Impact of anti-thyroid peroxidase and anti-thyroglobulin antibodies on the gestational outcome of euthyroid pregnancies: A retrospective study

Abstract

BACKGROUND:

Thyroglobulin (anti-TG) and/or thyroid peroxidase (anti-TPO) autoantibodies are associated with higher rates of poor gestational outcomes.

OBJECTIVE:

To demonstrate the impact of anti-TPO and anti-TG autoantibodies on the gestational outcomes of euthyroid pregnant women with a history of poor gestational outcome and thyroid gland disorders.

METHODS:

This retrospective study included totally 75 euthyroid pregnant, 30 of women with high thyroid autoantibodies (Anti-TPO/Thyroglobulin-positive group) and 45 of them without autoantibodies (control group).

RESULTS:

We could not demonstrate significant differences between two groups in terms of risk factors/co-morbidities, obstetric complications, gestational outcomes, and birth data ( $p>$ 0.05). However, enhanced miscarriage rates were observed among the Anti-TPO/Thyroglobulin-positive and control groups without significance (36.7% and 17.8% respectively, $p=$ 0.116). High neonatal intensive care unit (NICU) admission rates were found for control and Anti-TPO/Thyroglobulin-positive groups (16.2% and 21.1%, respectively) ( $p=$ 0.720). Clinically, we compared the two groups in terms of the existence and the types of goiter (diffuse and nodular), and demonstrated that nodular goiter was statistically more frequent in the control group (40.0% vs. 8.7%, $p=$ 0.015). Alongside, relatively high hereditary thrombophilia and type-2 diabetes mellitus rates were found in the Anti-TPO/Thyroglobulin-positive group (20.0% and 20.0%).

CONCLUSION:

Thyroid autoantibody positivity is likely a risk factor for early pregnancy loss and NICU admission.

Keywords

Thyroid gland anti-thyroperoxidase antibody anti-thyroglobulin antibody pregnancy gestational outcome

1. Introduction

Thyroid dysfunction and/or autoimmunity are common in women of reproductive age with a prevalence of 2–3% [1]. Circulating autoantibodies against thyroglobulin and/or thyroid peroxidase may be associated with thyroid problems, and even in the absence of thyroid dysfunction, anti-thyroid autoantibodies have been linked to poor gestational outcomes such as miscarriage, preterm birth, and postpartum thyroiditis [2, 3, 4, 5, 6].

Thyroid peroxidase is located at the apical surface of thyroid follicular cells to induce iodine oxidation and iodination of tyrosyl residues of the thyroglobulin. Anti-thyroid peroxidase (anti-TPO) autoantibodies have the ability to induce infiltration of lymphocytic cells to the thyroid gland, fix complement, cause cytotoxicity in thyroid follicular cells, and act as an enzymatic inhibitor, most probably reflecting the activity of Hashimoto’s thyroiditis (HT) [7, 8, 9]. Anti-thyroglobulin (Anti-TG) autoantibody is also a conventional marker for thyroid autoimmunity as well as differentiated thyroid cancer (DTC) [10, 11]. Antibodies against TPO and TG belong to the immunoglobulin G (IgG) class and have a strong affinity for related autoantigens. They are most likely both required for thyroid hormone production and secretion [11, 12]. From the clinical perspective, anti-TG seems to be less prevalent than anti-TPO for the prediction of thyroid dysfunction, but more effective in the surveillance of DTC management [10]. However, it has been reported that the screening anti-TG together with anti-phospholipid (aPL) might be considered in the first step in patients with recurrent pregnancy loss [5].

It was previously reported that the prevalence of high anti-TG was 2%, while anti-TPO was present in 6.8% of the population [13]. Anti-TPO and Anti-TG autoantibodies seem to be a secondary response to thyroid inflammation and HT, leading to higher adverse gestational and perinatal morbidity rates regardless of thyroid hormone status [2, 3, 4, 5, 6, 12]. Moreover, HT frequently causes hypothyroidism in pregnancy and many children exposed to thyroid autoantibodies may have hypothyroidism in utero [12]. For this reason, knowing thyroid autoantibody positivity in advance is a great advantage in perinatal surveillance.

