The Effect of TPOAb on Embryologic and Pregnancy Outcomes Among Infertile PCOS Patients with Euthyroidism Undergoing IVF/ICSI Cycle: A Retrospective Cohort Study

doi:10.21203/rs.3.rs-4860004/v1

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The Effect of TPOAb on Embryologic and Pregnancy Outcomes Among Infertile PCOS Patients with Euthyroidism Undergoing IVF/ICSI Cycle: A Retrospective Cohort Study

https://doi.org/10.21203/rs.3.rs-4860004/v1

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Background PCOS is a complex endocrine disorder affecting fertility. PCOS patients combined with TAI have a higher risk of reproductive complications. The interplay between TAI and PCOS in the context of ART outcomes represents an unsolved problem. Therefore, the relationship between TPOAb and embryologic or pregnancy outcomes of IVF/ICSI in a cohort of infertile female patients diagnosed PCOS with euthyroidism should be evaluated.

Methods A retrospective cohort study is conducted. After selected with standard diagnostic code, strict inclusion and exclusion criteria and 1:4 PSM, 62 PCOS patients with TPOAb positive matched with 216 TPOAb negative PCOS patients from October 2014 to September 2022 are included in the study. The primary outcomes are live birth rate and clinical pregnancy rate, and secondary outcomes include other pregnancy-related outcomes and laboratory parameters related to embryologic quality.

Results In the TPOAb-positive group, fertilization rate, 2PN fertilization rate, and 2PN cleavage rate are significantly higher than those in the TPOAb-negative group (P < 0.05). However, TPOAb levels are not significantly associated with those embryo parameters in two groups after adjusting for propensity scores (P > 0.05). Then, we show that there are no correlation between TPOAb and pregnancy outcomes in TPOAb-positive and TPOAb-negative PCOS populations (P > 0.05).

Conclusions TPOAb is not a risk factor for embryonic or pregnancy outcomes in PCOS patients with euthyroidism undergoing IVF/ICSI. TPOAb-positive indicator should not be paid too much attention, and does not need to be overtreated for PCOS patients with euthyroidism undergoing IVF/ICSI.

Health sciences/Diseases/Reproductive disorders/Infertility

Health sciences/Diseases/Reproductive disorders/Endocrine reproductive disorders

Health sciences/Endocrinology/Endocrine system and metabolic diseases/Thyroid diseases

Polycystic ovarian syndrome (PCOS) is an endocrine disorder that predominantly affects women of reproductive age. This condition is characterized by a variety of symptoms, including irregular menstrual cycles, hyperandrogenism (excess male hormones), and polycystic ovaries. As a common issue in the fields of obstetrics and gynecology, reproductive medicine, endocrinology, and metabolism, PCOS presents a significant challenge for healthcare providers and patients alike. According to estimates, the prevalence rate of PCOS ranges from 9–19.9%, which translates to over 100 million women worldwide being affected by this condition ¹. In addition to its hallmark symptoms, PCOS is associated with a range of metabolic and reproductive complications ².

For women undergoing in vitro fertilization and embryo transfer (IVF-ET), PCOS presents unique challenges. These patients often exhibit a poor ovarian response or an exaggerated response to ovarian stimulation, making it difficult to achieve optimal outcomes in assisted reproductive technology (ART) treatments. The hormonal imbalances and metabolic issues inherent to PCOS can complicate the management of IVF-ET cycles, necessitating tailored approaches to improve the chances of successful conception and pregnancy. In addition, PCOS patients are accompanied by immune abnormalities, such as thyroid autoimmunity (TAI). The prevalence of TAI in PCOS patients is 18–40%, about three times that of non-PCOS patients^3–6. Compared with TAI or PCOS alone, TAI combined with PCOS has a higher risk of metabolic and reproductive complications ^7,8. Moreover, TAI is associated with poor response to treatment in infertility patients with PCOS⁹. The correlation between thyroid autoimmunity (TAI) and pregnancy outcomes has been investigated, revealing that women with TAI have an increased risk of miscarriage and preterm birth^10,11. However, the associations between TAI and pregnancy outcomes in ART remain controversial. Tünde Herman et al. observed that the presence of TAI negatively influences the clinical pregnancy rate (CPR) and is associated with a higher miscarriage rate (MR), ultimately resulting in a lower live birth rate (LBR). Similarly, Katarzyna Litwicka et al. found a strong association between the presence of thyroid autoantibodies and poor IVF outcomes^12,13. Conversely, K Łukaszuk et al. showed that patients with anti-thyroid peroxidase antibodies (TPOAb) exhibited no significant differences in fertilization, implantation, pregnancy rates, live birth rates, and no higher risk of miscarriage following IVF-ET compared to those negative for anti-thyroid antibodies. Furthermore, Ning Huang et al. demonstrated that the presence of TAI in patients with infertility did not impair embryo quality or affect pregnancy outcomes, including clinical pregnancy, miscarriage, preterm delivery, and live birth^14,15.

