analyses, which included
mains unclear whether TPOAb positivity is a risk factor cohort studies, suggest that TPOAb positivity is associ-
for preterm birth in euthyroid women. In this study, ated with preterm birth. Although the subgroup analysis
TPOAb positivity was not associated with a higher risk of the fetus sex in this study found that TPOAb positiv-
of preterm birth except when the sex of the fetus was ity was only associated with preterm birth in pregnant
considered; in particular, TPOAb positivity in women women with a female fetus, TPOAb-positive euthyroid
with a female fetus was associated with preterm birth. women should be emphasized in clinical practice.
Therefore, the risk of preterm birth in euthyroid women Moreover, the potential benefit of LT4 therapy remains
with TPOAb positivity should be clinically emphasized unclear. A meta-analysis [27] found that LT4 supple-
since consistent results have been obtained in previous mentation reduced the risks of pregnancy loss and pre-
studies. In a birth cohort study in Ma’anshan, which is term birth in women with TAI. However, a separate
an iodine-sufficient area of China, TPOAb positivity was meta-analysis [28] showed that there was no definitive
associated with a higher risk of preterm birth [25]. A evidence that LT4 supplementation improved the preg-
meta-analysis showed pregnant women with TPOAb nancy outcomes in euthyroid women with TAI.
positivity had a substantial risk of preterm delivery com- On the contrary, published data have suggested that
pared with the reference group (RR: 1.69, 95% CI 1.19– TAI has no association with preterm births. Among
2.41, P = 0.003); however, this relationship was not found women with 1–2 previous pregnancy losses, TAI was
in pregnant women with TGAb positivity [26]. A separ- not associated with an increased risk of preterm delivery
ate meta-analysis found that TPOAb-positive women in euthyroid women [29]. Chen et al. showed that there
Yuan et al. BMC Pregnancy and Childbirth (2020) 20:491 Page 8 of 10

was no difference in the incidence of preterm births be- female fetus is still not clear. Lee et al. showed that TSH
tween TPOAb-positive with or without TGAb positivity levels were significantly higher in females than in males
and euthyroid women [21]. A secondary analysis of a (75 and 41%, respectively; p = 0.037) and that the genetic
prospective cohort in Denmark reported that there was influences on individual TSH levels were more promin-
more than double the number of pregnant women with ent in females than in males [5]. It is known that females
thyroid antibody positivity as part of an iodine fortifica- are more likely than males to develop thyroid disease. It
tion program without an increase in preterm birth-rate has been shown that women carrying a female fetus had
[30]. The disparate results may be due to multiple fac- a greater inflammatory response after an immune chal-
tors, including the year the research was conducted, the lenge than those carrying a male fetus [36]. Pregnancies
iodine-related nutrition status of the study participants, with a female fetus have a greater predisposition to pre-
the definitions and measures for the outcomes, and the term birth associated with hypertension [35, 37] and
demographic situation of the enrolled pregnant women. TAI may be involved in this process [38]. In addition,
In addition, none of the studies conducted subgroup some studies have shown that male fetuses may be more
analysis by sex of the fetus. Further randomized con- vulnerable to certain poor outcomes. For example, in a
trolled trials and fundamental studies are warranted to retrospective study that included pregnant women with
confirm the pregnancy outcomes and treatment of preeclampsia, among the preterm infants born, male fe-
euthyroid women with TPOAb positivity. tuses were more likely to be impaired in growth than fe-
The pathophysiological mechanism of preterm birth male fetuses [39]. In another study, male fetuses may
caused by TAI remains unclear. Some preterm births are have been more vulnerable to intrauterine adversity than
caused by impaired thyroidal response to HCG, inflam- female fetuses [40]. However, this study mainly indicated
mation, or accompanied by other autoimmune diseases that males who were small for gestational age at birth
and obstetric complications. TPOAb positivity is an indi- were more likely to have decreased physical develop-
cation of an impaired thyroidal response to HCG and an ment after birth. Therefore, the association of fetal sex
inadequate FT4 response to HCG has been associated on pregnancy-related and fetal outcomes should arouse
with a higher risk of preterm birth [31]. Interleukin-6 the concern of researchers.
(IL-6) levels are significantly higher in pregnant women Previous studies regarding TPOAb positivity and
with thyroid antibody positivity, suggesting that TAI is pregnancy-related and fetal outcomes have yielded
associated with low-grade inflammation [32]. A few mixed results. In this study, there was no significant dif-
studies showed a significant relationship between in- ference in the incidence of GDM, spontaneous abortion,
creased IL-6 levels and the risk of preterm birth [33]. PROM, fetal distress, low birth weight, or fetal macroso-
Furthermore, many pregnant women with TAI often mia between the two groups. Our results are consistent
suffer from other autoimmune diseases, such as systemic with the results of several studies [21, 41, 42]. However,
lupus erythematosus and antiphospholipid syndrome, some studies have found an association between TAI
which are well-known causes of preterm births. Several and other poor pregnancy and fetal outcomes. For ex-
studies found that TAI was associated with the risk of ample, one meta-study showed that there was an associ-
placental abruption, preeclampsia, and intrauterine ation between thyroid antibodies and the risk of GDM
growth restriction, obstetric complications that are [43]. Chen et al. showed that TPOAb positivity was asso-
known to be involved in preterm births [15, 31]. ciated with PROM and low birth weight [21]. The differ-
In this study, TPOAb positivity was independently as- ent findings between studies may be due to the varying
sociated with preterm birth only in pregnant women methodology and study populations. Therefore, incon-
with a female fetus. Some studies have suggested differ- sistent evidence remains and the relationship between
ences in pregnancy and fetal outcomes according to the pregnancy-related and fetal outcomes and TPOAb posi-
sex of the fetus. For example, fetal sex exerts a differen- tivity in euthyroid women needs to be studied further.
tial effect on the placental pathology that mediates se- In this study, univariable logistic regression analysis
vere preeclampsia and/or intrauterine growth restriction showed that GDM was associated with advanced mater-
[34]. A recent meta-analysis found preterm preeclampsia nal age and high maternal BMI, fetal macrosomia was
(delivered < 34 weeks) was even more prevalent among associated with high maternal BMI, and fetal distress
pregnancies with a female fetus compared with pregnan- was associated with first live birth. Therefore, the poor
cies with a male fetus [35]. Mitchell et al. [36] suggested pregnancy-related and fetal outcomes were associated
that examination of the moderating role of fetal sex dif- with demographic parameters and not thyroid disorders
ferences among women with adverse pregnancy out- or TAI. It should be noted that there are multiple con-
comes (e.g., preterm birth) in future studies would be tributing factors between poor pregnancy-related and
informative. However, the mechanism associating pre- fetal outcomes. It may be because the impact of TPOAb
term birth caused by TAI in pregnant women with a positivity on poor pregnancy and fetal outcomes in
Yuan et al. BMC Pregnancy and Childbirth (2020) 20:491 Page 9 of 10