In this study, we aimed to demonstrate the impact of thyroid autoantibody positivities on the gestational outcomes of euthyroid women with a history of poor gestational outcomes and thyroid gland problems.

2. Materials and methods

Between 2016 and 2019, 75 euthyroid pregnant women with history of poor gestational outcomes and thyroid gland disorders were evaluated retrospectively. Autoimmune antibody positivity was defined as positive when the levels were $\geqslant$ 4.5 IU/ml and $>$ 60 U/ml for anti-TG and anti-TPO, respectively. The Anti-TPO/Thyroglobulin-positive group consisted of 30 women with high thyroid autoantibodies and the remaining 45 women with negative thyroid autoimmune antibodies were accepted as a control group. This study was approved by our institutional ethic committee with a reference number-GO 19/1064. Necessary data were collected in compliance with the Declaration of Helsinki.

In this study, we evaluated and compared groups in terms of demographic and clinical findings as well as maternal risk factors for placenta-related obstetric complications including metabolic disorders (Diabetes mellitus, homozygous Methylenetetrahydrofolate reductase (MTHFR) mutations, etc.), immune system problems (autoimmune diseases and chronic inflammatory diseases), and thrombotic events. In addition to this, obstetric complications (miscarriage, preterm birth, stillbirth, etc.), gestational at birth age (days), birth weight (g), APGAR scores ( $<$ 7 or $\geqslant$ 7), neonatal intensive care unit (NICU) admissions were also analyzed. Beksac Obstetric Index (BOI) which is “[number of living child $+$ ( $\pi$ /10)]/gravida” was used for the evaluation of obstetric history of the cohort [14]. BOIp is the BOI value calculated during pregnancy.

SPSS 23.0. (Chicago, IL, USA) was used for statistical analysis. Maternal age, birthweight, gestational age, and Boip were represented as the mean $\pm$ standard deviation (SD). The assumption of normality was checked by the Shapiro-Wilks normality test. The student t-test was used to compare normally distributed data. The Mann-Whitney U test was performed for non-normally distributed data. Qualitative data were given as a number ( $n$ ) and percentage (%). Data were compared by Yates’ Continuity Test and Fisher’s Exact Tests. A $p$ -value less than 0.05 was accepted as statistically significant.

Table 1
The comparison of Anti TPO and/or Anti Thyroglobulin antibody positive cases ( $n=$ 30) and control group ( $n=$ 45) in terms of demographic findings such as maternal age, gravidity, parity, number of miscarriage, and BOIp

	Control $n=$ 45	Anti TPO/Anti Thyroglobulin ( $+$ ) $n=$ 30	Total $n=$ 75	$P$
Maternal age
Mean $\pm$ SD	33.77 $\pm$ 4.55	34.07 $\pm$ 4.86	33.89 $\pm$ 4.65	0.794 ${}^{\text{a}}$
Min-max	23–44	24–44	23–44
Gravidity
Mean $\pm$ SD	3.58 $\pm$ 1.60	4.20 $\pm$ 2.12	3.83 $\pm$ 1.84
Min-max	1–7	1–11	1–11	0.236 ${}^{\text{b}}$
Median	3.00	4.00	4.00
Parity
Mean $\pm$ SD	1.87 $\pm$ 1.01	1.50 $\pm$ 1.13	1.72 $\pm$ 1.07
Min-max	0–4	0–4	0–4	0.067 ${}^{\text{b}}$
Median	2.00	1.00	2.00
Miscarriage
Mean $\pm$ SD	1.37 $\pm$ 1.6	1.73 $\pm$ 2.1	1.52 $\pm$ 1.8
Min-max	0–6	0–11	0–11	0.398 ${}^{\text{b}}$
Median	1.00	1.00	1.00
BOIp
Mean $\pm$ SD	0.94 $\pm$ 0.6	0.61 $\pm$ 0.6	0.81 $\pm$ 0.6	0.018 ${}^{\text{b,*}}$
Median	0.7713	0.4628	0.6570

a: Independent $t$ test, b: Mann Whitney $U$ , *: $p<$ 0.05.