However, the interplay between TAI and PCOS in the context of ART outcomes represents an unsolved problem, necessitating further research to clarify these associations and develop targeted interventions for improving reproductive success in this subgroup of patients. In this study, we aim to evaluate the relationship between TPOAb, an indicator of TAI, and embryologic or pregnancy outcomes of in vitro fertilization or intracytoplasmic sperm injection (IVF/ICSI) in a cohort of infertile female patients who had been diagnosed PCOS with euthyroidism.

Study design and population

This retrospective cohort study is conducted at the Assisted Reproductive Centre of Shandong Provincial Maternal and Child Health Care Hospital affiliated with Qingdao University and Sichuan Jinxin Xinan Women and Children’s Hospital from October 2014 to September 2022. The study protocol is approved by the Ethics Committees of both hospitals (approval nos. 2023-77; 202104), and a waiver of informed consent was granted. Clinical and IVF/ICSI characteristic data are retrieved from electronic medical records. The flowchart of inclusion and exclusion of research participants is shown in Fig. 1. Patients are included in this study: 1) the females were aged 20–45 years old; 2) the first oocyte retrieval cycle had resulted in clinical pregnancy or not after a fresh embryo transfer with autologous sperm and oocytes had been transferred; 3) TSH concentrations ≤ 4 uIU/mL and had TPOAb test; 4) diagnosed with PCOS according to the 2003 Rotterdam ESHRE/ASRM PCOS Consensus Workshop Group diagnostic criteria. Patients are excluded: 1) history of thyroid disease, thyroid hormone/antithyroid hormone medication or thyroid surgery; 2) the other autoimmune disease; 3) the females have recurrent spontaneous abortion; 4) the female or male partner has a chromosomal abnormality; 5) the females have been diagnosed with endometriosis or a uterine abnormality.

Thyroid function measurement

Patients are tested for thyroid function before the initiation of IVF/ICSI treatment. Thyroid functional parameters, including the serum TSH, FT3, FT4, T3, T4 and TPOAb concentrations, are measured by chemiluminescent immunoassay using UniCel DxI 800 (Beckman Coulter, CA, USA), as previously described¹⁶. The TPOAb level ≥ 9 IU/mL is defined as TPOAb positive¹⁷.

Controlled ovarian stimulation and embryo transfer

In our center, the controlled ovarian stimulation (COS) protocols mainly include the gonadotropin-releasing hormone (GnRH) antagonist protocol, the long follicular phase protocol, and other protocols such as mild stimulation and the luteal phase stimulation protocol. Details of the COS protocols have been explained in detail in previous studies ¹⁸. Following the application of a dual protocol involving human chorionic gonadotropin (hCG) or GnRH agonist (GnRH-a) for ovulation induction, oocyte retrieval surgery is conducted. Either IVF or ICSI is performed according to sperm quality. Subsequently, fresh embryo transfer occurs on either the third or fifth day after the surgery.

Outcome measures and definitions

The primary outcoms are live birth rate and clinical pregnancy rate. Secondary outcomes include other pregnancy-related outcomes (biochemical pregnancy rate and miscarriage rate) and laboratory parameters related to embryologic quality (mature oocyte rate, fertilization rate, normal fertilization [2PN] rate, 2PN cleavage rate, high-quality embryo rate, blastocyst formation rate, high-quality blastocyst rate, and available blastocyst rate).

Biochemical pregnancy is defined as the serum β-hCG > 25 U/L 14 days after embryo transfer. Clinical pregnancy is confirmed through transvaginal ultrasound 28 days after embryo transfer, indicated by the presence of a gestational sac or fetal heart. Miscarriages are categorized as early or late. Early miscarriage is defined as the ratio of the number of spontaneous miscarriages occurring within 12 weeks of gestation to the total number of clinical pregnancies. Late miscarriage is defined as the ratio of spontaneous miscarriages occurring between 12 and 28 weeks of gestation. The live birth rate is calculated as the number of live births divided by the number of cycles in which embryos were transferred.