euthyroid women varies with the sex of the fetus, and LDL: Low-density lipoprotein cholesterol; PROM: Precmature rupture of
demographic and obstetric parameters, according to membranes; SCH: Subclinical hypothyroidism; SGA: Small for gestational age;
TAI: Thyroid autoimmunity; TGAb: Thyroglobulin antibody; TPOAb: Anti-
different studies [21, 26, 42]. thyroid peroxidase antibody; TSH: Thyroid-stimulating hormone; UA: Uric
Several strengths of this study need to be underscored. acid; CV: Coefficient of variability; IL-6: Interleukin-6; IQR: Interquartile range;
First, this was a prospective cohort study to investigate LT4: Levothyroxine

the relationship between TPOAb positivity and Acknowledgments

pregnancy-related and fetal outcomes in euthyroid I would like to express my gratitude to all those who helped me during the
women. Secondly, numerous outcome variables were in- writing of this thesis.
cluded such as spontaneous abortion, GDM, HDP and Authors’ contributions
preterm birth, as well as other less frequently studied XM Z, LN J and NY designed the research, collected, and analyzed data, and
outcomes, such as PROM, fetal distress, low birth wrote the paper. JB S, Z L and SB C contributed to data acquisition. XM Z,
LN J and NY finally revised the manuscript. All authors read and approved
weight, fetal macrosomia, and SGA infant. Thirdly, we the final manuscript.
performed a subgroup analysis based on fetus sex and
found that there was a difference according to sex on Funding
the occurrence of preterm birth. Fetus sex examinations This work was supported by the Capital Featured Clinical Application
Research Project(Z171100001017126) and the key project of Peking
are strictly banned unless medically necessary in China; University International Hospital Fund (YN2019ZD04). The funders supported
therefore, the risks of preterm birth in all euthyroid the costs of this study.
women with TPOAb positivity should be emphasized in
Availability of data and materials
clinical practice. This study also had some limitations to The datasets used and/or analyzed during the current study are available
consider. Firstly, this study was a single-center cohort from the corresponding author on reasonable request.
study which limited the generalizability of the results
Ethics approval and consent to participate
and involved only a few demographic parameters that This study was approved by the Ethics Committee of Peking University
may influence pregnancy-related and fetal outcomes. International Hospital [2017–021(BMR)]. Written informed consent was
Other demographic parameters, such as socioeconomic obtained from each participant before enrolment in this study before
samples collection. This study was registered on ClinicalTrials.gov (Identifier
status, education level, and nutritional status, were not NCT02966405).
considered, although data on these factors would help to
guide services for pregnant women in this region. Sec- Consent for publication
Not applicable.
ondly, women in this study were enrolled at 4 to 8
weeks’ gestation; hence, spontaneous abortions that oc- Competing interests
curred early in the first trimester of pregnancy might The authors declare that they have no competing interests.
have been missed. However, in Beijing, it is common for
Author details
women to seek prenatal care during the first 4 weeks of 1
Department of Endocrinology, Peking University People’s Hospital, Beijing
gestation. Thus, only a very small number of patients 100044, China. 2Department of Endocrinology, Peking University International
Hospital, Beijing 102206, China. 3Department of gynaecology and obstetrics,
who underwent spontaneous abortions might have been
Peking University International Hospital, Beijing 102206, China.
missed. In addition, some subgroup analyses involved a
small study population; hence, the lack of association of Received: 30 March 2020 Accepted: 14 August 2020
TPOAb status and preterm birth and miscarriages may
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