Effects of maternal levothyroxine supplementation during pregnancy on miscarriage and preterm delivery

To the Editor: Maternal overt hypothyroidism (OH), subclinical hypothyroidism (SCH), or thyroid autoimmunity (TAI) can lead to adverse pregnancy outcomes. During the last decade, the American Thyroid Association (ATA), the European Thyroid Association, the Chinese Society of Endocrinology (CSE), and the American College of Obstetricians and Gynecologists (ACOG) issued several guidelines for the management of thyroid disorders during gestation. Over 13 years ago, SCH during pregnancy was defined as a serum thyroid stimulating hormone (TSH) level between 2.5 mIU/L and 10.0 mIU/L with a normal free thyroxine (FT4) concentration.[1] Six years later, the upper limit of the pregnancy-specific TSH reference was raised to 4.0 mIU/L.[2] Levothyroxine (LT4) is the most recommended drug for thyroid hormone supplementation in pregnant women. However, according to diverse guidelines, the conditions triggering the initiation of LT4 supplementation differ among pregnant women. Previously, several meta-analyses were conducted to investigate whether LT4 improves gestational outcomes among women with SCH, but the findings were inconclusive.[3,4] These inconsistent results might be due to different definitions of SCH, discrepant TAI statuses, different timings of LT4 initiation, varying TSH targets during treatment, and differences in ethnicity. Hence, whether LT4 ameliorates adverse pregnancy outcomes remains unknown. Additionally, whether quitting LT4 supplementation is harmless for women with a gestational TSH level ranging from 2.5 mIU/L to 4.0 mIU/L needs to be determined. Therefore, we performed a systematic review and meta-analysis of randomized controlled trials (RCTs) to validate the effects of LT4 on maternal and neonatal outcomes and aimed to provide valuable information for clinical practice. We searched EMbase, MEDLINE, Web of Science, Conference Proceedings Citation Index, Cochrane Central Register of Controlled Trials, SciELO Citation Index, Derwent Innovations Index, PubMed, and ClinicalTrial.gov from inception to June 2024. The details of the protocol registration, search strategy, study selection and inclusion process, data extraction and outcome measures, risk of bias assessment, data synthesis, and statistical analysis are presented in Supplementary Part 1, https://links.lww.com/CM9/C357. Notably, since pregnant participants might have been classified into SCH chaotically according to diverse diagnostic criteria, eligible studies in our analysis were categorized into different thyroid function statuses on the basis of the baseline TSH values in the LT4 arm (referring to the means or the interquartile range) and according to the 2017 ADA diagnostic criteria[2] (details in Supplementary Part 1, https://links.lww.com/CM9/C357). In total, 13 RCTs met our predefined inclusion criteria and were included in the meta-analysis, which included 2468 participants assigned to LT4 and 2436 individuals assigned to comparators. The main characteristics of the 13 included studies are presented in Supplementary Table 1 and Supplementary Part 1, https://links.lww.com/CM9/C357. Details of the process are shown in Supplementary Figure 1, https://links.lww.com/CM9/C357. All the included studies had a low to moderate risk of bias [Supplementary Table 2 and Supplementary Figure 2, https://links.lww.com/CM9/C357]. The incidences of miscarriage and preterm delivery were considered the primary outcomes, while the secondary outcomes included intrauterine pregnancy, placental abruption, gestational diabetes mellitus, gestational hypertension, preeclampsia, and so on [Supplementary Table 3, https://links.lww.com/CM9/C357]. Overall, miscarriage incidence was reported in 12 studies with 17 specific comparison pairs and 3573 participants, which revealed that, compared with the controls, LT4 was associated with a decreased risk of miscarriage (relative risk [RR] 0.74, 95% confidence interval [CI] 0.63–0.87, I2 = 24%) [Supplementary Figure 3, https://links.lww.com/CM9/C357]. Preterm delivery occurred in 169 out of 1910 women assigned to the LT4 group and in 207 out of 1881 subjects assigned to the control group, indicating that LT4 was associated with a decreased rate of preterm delivery (RR = 0.73, 95% CI = 0.55–0.98, I2 = 39%) [Supplementary Figure 4, https://links.lww.com/CM9/C357]. The