Meta-analysis of ART outcomes in women with different preconception TSH levels

SCH affects 2–5% of all pregnant women in the United States. This disease is characterized by abnormalities in the hypothalamic-pituitary-thyroid axis that are reflected by alter standard serum thyroxine (T4) levels and increased serum TSH levels [1]. Opinions vary regarding the different guidelines available related to the treatment of women with SCH seeking to use ART because the optimal therapy for these patients remains unknown. This is partly because of limitations related to a lack of consequence data on miscarriages that occur in early pregnancy.

Overt hypothyroidism (OH) is defined as a high level of TSH and a low level of T4 and is related to infertility as well as adverse pregnancy outcomes [2], including early pregnancy miscarriage, stillbirth and preterm delivery [3‐5]. Recently, many studies have emerged that have evaluated the association between SCH during pregnancy and multiple poor maternal outcomes [6‐8]. However, their conclusions have not been consistent. One meta-analysis demonstrated that SCH during pregnancy is related to multiple adverse neonatal and maternal consequences [9].

The relationship between ART outcomes and thyroid function has been a hot topic and the subject of a great deal of debate in recent years [10]. The reason for this interest seems obvious, at least from an epidemiological point of view, because ART is continually being performed and thyroid disorders are highly prevalent in women of reproductive age. In accordance with the results described in a recent report by the European Society of Human Reproduction and Embryology (ESHRE), between 0.8 and 4.1% of children born in Europe are the result of in vitro fertilization (IVF) [11]. Until recently, societies governing the use of human reproductive technologies did not recommend measuring TSH levels in asymptomatic ovulatory women [12, 13]. However, the new guidelines reported by the American Society for Reproductive Medicine (ASRM) endorse measuring TSH concentrations in infertile women seeking to become pregnant [14]. The prevalence of thyroid disorders has increased in subfertile women, and this has been recognized by the American Thyroid Association (ATA) [15] and the Endocrine Society. These organizations have consequently produced recommendations regarding the measurement of TSH levels in woman at “high-risk” of thyroid disease, including asymptomatic infertile patients [16].

During a pregnancy, variations occur in the normal range of TSH levels, and this has led to the introduction of SCH, a more vaguely defined complication observed in pregnant patients [17]. While the lower range of normal serum TSH levels has remained consistent, the upper limit for normal TSH levels has changed dramatically in recent years [18]. The ATA and The National Association of Clinical Biochemistry (NACB) [19] have lowered the upper limit for normal TSH levels in the first trimester of pregnancy from 4.5 mIU/L to 2.5 mIU/L. [15] Other clinical institutions, such as the American Association for Clinical Chemistry (AACC), have traditionally set 5.0 mIU/L as the upper limit for normal TSH levels [20].

ART patients experience many barriers when attempting to achieve conception, and identifying the optimal range of pregestational TSH levels is now specifically recognized as an important parameter. Furthermore, the superovulation caused by ART generates a rapid increase in E2 levels [21] that increases the hepatic synthesis of thyroid-binding globulin and leads to a reduction in free, unbound T4 [22‐24]. These events can potentially aggravate the condition of a patient with underlying SCH. The risk of poor iatrogenic-related reproductive outcomes in ART has made SCH a special focus in the ART population.

Though obstetricians can correct TSH in patients who are already pregnant, by inspecting data associated with a large cohort of ART patients, in this study, we attempt to determine whether elevated TSH levels in the preconception period predict adverse outcomes in ART patients. We seek to address whether it is appropriate to apply traditional TSH criteria in patients about to undergo ART (i.e., are these criteria associated with any clinical benefit) and to prompt reproductive medical organizations to develop methods to increase the ability of practitioners to identify and treat ART patients whose TSH status puts them at high risk of adverse results.

This meta-analysis was specifically aimed at evaluating the associations between preconception maternal TSH levels and ART outcomes. We found that a stricter TSH cut-off value did not seem to influence ART outcomes including the LBR, PR, CPR, and MR. Furthermore, using a broader TSH cut-off value resulted in a significant difference in poor ART outcomes including the MR.

Many previous studies have researched the association between SCH during conception and maternal outcomes, but their conclusions have been inconsistent. In 2016, a meta-analysis focused on thyroid dysfunction indicated that SCH during pregnancy is related to multiple poor neonatal and maternal outcomes, especially abortion [9]. However, the studies evaluated in that analysis had enrolled participants who were normal fertile woman. However, we should not ignore the fact that more and more infertile patients are undergoing ART treatment. Recently, many articles have focused on the relationship between preconception SCH in infertile patients and multiple ART outcomes. However, their conclusions have been conflicting. Nevertheless, this information is very important because most reproductive endocrinologists routinely perform preconception tests for serum TSH levels as a part of an elementary infertility workup.

Moreover, subclinical thyroid function disorder is a focus of studies evaluating patients undergoing ovarian stimulation because it has been suggested that these patients experience a decrease in thyroxin levels and an increase in TSH levels during ovulation induction.