3. Results

Demographic findings (maternal age, gravidity, parity, miscarriage, and BOIp) of 75 euthyroid pregnant women with a history of poor gestational outcome and thyroid gland disorder are shown in Table 1. The mean maternal age of the study population was 33.89 $\pm$ 4.65 years and similar to Anti-TPO/Thyroglobulin-positive (34.07 $\pm$ 4.86 years) and control groups (33.77 $\pm$ 4.55 years). Low BOIp values indicate poor obstetric history of the control and Anti-TPO/Thyroglobulin-positive groups (0.7713 versus 0.4628 respectively, $p=$ 0.018).

Table 2
The comparison of the two groups in terms the presence and types of goiter

	Control $n$ (%)		Anti TPO/Anti Thyroglobulin ( $+$ ) n (%)		Total $n$ (%)		$P$
Goiter (-)	21	(46.7)	21	(70)	42	(56)	0.079 ${}^{\text{a}}$
Goiter (+)	24	(53.3)	9	(30)	33	(44)
Total	45	(100)	30	(100)	75	(100)
Goiter (-)	21	(67.7)	21	(75)	42	(71.2)
Diffuse Goiter	10	(32.3)	7	(25)	17	(28.8)	0.744 ${}^{a}$
Total	31	(100)	28	(100)	59	(100)
Goiter (-)	21	(60.0)	21	(91.3)	42	(72.4)
Nodular (single/multi) goiter	14	(40.0)	2	(8.7)	16	(27.6)	0.015 ${}^{\text{b,*}}$
Total	35	(100)	23	(100)	58	(100)

a: Yates continuity correction, b: Fisher’s exact test, ${}^{*}$ : $p<$ 0.05.

Table 3

The comparison of the two groups in terms of the presence of some co-morbidities such as immune system problems (Hashimoto’s thyroiditis is not included), metabolic problems (MTHFR polymorphisms), carbohydrate metabolism disorders (Diabetes Mellitus Type-2) and hereditary thrombophilia

	Control $n$ (%)		Anti TPO/Anti Thyroglobulin ( $+$ ) $n$ (%)		Total $n$ (%)		$P$
Immune system problems (-)	38	(84.4)	24	(80.0)	62	(82.7)	0.757 ${}^{\text{a}}$
Immune system problems (+)	7	(15.6)	6	(20.0)	13	(17.3)
MTHFR polymorphisms (-)	26	(57.8)	16	(53.3)	42	(56)	0.887 ${}^{\text{b}}$
MTHFR polymorphisms (+)	19	(42.2)	14	(46.7)	33	(44)
Hereditary thrombophilia (-)	35	(77.8)	24	(80)	59	(78.7)	0.817 ${}^{\text{c}}$
Hereditary thrombophilia (+)	10	(22.2)	6	(20)	16	(21.3)
Diabetes Mellitus Type-2 (-)	36	(80)	24	(80)	60	(80)	1.000 ${}^{\text{a}}$
Diabetes Mellitus Type-2 (+)	9	(20)	6	(20)	15	(20)
Total	45	(100)	30	(100)	75	(100)

a: Fisher’s exact test, b: Yates continuity correction, c: Likelihood ratio, $p>$ 0.05, Immune system problems include autoimmune diseases and chronic inflammatory diseases.