Embryo and blastocyst assessment are conducted using an adaptation of the Istanbul consensus workshop and the Gardner blastocyst grading system^19,20. The mature oocyte rate is calculated as the number of metaphase 2 oocytes divided by the number of oocytes retrieved during ICSI. The fertilization rate is defined as the number of 2PN, 1PN, 3PN embryos, and cleavage embryos from 0PN, divided by the number of retrieved oocytes in IVF or by the number of mature oocytes in ICSI, respectively. The 2PN rate is calculated as the number of 2PN embryos divided by the number of retrieved oocytes in IVF or by the number of mature oocytes in ICSI, respectively. The 2PN cleavage rate is defined as the number of cleavage embryos from 2PN divided by the number of 2PN zygotes. The high-quality embryo rate is defined as the number of high-quality embryos divided by the number of cleavage stage embryos. The blastocyst formation rate is calculated as the number of blastocysts divided by number of embryos cultured to the blastocyst stage. The available blastocyst rate is defined as the number of blastocysts suitable for cryopreservation and transplantation divided by the total number of blastocysts.

Statistical analysis

All statistical analyses are performed using SPSS version 27.0 and R version 4.2.3. The Kolmogorov-Smirnov test is used to assess normality assumptions for continuous variables. Baseline patient characteristics across different groups are summarized as follows: categorical data are presented as frequencies (percentages); normally distributed continuous data are expressed as mean ± standard deviation, while non-normally distributed data are presented as median (interquartile range). Differences between groups in continuous variables are evaluated using independent sample t-tests or Mann-Whitney U tests, as appropriate. Categorical variables are compared using the chi-square test. The impact of TPOAb positivity on embryo quality metrics and clinical outcomes are assessed using generalized linear models (GLM). Continuous outcomes are analyzed with an identity link function, while binomially distributed measurements are evaluated using a logistic link function. The results are reported as β coefficients with corresponding 95% confidence intervals (CI) for continuous outcomes, and odds ratios (OR) with their respective 95% CI for binomial outcomes. A P-value less than 0.05 is considered statistically significant for all tests.

Propensity score matching (PSM)

Multiple maternal factors, such as BMI and FSH, are known to be associated with embryo quality and pregnancy outcomes. To mitigate the impact of confounding factors associated with these outcomes, we perform propensity score matching (PSM). PSM is a robust technique for reducing bias in observational cohort studies, offering advantages over traditional regression-based methods. Through PSM, baseline covariates between the two groups are balanced, approximating the random assignment of subjects in a randomized controlled trial. Variables included in the PSM model comprised BMI, TSH, T3, basal serum FSH, and Gn dosage. TPOAb-positive and TPOAb-negative populations are matched using the nearest neighbor matching at a ratio of 1:4, and a caliper value set at 0.2.

Baseline Characteristics

Patients are grouped based on TPOAb status into TPOAb-positive (n = 64) and TPOAb-negative (n = 497) groups (Table 1). Before PSM, the TPOAb-positive group exhibits significantly different baseline characteristics compared to the TPOAb-negative group. Specifically, the levels of body mass index (BMI), thyroid-stimulating hormone (TSH), T3, follicle-stimulating hormone (FSH), and gonadotropin (GN) dosage are significantly higher in the TPOAb-positive group. After PSM, the distribution of all baseline characteristics between the TPOAb-positive (n = 62) and TPOAb-negative (n = 216) groups are balanced. There are no significant differences between the groups in terms of female age, BMI, infertility duration, thyroid functional parameters, hormone levels, antral follicle count (AFC), GN, COS protocol, infertility type, and fertilization type.