Due to the increased subsequent risk of hypothyroidism in participants with a TSH level above 2.0 mIU/L (e.g., as demonstrated in the Whickham survey [42]), the NACB guidelines suggest that 2.5 mIU/L should be regarded as the upper limit for a normal TSH reference range [43]. In patients previously diagnosed with hypothyroidism, the Endocrine Society (TES) practice guidelines suggest that preconception TSH values should be under 2.5 mIU/ mL [44]. The ATA and the American Association of Clinical Endocrinologists co-sponsored guidelines for the treatment of hypothyroidism in patients attempting to conceive [19]. Their proposal reinforces the notion that TSH levels should be maintained at lower than 2.5 mIU/L in women with hypothyroidism, including those with overt hypothyroidism and SCH before pregnancy. Moreover, there is a lack of consistency regarding what cut-off value for serum TSH levels should be used to define SCH in individuals undergoing ART. Several studies have relied on the use of a recommended basal cut-off value of TSH < 2.5 mIU/l in individuals termed “desirable” for conception. However, we cannot ignore that some prospective and retrospective studies found no difference in IVF outcomes between women with serum TSH < 2.5 mU/L and those with mild TSH elevations, defined as a TSH level between 2.5 and 5 mU/L. The results of these studies were inconsistent with our outcomes. The underlying reason remains uncertain. One of the probable reasons is the distribution of TSH levels in infertile women. Braverman et al. found that the distribution of TSH levels in infertile individuals presented a left skew with a long tail [20]. The argument for decreasing the upper TSH reference range presumes that it conforms to a Gaussian distribution in nature. However, studies have found that in some euthyroid outliers, such as patients recovering from nonthyroidal illness, measurements that include bioinactive TSH isoforms or receptor gene polymorphisms as well as occult autoimmune thyroid dysfunction show that the upper tail of the distribution is skewed [45, 46]. Additionally, TSH levels can be influenced by strenuous exercise, the timing of phlebotomy and sleep deprivation [47]. Previous publications have also indicated that the distribution of TSH levels gradually shifts toward higher values with age [48]. Hence, TSH concentrations could represent an epiphenomenon in which the above-mentioned factors account for its influence on pregnancy outcomes.

When a broader TSH cut-off value was used, we found a significant difference in the MR between SCH patients and normal women. This outcome is consistent with some random clinical trials (RCTs). These trials demonstrated that treatment of SCH patients who were defined using a broader TSH cut-off value appeared beneficial. An RCT was conducted in patients aged 20–40 years old with SCH (serum TSH > 4.5 mU/L, normal fT4) who were undergoing IVF [49]. A total of 64 participants were randomized for supplementation with LT4 (to maintain TSH levels < 2.5 mU/L) vs. placebo. The treated patients had MRs, higher CPRs, and higher LBRs. Another RCT randomized 64 infertile women with SCH (TSH > 4.2 mU/L, normal fT4) to a treatment group receiving 50 mcg/day LT4 vs. a placebo group [50]. Similar to the above trial, the study showed higher PRs, lower MRs, and higher LBRs in the treatment group than in the control group. Taken together, these data suggest that SCH likely impacts ART in a dose-dependent manner, and the impact worsens as TSH concentrations increase. Hence, in 2017, the ATA guidelines recommended that women with SCH undergoing IVF or ICSI should be treated with LT4 with a goal of maintaining a TSH concentration < 2.5 mU/L. It is worth noting that this recommendation is focused on women who are undergoing ART. However, the effect of SCH before ART on ART outcomes remains uncertain. Our results suggest that applying a broader TSH cut-off value during the preconception period may improve ART outcomes such as the pregnancy loss rate.

In addition, we found that an increasing number of clinicians are uncertain regarding whether to perform preconception thyroid function tests, especially for women seeking ART [51]. Routine preconception testing for all women is not recommended by any relevant professional body (ATA, ACOG, RCOG) primarily because there is no high-level evidence to support its use. Our search also provided high-level evidence regarding the necessity of routine thyroid function tests before conception in women seeking to ART. We found that women with SCH defined using the broader TSH cut-off value before conception could have poor ART outcomes, such a higher MR.

In contrast to our findings, a recent prospective trial published by Negro et al. [7] included 4123 thyroid antibody–negative subjects and found that the risk of miscarriage was higher in women with TSH values between 2.5 and 5.0 mIU/L at < 11 weeks of pregnancy. The reasons for this discrepancy may include the following. For example, the subjects were individuals with spontaneous conceptions who were already in the first trimester and did not include infertile women. Therefore, TSH levels were tested only in subjects who were already pregnant, whereas in our study, all TSH concentrations were measured before conception. This difference could be partially responsible for the difference in the effect in that if TSH values decreases during early pregnancy, as suggested in a previous study [52], then individuals with TSH values above 2.5 mIU/L during the first trimester might have had higher TSH levels before pregnancy. In addition, ovarian stimulation seems to influence TSH concentrations [24, 53].

Our data indicate no difference in ART outcomes when a TSH cut-off value of 2.5 mIU/L is used. However, using a broader cut-off value of TSH, we found a higher MR in SCH patients seeking ART than in the control group. We suggest that a thyroid function test should be a routine examination in women seeking ART.