Table 4

The comparison of two groups in terms of gestational outcomes, obstetric complications, and birth data

	Control $n$ (%)		Anti TPO/Anti Thyroglobulin (+) $n$ (%)		Total $n$ (%)		$P$
Miscarriage
(-)	37	(82.2)	19	(63.3)	56	(74.7)	0.116 ${}^{\text{b}}$
(+)	8	(17.8)	11	(36.7)	19	(25.3)
Total	45	(100)	30	(100)	75	(100)
Preterm birth
(-)	35	(94.6)	17	(89.5)	52	(92.9)	0.598 ${}^{\text{a}}$
(+)	2	(5.4)	2	(10.5)	4	(7.1)
Total	37	(100)	19	(100)	56	(100)
APGAR score
$<$ 7	1	(2.7)	0	(0)	1	(1.8)
$\geqslant$ 7	36	(97.3)	19	(100)	55	(98.2)	0.661 ${}^{\text{a}}$
Total	37	(100)	19	(100)	56	(100)
Neonatal Intensive Care Unit (NICU)
(-)	31	(83.8)	15	(78.9)	46	(82.1)	0.720 ${}^{\text{a}}$
(+)	6	(16.2)	4	(21.1)	10	(17.9)
Total	37	(100)	19	(100)	56	(100)
Birthweight
N	37		19		56		0.156 ${}^{\text{c}}$
Mean $\pm$ SD	3016 $\pm$ 392.9		2863 $\pm$ 341.3		2964 $\pm$ 380.1
Median	3070		2940
Gestational age at birth
N	37		19		56		0.112 ${}^{\text{d}}$
Mean $\pm$ SD	260.08 $\pm$ 6.30		257.47 $\pm$ 6.53		259.19 $\pm$ 6.44
Median	260		259

a: Fisher’s exact test, b: Yates continuity correction, c: student $t$ -test, d: Mann Whitney $U$ test, $p>$ 0.05.

As seen in Table 2, Anti-TPO/Thyroglobulin-positive and control groups were compared regarding the presence of goiter, and it was found that nodular (single/multinodular) goiter was statistically more common in the control group ( $p=$ 0.015). However, there was no significant difference in terms of the presence of goiter in general ( $p=$ 0.079).

Rates of co-morbidities such as immune system problems (other than HT), MTHFR gene polymorphisms, hereditary thrombophilia and type-2 diabetes mellitus were similar in both groups ( $p>$ 0.05, for all) (Table 3). The rates of immune system problems, MTHFR polymorphisms, hereditary thrombophilia, and type-2 diabetes mellitus were found to be 17.3% (13/75), 44.0% (33/75), 21.3% (16/75) and 20.0% (15/75) respectively in the cohort population.

We also compared the two groups in terms of gestational outcomes and birth findings, and could not demonstrate statistically significant differences ( $p>$ 0.05, for all) (Table 4). However, miscarriage rates were found to be relatively high both in control and Anti-TPO/Thyroglobulin-positive groups such as 17.8% and 36.7%, respectively. The mean gestational day at birth of the cohort was 259.19 $\pm$ 6.44 days (37.03 weeks), which seems to be challenging in terms of antenatal care strategies. Nevertheless, gestational age at birth was similar with a mean of 257.47 $\pm$ 6.53 and 260.08 $\pm$ 6.30 days in the Anti-TPO/Thyroglobulin-positive and control groups respectively ( $p=$ 0.112). The mean birth weight of the study population was 2964 $\pm$ 380.1 g and also similar in Anti-TPO/Thyroglobulin-positive (2863 $\pm$ 341.3 g) and control groups (3016 $\pm$ 392.9 g) ( $p=$ 0.156). APGAR scores and NICU admissions had similar rates in both Anti-TPO/Thyroglobulin-positive and control groups ( $p=$ 0.661 and 0.720, respectively). Relatively high NICU admission rates for both control and Anti-TPO/Thyroglobulin-positive groups (16.2% vs. 21.1%) were also of interest in terms of neonatal surveillance.