Table 1

Baseline characteristics and clinical parameters in TPOAb positive and negative PCOS patients before and after PSM
Characteristic	Before PSM			After PSM
Characteristic	TPOAb-negative group (n = 497)	TPOAb-positive group (n = 64)	P	TPOAb-negative group (n = 216)	TPOAb-positive group (n = 62)	P
Female age, median (IQR), Y	29.00 (27.00, 32.00)	29.00 (27.00, 32.00)	0.255	29.00 (27.00, 31.25)	29.00 (27.25, 32.00)	0.198
BMI, median (IQR), kg/m²	23.63 (21.48, 26.67)	25.00 (22.53, 28.08)	0.036	24.23 (22.05, 26.95)	25.00 (22.39, 27.84)	0.449
Infertility duration, median (IQR), Y	3.00 (2.00, 5.00)	3.00 (2.00, 5.00)	0.915	3.00 (2.00, 5.00)	3.00 (2.00, 4.75)	0.826
Thyroid functional parameters
TSH, median (IQR), uIU/mL	2.24 (1.58, 2.93)	2.88 (2.04, 3.78)	< .001	2.59 (1.80, 3.32)	2.82 (1.99, 3.79)	0.227
T3, median (IQR), pmol/L	1.70 (1.54, 1.92)	1.77 (1.66, 1.99)	0.014	1.73 (1.61, 1.96)	1.77 (1.66, 2.00)	0.319
T4, median (IQR), nmol/L	114.89 (100.77, 129.44)	116.73 (100.17, 129.56)	0.570	115.78 (100.96, 129.98)	117.77 (100.24, 130.87)	0.695
FT3, median (IQR), pmol/L	5.50 (5.10, 5.90)	5.67 (5.21, 6.14)	0.087	5.62 (5.20, 5.97)	5.64 (5.17, 6.11)	0.783
FT4, median (IQR), pmol/L	11.30 (10.06, 12.42)	11.21 (10.13, 12.34)	0.636	11.32 (9.91, 12.38)	11.21 (10.18, 12.35)	0.791
Hormone levels
AMH, median (IQR), ng/mL	6.02 (4.53, 8.38)	6.59 (4.55, 8.33)	0.745	5.93 (4.41, 8.36)	6.59 (4.48, 8.30)	0.708
FSH, median (IQR), mIU/mL	6.77 (5.64, 7.83)	7.03 (6.38, 8.14)	0.015	7.13 (5.97, 8.21)	6.96 (6.38, 8.01)	0.698
LH, median (IQR), mIU/mL	5.28 (3.46, 9.00)	6.12 (4.17, 9.54)	0.199	5.44 (3.59, 9.65)	6.00 (3.98, 8.88)	0.690
E₂, median (IQR), pg/mL	35.00 (27.00, 47.00)	37.16 (27.50, 52.25)	0.462	34.50 (27.00, 47.25)	36.00 (26.50, 51.75)	0.730
P, median (IQR), ng/mL	0.53 (0.35, 0.77)	0.53 (0.40, 0.75)	0.987	0.56 (0.36, 0.79)	0.53 (0.39, 0.76)	0.851
T, median (IQR), ng/dL	45.94(33.17,62.44)	47.79(30.26,65.05)	0.890	48.26(35.06,79.56)	47.78(30.20,75.30)	0.659
PRL, median (IQR), ng/mL	237.14(171.30,331.81)	244.70(164.86,332.31)	0.924	230.56(175.94,333.09)	244.70(165.70,333.72)	0.899
AFC, median (IQR), N	27.00 (22.00, 33.00)	29.00 (21.75, 36.00)	0.357	28.00 (22.00, 34.00)	29.00 (22.25, 36.00)	0.440
Gn used dosage, median (IQR), IU	1688.00 (1350.00, 2213.00)	1875.00 (1643.75, 2400.00)	0.012	1800.00 (1443.75, 2325.00)	1850.00 (1631.25, 2400.00)	0.329
Gn used duration, median (IQR), D	9.00 (8.00, 11.00)	10.00 (9.00, 11.00)	0.202	10.00 (8.75, 11.00)	10.00 (9.00, 11.00)	0.789
COS protocol, N (%)			0.963			0.900
GnRH antagonist protocol	370 (74.45)	47 (73.44)		160 (74.07)	45 (72.58)
Long follicular phase protocol	6 (1.21)	1 (1.56)		5 (2.31)	1 (1.61)
Other protocols	121 (24.35)	16 (25.00)		51 (23.61)	16 (25.81)
Infertility type, N (%)			0.435			0.696
Primary infertility	309 (62.17)	43 (67.19)		137 (63.43)	41 (66.13)
Secondary infertility	188 (37.83)	21 (32.81)		79 (36.57)	21 (33.87)
Fertilization type, N (%)			0.154			0.772
IVF	426 (85.71)	59 (92.19)		196 (90.74)	57 (91.94)
ICSI	71 (14.29)	5 (7.81)		20 (9.26)	5 (8.06)

Embryo quality

The comparison of embryo quality between the TPOAb-positive and TPOAb-negative groups is shown in Table 2. After PSM, the TPOAb-positive group shows significantly higher fertilization rate, 2PN fertilization rate, and 2PN cleavage rate compared to the TPOAb-negative group (83.13% vs 79.36%, P = 0.023; 73.55% vs 68.63%, P = 0.010; 98.35% vs 96.70%, P = 0.046). However, there are no significant differences in the mature oocyte rate, high-quality embryo rate, blastocyst rate, high-quality blastocyst rate and available blastocyst rate between the two groups (P > 0.05).