funnel plots and Peter’s test revealed no evidence of publication bias in the incidence of miscarriage (P = 0.058) [Supplementary Figure 5A, https://links.lww.com/CM9/C357] or preterm delivery (P = 0.067) [Supplementary Figure 5B, https://links.lww.com/CM9/C357]. Subgroup analyses were conducted as follows. First, for miscarriage incidence, according to the baseline thyroid function categories, LT4 was associated with a decreased rate of miscarriage in women with isolated euthyroidism (RR = 0.80, 95% CI = 0.66–0.98, I2 = 17%), isolated SCH (RR = 0.35, 95% CI = 0.16–0.77, I2 = 0%), and euthyroidism mixed with SCH (RR = 0.71, 95% CI = 0.53–0.96, I2 = 35%) [Supplementary Table 4, https://links.lww.com/CM9/C357]. Compared with the controls, LT4 was associated with a reduced risk of miscarriage in gestational women with TAI (RR = 0.79, 95% CI = 0.65–0.95, I2 = 19%). For trials in which TSH <2.5 mIU/L was the prescribed target value during treatment, LT4 significantly reduced the risk of miscarriage compared with that in the control group (RR = 0.68, 95% CI = 0.55–0.84, I2 = 25%). LT4 supplementation reduced the miscarriage rate when it was initiated before or within the first trimester (RR = 0.71, 95% CI = 0.56–0.90, I2 = 35%). In addition, LT4 significantly lowered the risk of miscarriage in both Asian (RR = 0.68, 95% CI = 0.52–0.88, I2 = 35%) and non-Asian (RR = 0.78, 95% CI = 0.64–0.95, I2 = 13%) pregnant women. Second, for preterm delivery, for women with diverse thyroid function statuses at baseline, LT4 was associated with a decreased rate of preterm delivery only in the population with euthyroidism mixed with SCH (RR = 0.56, 95% CI = 0.39–0.81, I2 = 20%) [Supplementary Table 5, https://links.lww.com/CM9/C357]. Compared with controls, LT4 significantly lowered the risk of preterm delivery in women with TAI (RR = 0.65, 95% CI = 0.46–0.92, I2 = 23%) and without TAI (RR = 0.63, 95% CI = 0.42–0.93, I2 = 9%). Like the miscarriage rate, LT4 reduced the risk of preterm delivery in studies with a prescribed cut-off value of TSH <2.5 mIU/L during treatment (RR = 0.70, 95% CI = 0.56–0.87, I2 = 12%). LT4 decreased the preterm delivery risk when it was initiated before or within the first trimester (RR = 0.63, 95% CI = 0.48–0.82, I2 = 15%). Moreover, LT4 reduced the risk of preterm delivery only among Asian women (RR = 0.66, 95% CI = 0.49–0.88, I2 = 16%). Finally, the subgroup analysis focused on a special group of pregnant women with isolated euthyroid status or euthyroid mixed with SCH status at baseline. According to the TSH data in the original studies, the majority of pregnant women in the special group had TSH levels ranging from 2.5 mIU/L to 4.0 mIU/L. Both the miscarriage rate (RR = 0.78, 95% CI = 0.66–0.91, I2 = 21%) and preterm delivery rate (RR = 0.64, 95% CI = 0.50–0.83, I2 = 17%) were much lower in the LT4 group than in the control group [Supplementary Table 6, https://links.lww.com/CM9/C357]. LT4 significantly lowered the risk of miscarriage in participants with TAI (RR = 0.81, 95% CI = 0.67–0.98, I2 = 5%), in participants with a prescribed target value of TSH <2.5 mIU/L (RR = 0.70, 95% CI = 0.57–0.87, I2 = 26%), in subjects with treatment initiation before or within the first trimester (RR = 0.77, 95% CI = 0.66–0.91, I2 = 27%), and among pregnant Asian women (RR = 0.71, 95% CI = 0.54–0.92, I2 = 30%). LT4 substantially decreased the risk of preterm delivery among Asian participants (RR = 0.66, 95% CI = 0.49–0.89, I2 = 24%), among participants with a prescribed cut-off value of TSH <2.5 mIU/L during treatment (RR = 0.65, 95% CI = 0.50–0.85, I2 = 20%), and among subjects with treatment initiation before or within the first trimester (RR = 0.63, 95% CI = 0.49–0.82, I2 = 22%). Additionally, LT4 reduced the incidence of preterm labor among those women irrespective of TAI status (P <0.05). Briefly, our results provide compelling evidence that LT4 supplementation reduces the incidence of both miscarriage and preterm delivery, especially among pregnant Asian women, individuals with TAI, and those with sustained TSH levels below 2.5 mIU/L during LT4 treatment. The 2017 ATA guideline issued a fixed upper limit of the TSH interval of up to 4.0 mIU/L throughout the entire gestational period, which is quite different from the values issued by previous guidelines.