4. Discussion

Thyroid gland disorders in pregnant women may raise the risk of poor maternal and fetal outcomes such as preeclampsia, miscarriage, stillbirth, preterm delivery, and fetal growth restriction [2, 4, 5, 6, 15, 16, 17]. HT is the most common disorder of the thyroid gland influencing 3.5/1000 annually in women and roughly 1% of the general population. HT itself and/or hypothyroidism, which is most commonly the continuum of HT, might be associated with placenta-related obstetric complications and poor gestational outcomes [3, 4, 5, 15, 16, 17]. Besides, subclinical thyroid problems and circulating thyroid autoantibodies can also be observed in about 15% of euthyroid people [18, 19, 20]. In this study, we evaluated the effects of thyroid autoantibodies (Anti-TPO and Anti-TG) on the gestational outcomes of euthyroid women with a history of poor gestational outcomes and thyroid gland problems.

Anti-nuclear antibody (ANA), extractable nuclear antigen (ENA), anti-double-stranded DNA (anti-dsDNA), anti-phospholipid antibody (aPLA), anti-parietal cell antibody (APA), anti-smooth muscle antibody (ASMA), anti-mitochondrial antibody (AMA) as well as anti-TPO and anti-TG positivities have all been linked to thrombotic events and placenta-related (placental inflammation) obstetric complications [6, 21, 22, 23, 24, 25]. The damaging effects of autoimmune antibodies such as anti-TG and anti-TPO on the cellular components of the placental intervillous region could be the cause of placental inflammation. Thus, anti-TPO and anti-TG might be related to poor gestational outcomes including miscarriage and preterm birth even when there is no thyroid dysfunction.

In this study, we could not demonstrate statistically significant differences between the two groups in terms of demographic findings, clinical findings, risk factors/co-morbidities, obstetric complications, gestational outcomes and birth data, most probably due to the limited number of patients in each group and complexity of the study population. The cohort was composed of euthyroid pregnant women with a history of poor gestational outcomes and thyroid gland disorders, and these specifications are the reason for the elusiveness of the findings. BOIp value was significantly lower in the Anti-TPO/Thyroglobulin-positive group, indicating that previous gestational outcomes of the Anti-TPO/Thyroglobulin-positive group were poorer compared to pregnancies of the control group. Besides, miscarriage rates were found to be relatively high both in control and Anti-TPO/Thyroglobulin-positive groups such as 17.8% and 36.7% respectively. The miscarriage rate of our institution was previously reported to be 10.7% [26].

Immune system disorders, MTHFR gene polymorphisms, hereditary thrombophilia, type-2 diabetes mellitus are all risk factors for poor gestational outcome [21, 24, 27, 28, 29]. Interrelatedly, 80% of all individuals affected by autoimmune disorders [30], while the frequencies of MTHFR C677T and A1298C were reported to be 42.9% and 43.7% respectively [31]. It was also reported that the allelic frequency of MTHFR 677 and MTHFR 1298 mutations were 0.296 and 0.283 and the prevalence of homozygous MTHFR C677T and MTHFR A1298C polymorphisms were 10.2% and 11.1%, respectively [32]. On the other hand, hereditary thrombophilias were reported to be present in at least 15% of the general population [33], while approximately 462 million individuals were affected by type 2 diabetes in 2017, corresponding to 6.28% of the world’s population [34]. In this study, the rates of immune system problems, MTHFR polymorphisms, hereditary thrombophilia and type-2 diabetes mellitus were found to be 17.3% (13/75), 44.0% (33/75), 21.3% (16/75) and 20.0% (15/75) respectively. However, we could not demonstrate statistically significant differences between the control and Anti-TPO/Thyroglobulin-positive groups in terms of the presence of these risk factors. The over rates of hereditary thrombophilia and type-2 diabetes mellitus were most probably due to the complicated nature of the study population.