Table 2

The correlation between embryo quality and TPOAb in TPOAb-positive and TPOAb-negative PCOS patients
Embryo Parameters	TPOAb-positive group (n = 62)	TPOAb-negative group (n = 216)	P	Unadjusted analysis		Adjusted analysis
Embryo Parameters	TPOAb-positive group (n = 62)	TPOAb-negative group (n = 216)	P	β (95% CI)	P	β (95% CI)	P
Mature oocyte rate (%)	94.94 (713/751)	94.09 (2452/2606)	0.377	0.330 (-2.551, 3.211)	0.822	-0.032 (-2.906, 2.814)	0.982
Fertilization rate (%)	83.13 (616/741)	79.36 (2034/2563)	0.023	2.429 (-2.767, 7.626)	0.358	2.448 (-2.787, 7.684)	0.358
2PN rate (%)	73.55 (545/741)	68.63 (1759/2563)	0.010	3.422 (-1.934, 8.777)	0.210	3.609 (-1.783, 9.000)	0.189
2PN cleavage rate (%)	98.35 (536/545)	96.70 (1701/1759)	0.046	1.885 (-0.186, 3.956)	0.074	1.909 (-0.178, 3.995)	0.073
High-quality embryo rate (%)	40.73 (222/545)	37.52 (660/1759)	0.178	4.787 (-3.200, 12.775)	0.239	4.698 (-3.348, 12.745)	0.251
Blastocyst formation rate (%)	84.59 (461/545)	83.51 (1469/1759)	0.553	2.950 (-6.189, 12.088)	0.526	2.763 (-6.442, 11.967)	0.555
High-quality blastocyst rate (%)	14.13 (77/545)	17.00 (299/1759)	0.113	-2.851 (-10.034, 4.331)	0.435	-2.851 (-10.087, 4.385)	0.439
Available blastocyst rate (%)	42.57 (232/545)	44.68 (786/1759)	0.385	-2.195 (-10.908, 6.518)	0.620	-2.389 (-11.164, 6.386)	0.592

To further address potential confounding factors and baseline characteristic imbalances, we adjust for propensity scores and calculate adjusted β-values for the correlation between TPOAb levels and embryo quality in TPOAb-positive and TPOAb-negative PCOS patients (Table 2). The results indicate that TPOAb levels are not significantly associated with mature oocyte rate, fertilization rate, 2PN fertilization rate, 2PN cleavage rate, high-quality embryo rate, blastocyst rate, high-quality blastocyst rate, or available blastocyst rate in TPOAb-positive and TPOAb-negative PCOS patients (P > 0.05).

Pregnancy outcomes

The comparison of pregnancy outcomes between TPOAb-positive and TPOAb-negative group is shown in Table 3. After PSM, there are no statistically significant differences in biochemical pregnancy rate, clinical pregnancy rate, live birth rate and miscarriage rate (including early and late miscarriage rates) between the two groups (P > 0.05).

Table 3

The pregnancy outcomes according to TPOAb-positive and TPOAb-negative group
Outcome	TPOAb-positive group (n = 62)	TPOAb-negative group (n = 216)	P	Unadjusted analysis		Adjusted analysis
Outcome	TPOAb-positive group (n = 62)	TPOAb-negative group (n = 216)	P	OR (95% CI)	P	OR (95% CI)	P
Biochemical pregnancy rate (%)	44 (70.97)	151 (69.91)	0.872	1.052 (0.566, 1.957)	0.872	1.030 (0.552, 1.924)	0.925
Clinical pregnancy rate (%)	39 (62.90)	136 (62.96)	0.993	0.997 (0.556, 1.790)	0.993	0.964 (0.535, 1.737)	0.902
Miscarriage rate (%)	4 (10.26)	31 (22.79)	0.084	0.387 (0.128, 1.174)	0.094	0.413 (0.135, 1.263)	0.121
Early miscarriage rate (%)	3 (7.69)	28 (20.59)	0.063	0.321 (0.092, 1.121)	0.075	0.344 (0.098, 1.212)	0.097
Late miscarriage rate (%)	1 (2.56)	3 (2.21)	0.895	1.167 (0.118, 11.540)	0.895	1.108 (0.109, 11.307)	0.931
Live birth rate (%)	30 (48.39)	79 (36.57)	0.093	1.626 (0.920, 2.874)	0.095	1.594 (0.899, 2.828)	0.111

Furthermore, the results of the multivariate analyses to adjust for propensity scores are also shown in Table 3. The analyses indicate that TPOAb levels are not significantly associated with biochemical pregnancy rate, clinical pregnancy rate, live birth rate, or miscarriage rate (including early and late miscarriage rates) in TPOAb-positive and TPOAb-negative PCOS patients (P > 0.05).

The hormonal imbalances and metabolic issues inherent to PCOS can significantly complicate the management of in vitro fertilization-embryo transfer (IVF-ET) cycles ^21–24. Epidemiological data indicate that TAI is highly prevalent in PCOS patients, with rates approximately three times higher than those observed in non-PCOS patients. This high prevalence adds another layer of complexity to the treatment and management of infertility in women with PCOS. Despite these observations, the interplay between TAI and PCOS in the context of ART outcomes remains poorly understood and represents an unsolved problem in reproductive medicine^7,8.

Various studies have investigated the correlation between TPOAb, an indicator of TAI, and embryo quality in ART patients, but the results have been inconsistent. Some research suggests that TPOAb-positive patients show immune dysregulation during ART treatment for COS, which may affect follicle development and egg quality²⁵. Other studies indicate significantly reduced fertilization and high-quality embryo rates in TPOAb-positive patients²⁶. However, recent studies have found no significant association between TPOAb and fertilization rates or embryo quality^27,28. These findings suggest that the demographic and clinical characteristics of study populations, such as age, causes of infertility, underlying health conditions, and treatment protocols, can vary widely and thus influence outcomes and contribute to inconsistent results. Given that PCOS patients have a high prevalence of TAI, we focus on this subgroup. TPOAb is commonly used marker for TAI. Our study specifically examines the impact of TPOAb on fertilization and embryo quality in PCOS patients undergoing IVF/ICSI cycles. Our results show that there is no significant correlation between TPOAb and overall embryo quality in PCOS populations undergoing IVF/ICSI cycles, although TPOAb-positive PCOS patients have higher fertilization rates, 2PN fertilization rates, and 2PN cleavage rates. This lack of association suggests that while TPOAb may influence early fertilization processes, it does not have a lasting impact on the developmental competence of the embryos.

Several studies have consistently linked TPOAb positivity to adverse pregnancy outcomes in the general population. Meta-analyses have demonstrated increased risks of miscarriage and preterm birth among TPOAb-positive women^10,11. Other studies have shown that the abortion rate of TPOAb-positive women is significantly higher than that of TPOAb-negative women^{11,13,29–31}. However, the impact of TPOAb on pregnancy outcomes in ART remains controversial. Some studies report significantly lower clinical pregnancy and live birth rates among TPOAb-positive infertility women receiving ART^12,29,32, while others find no effect on pregnancy outcomes^15,33–35. Furthermore, some research indicate that TPOAb positivity does not affect clinical pregnancy and live birth rates in ART patients^13,14,36. Additionally, certain studies suggest no difference in miscarriage rates between TPOAb-positive and TPOAb-negative women¹³. In our study, utilizing a strict PSM method to adjust for confounders, we find no significant correlation between TPOAb positivity and adverse pregnancy outcomes in euthyroid PCOS patients. Specifically, our analysis shows no difference in biochemical pregnancy rate, clinical pregnancy rate, miscarriage rate, and live birth rate between TPOAb-positive and TPOAb-negative groups. These findings are particularly noteworthy given the extensive adjustments for potential confounders, including age, BMI, duration of infertility, type of infertility, ovarian stimulation protocols, and other clinical parameters. Our rigorous approach ensures that the observed outcomes are robust and less likely to be influenced by underlying population differences.

Clinical implications

Given the complex pathogenesis of PCOS, clinicians treating euthyroid PCOS patients may not need to prioritize monitoring TPOAb levels during IVF/ICSI treatments. Instead, attention should be directed towards other endocrine, metabolic, and immune factors that may impact embryonic and pregnancy outcomes.

Strengths and limitations

The strength of our study lies in the stringent inclusion criteria we employed. We exclude women with a history of thyroid disease, thyroid hormone or anti-thyroid medication use, thyroid surgery, as well as those with a history of autoimmune diseases or recurrent miscarriages. To address the significant difference in sample sizes between the TPOAb-positive and TPOAb-negative PCOS patients, we perform PSM at a ratio of 1:4 to reduce the effect of confounding bias between the two groups in this observational cohort study.