Thyroid glands of the patients were examined in terms of the existence of goiter. Despite the fact that there was no substantial difference in the existence rates of goiter between the control and Anti-TPO/Thyroglobulin-positive groups (53.3% vs. 30.0%), we found that nodular goiter was statistically more common in the control group (40.0% vs. 8.7%). Associatively, worldwide prevalence of goiter in the general population is estimated to be 15.8% varying between 4.7% in America and 28.3% in Africa [35]. Pregnancy is a goitrogenic stimulant, however, the development of goiter during pregnancy can be avoided by iodine supply if iodine consumption is restricted or even moderately low [36]. A goiter may be associated with no change in thyroid function or with an increase or decrease in thyroid hormones. One of the most prevalent thyroid gland disorders is multinodular goiter, and thyroid function tests are either normal or suggest subclinical or overt hyperthyroidism, depending on the physical examination [37]. The vast majority of thyroid nodules are non-neoplastic lesions (benign hyperplasia), with only 5–20% of thyroid nodules being cancerous. Distinguishing hyperplasia from neoplasms is one of the most important aspects of examining a solitary thyroid nodule [38, 39, 40]. High rate of nodular goiter in the control group is presumably due to the clinical features of the control group.

The mean gestational day at birth of the cohort was 37.03 weeks, which seems to be challenging in terms of antenatal care strategies. Nevertheless, Gestational age at birth was similar with a mean of 257.47 $\pm$ 6.53 and 260.08 $\pm$ 6.30 days in the study and control groups, respectively ( $p=$ 0.112). Besides, the mean birthweights were found to be 3016 $\pm$ 392.9 g and 2863 $\pm$ 341.3 g for the control and Anti-TPO/Thyroglobulin-positive groups respectively without statistical significance. Mean birth weight in the total group of infants in Turkey was reported to be 3252 $\pm$ 504 g [41]. In this study, we have demonstrated high NICU admission rates for both control and Anti-TPO/Thyroglobulin-positive groups (16.2% and 21.1% respectively) without statistically significant difference. These relatively high NICU admission rates might be of interest in terms of neonatal care measures. It was previously reported that crude NICU admission rates increase from 6.62% to 9.07% between 2008 and 2018 [42], and an epidemiologic time-trend analysis was conducted on 2015, of live births ( $\geqslant$ 500 g) from 2007, to December 2012, and overall admission rates during the 6-year study period increased from 64.0 to 77.9 per 1000 live births [43].

Limitations of this study include the limited number of patients in each group. Despite this limitation, the cohort was composed of 75 euthyroid pregnant women with a history of poor gestational outcomes and thyroid gland disorders, and the selection of the control group was an advantage in the evaluation of the impact of thyroid autoantibodies. In conclusion, thyroid autoantibody positivity is likely a risk factor for early pregnancy loss and NICU admission in euthyroid women.

Footnotes

Acknowledgments

Funding Sources: There is no financial support for this study.

Author contributions

Conception: KB, HGD, MC, and MSB.

Methodology: KB and HGD.

Data collection: HGD and MC.

Interpretation or analysis of data: HGD and MC.

Preparation of the manuscript: KB, HGD and MSB.

Revision for important intellectual content: MSB.

Supervision: MSB.

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Impact of anti-thyroid peroxidase and anti-thyroglobulin antibodies on the gestational outcome of euthyroid pregnancies: A retrospective study

Abstract

BACKGROUND:

OBJECTIVE:

METHODS:

RESULTS:

CONCLUSION:

Keywords

1. Introduction

2. Materials and methods

Table 1 The comparison of Anti TPO and/or Anti Thyroglobulin antibody positive cases ( n = 30) and control group ( n = 45) in terms of demographic findings such as maternal age, gravidity, parity, number of miscarriage, and BOIp

Table 2 The comparison of the two groups in terms the presence and types of goiter

Footnotes

Acknowledgments

Author contributions

References

Table 1
The comparison of Anti TPO and/or Anti Thyroglobulin antibody positive cases ( $n=$ 30) and control group ( $n=$ 45) in terms of demographic findings such as maternal age, gravidity, parity, number of miscarriage, and BOIp

Table 2
The comparison of the two groups in terms the presence and types of goiter