However, our study also has some limitations. For instance, we do not use a prospective research design, which may introduce certain biases. in addition, metabolic factors affecting PCOS, such as insulin metabolism, are not analyzed, which may contribute to the occurrence of insulin resistance in PCOS patients.

TPOAb is not a risk factor for embryonic and pregnancy outcomes in PCOS patients with euthyroidism undergoing IVF/ICSI. Therefore, we suggest that for PCOS patients with enthyroidism undergoing IVF/ICSI, a TPOAb-positive indicator should not be overly emphasized, and does not require excessive treatment.

Funding

This work received support from Foundation of Shandong Province Maternal and Child Health Association (YJKY2022-009; YJKY2022-033) and Foundation of Qingdao University.

Conflict of interest

The authors report no conflict of interest.

1Macklon, N. S., Polycystic ovary syndrome. BMJ-BRIT MED J 343 d6407 (2011).
2Williams, T., Mortada, R. & Porter, S., Diagnosis and Treatment of Polycystic Ovary Syndrome. AM FAM PHYSICIAN 94 106 (2016).
3Romitti, M., Fabris, V. C., Ziegelmann, P. K., Maia, A. L. & Spritzer, P. M., Association between PCOS and autoimmune thyroid disease: a systematic review and meta-analysis. ENDOCR CONNECT 7 1158 (2018).
4Garelli, S. et al., High prevalence of chronic thyroiditis in patients with polycystic ovary syndrome. EUR J OBSTET GYN R B 169 248 (2013).
5Janssen, O. E., Mehlmauer, N., Hahn, S., Offner, A. H. & Gartner, R., High prevalence of autoimmune thyroiditis in patients with polycystic ovary syndrome. EUR J ENDOCRINOL 150 363 (2004).
6Petrikova, J., Lazurova, I. & Yehuda, S., Polycystic ovary syndrome and autoimmunity. EUR J INTERN MED 21 369 (2010).
7Skrzynska, K. J., Zachurzok, A. & Gawlik, A. M., Metabolic and Hormonal Profile of Adolescent Girls With Polycystic Ovary Syndrome With Concomitant Autoimmune Thyroiditis. FRONT ENDOCRINOL 12 708910 (2021).
8Adamska, A. et al., Ovarian Reserve and Serum Concentration of Thyroid Peroxidase Antibodies in Euthyroid Women With Different Polycystic Ovary Syndrome Phenotypes. FRONT ENDOCRINOL 11 440 (2020).
9Ott, J. et al., Elevated antithyroid peroxidase antibodies indicating Hashimoto's thyroiditis are associated with the treatment response in infertile women with polycystic ovary syndrome. FERTIL STERIL 94 2895 (2010).
10Dong, A. C., Morgan, J., Kane, M., Stagnaro-Green, A. & Stephenson, M. D., Subclinical hypothyroidism and thyroid autoimmunity in recurrent pregnancy loss: a systematic review and meta-analysis. FERTIL STERIL 113 587 (2020).
11Thangaratinam, S. et al., Association between thyroid autoantibodies and miscarriage and preterm birth: meta-analysis of evidence. BMJ-BRIT MED J 342 d2616 (2011).
12Litwicka, K., Arrivi, C., Varricchio, M. T., Mencacci, C. & Greco, E., In women with thyroid autoimmunity, does low-dose prednisolone administration, compared with no adjuvant therapy, improve in vitro fertilization clinical results? J OBSTET GYNAECOL RE 41 722 (2015).
13Mintziori, G. et al., Association of TSH concentrations and thyroid autoimmunity with IVF outcome in women with TSH concentrations within normal adult range. GYNECOL OBSTET INVES 77 84 (2014).
14Lukaszuk, K. et al., The impact of the presence of antithyroid antibodies on pregnancy outcome following intracytoplasmatic sperm injection-ICSI and embryo transfer in women with normal thyreotropine levels. J ENDOCRINOL INVEST 38 1335 (2015).
15Huang, N. et al., Impact of Thyroid Autoimmunity on In Vitro Fertilization/Intracytoplasmic Sperm Injection Outcomes and Fetal Weight. FRONT ENDOCRINOL 12 698579 (2021).
16Rao, M. et al., Subclinical Hypothyroidism Is Associated with Lower Ovarian Reserve in Women Aged 35 Years or Older. THYROID 30 95 (2020).
17Webster, G. M., Venners, S. A., Mattman, A. & Martin, J. W., Associations between perfluoroalkyl acids (PFASs) and maternal thyroid hormones in early pregnancy: a population-based cohort study. ENVIRON RES 133 338 (2014).
18Chen, M. X. et al., An Individualized Recommendation for Controlled Ovary Stimulation Protocol in Women Who Received the GnRH Agonist Long-Acting Protocol or the GnRH Antagonist Protocol: A Retrospective Cohort Study. FRONT ENDOCRINOL 13 899000 (2022).
19The Istanbul consensus workshop on embryo assessment: proceedings of an expert meeting. HUM REPROD 26 1270 (2011).
20Gardner, D. K. & Schoolcraft, W. B., Culture and transfer of human blastocysts. CURR OPIN OBSTET GYN 11 307 (1999).
21Spritzer, P. M., Lecke, S. B., Satler, F. & Morsch, D. M., Adipose tissue dysfunction, adipokines, and low-grade chronic inflammation in polycystic ovary syndrome. REPRODUCTION 149 R219 (2015).
22Goverde, A. J. et al., Indicators for metabolic disturbances in anovulatory women with polycystic ovary syndrome diagnosed according to the Rotterdam consensus criteria. HUM REPROD 24 710 (2009).
23Daan, N. M. et al., Cardiovascular and metabolic profiles amongst different polycystic ovary syndrome phenotypes: who is really at risk? FERTIL STERIL 102 1444 (2014).
24Wiltgen, D. & Spritzer, P. M., Variation in metabolic and cardiovascular risk in women with different polycystic ovary syndrome phenotypes. FERTIL STERIL 94 2493 (2010).
25Miko, E. et al., Characteristics of peripheral blood NK and NKT-like cells in euthyroid and subclinical hypothyroid women with thyroid autoimmunity experiencing reproductive failure. J REPROD IMMUNOL 124 62 (2017).
26Steiner, A. Z. et al., Antimullerian hormone as a predictor of natural fecundability in women aged 30–42 years. OBSTET GYNECOL 117 798 (2011).
27Fleming, R., Seifer, D. B., Frattarelli, J. L. & Ruman, J., Assessing ovarian response: antral follicle count versus anti-Mullerian hormone. REPROD BIOMED ONLINE 31 486 (2015).
28Bedenk, J., Vrtacnik-Bokal, E. & Virant-Klun, I., The role of anti-Mullerian hormone (AMH) in ovarian disease and infertility. J ASSIST REPROD GEN 37 89 (2020).
29Poppe, K. et al., Assisted reproduction and thyroid autoimmunity: an unfortunate combination? J CLIN ENDOCR METAB 88 4149 (2003).
30Negro, R. et al., Levothyroxine treatment in thyroid peroxidase antibody-positive women undergoing assisted reproduction technologies: a prospective study. HUM REPROD 20 1529 (2005).
31Toulis, K. A. et al., Risk of spontaneous miscarriage in euthyroid women with thyroid autoimmunity undergoing IVF: a meta-analysis. EUR J ENDOCRINOL 162 643 (2010).
32Kilic, S. et al., The effect of anti-thyroid antibodies on endometrial volume, embryo grade and IVF outcome. GYNECOL ENDOCRINOL 24 649 (2008).
33Unuane, D. et al., Impact of thyroid autoimmunity on cumulative delivery rates in in vitro fertilization/intracytoplasmic sperm injection patients. FERTIL STERIL 106 144 (2016).
34Unuane, D. et al., Impact of thyroid autoimmunity in euthyroid women on live birth rate after IUI. HUM REPROD 32 915 (2017).
35Ke, H. et al., Impact of Thyroid Autoimmunity on Ovarian Reserve, Pregnancy Outcomes, and Offspring Health in Euthyroid Women Following In Vitro Fertilization/Intracytoplasmic Sperm Injection. THYROID 30 588 (2020).
36Negro, R. et al., Euthyroid women with autoimmune disease undergoing assisted reproduction technologies: the role of autoimmunity and thyroid function. J ENDOCRINOL INVEST 30 3 (2007).

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The Effect of TPOAb on Embryologic and Pregnancy Outcomes Among Infertile PCOS Patients with Euthyroidism Undergoing IVF/ICSI Cycle: A Retrospective Cohort Study

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Abstract

Figures

Introduction

Materials and Methods

Study design and population

Thyroid function measurement

Controlled ovarian stimulation and embryo transfer

Outcome measures and definitions

Statistical analysis

Propensity score matching (PSM)

Results

Baseline Characteristics

Embryo quality

Pregnancy outcomes

Discussion

Clinical implications

Strengths and limitations

Conclusion

Declarations

Funding

References

Additional Declarations

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