[1,2,5] However, the recommended target TSH threshold during LT4 treatment was still less than 2.5 mIU/L in the 2017 ATA guideline, which was the same as the former guidelines. These cut-off values lead to two main unsolved concerns. First, the most intriguing issue concerning thyroid hormone deficiency during pregnancy is the TSH concentration at which level LT4 supplementation should be implemented. It should be determined whether avoiding LT4 is harmless in pregnant women with TSH levels ranging from 2.5 mIU/L to 4.0 mIU/L. Second, it should be answered that the optimal target level of TSH during LT4 supplementation is either less than 2.5 mIU/L or less than 4.0 mIU/L. For the first concern, due to the lack of trials specifically focusing on women with a gestational TSH level of 2.5–4.0 mIU/L, direct evidence cannot be provided. Several analyses were performed in our study to investigate whether it is an overtreatment to prescribe LT4 for those women. First, the participants included in our study were categorized into several groups according to their baseline thyroid function test results. In pregnant populations with euthyroidism mixed with SCH, our findings revealed that LT4 decreased the risk of miscarriage and preterm delivery. Among women with isolated euthyroidism, treatment with LT4 lowered the risk of miscarriage. Notably, all pregnant women in the euthyroid group were positive for TAI. Second, a special group consisting of pregnant women with either isolated euthyroidism or euthyroidism mixed with SCH, where the majority were gestational women with TSH levels of 2.5–4.0 mIU/L, was further analyzed. Therefore, with respect to the first concern, our results showed that LT4 supplementation decreased the risk of miscarriage and preterm delivery in this population. Recently, a meta-analysis conducted by Sankoda et al[4] revealed that LT4 treatment initiated either preconception or during early pregnancy had no effect on miscarriage or preterm birth in pregnant women with TSH levels of 2.5–4.0 mIU/L. The reasons for the inconsistent findings in our work may involve several aspects. The definition of SCH in Sankoda’s study abided by the 2011 ATA diagnostic criteria,[1] in which the upper limit of the gestational TSH range was set as 2.5 mIU/L. In addition, the baseline TSH levels in two trials included in Sankoda’s study could not be observed. Conversely, all the studies included in our analysis provided valid information on TSH levels before and after LT4 treatment, which remarkably assisted in evaluating the baseline thyroid function status of pregnant women. As a result, the trials ultimately eligible for Sankoda’s analysis differed from those included in our work. With respect to the second unsolved concern, owing to the lack of enough trials adopting a prescribed TSH value of less than 4.0 mIU/L as the targeted threshold during LT4 treatment, it can hardly compare the two cut-off values directly. Since the prescribed TSH target thresholds were reported by all the studies included in our work, our findings indicated that after receiving LT4 therapy, women with a prescribed target value of TSH <2.5 mIU/L experienced a decreased risk of miscarriage and preterm delivery. On the basis of our study, which abided by the 2017 ATA diagnostic criteria, LT4 supplementation can lower the risk of miscarriage in pregnant women with SCH, regardless of TAI status. In women with a gestational TSH level of 2.5–4.0 mIU/L, especially those with concurrent TAI or Asian women, LT4 treatment could decrease the incidence of miscarriage and preterm delivery. Our findings support the recommendations of the 2017 ATA and the 2019 CSE guidelines but oppose the 2020 ACOG practice bulletin. This study has several limitations. First, the dose–response relationship between gestational TSH levels and adverse pregnancy outcomes is an intriguing topic worthy of further exploration. However, because of the lack of access to the required raw data, this part had to be suspended in the present work. Second, owing to the lack of trials specifically focusing on women with gestational TSH levels of 2.5–4.0 mIU/L, future endeavors need to verify our findings with well-designed RCTs. In conclusion, LT4 supplementation during pregnancy was associated with a reduced incidence of miscarriage in SCH patients, as well as decreased risks of miscarriage and preterm delivery in TAI patients. Avoiding LT4 treatment for each woman with a gestational TSH level of 2.5–4.0 mIU/L seems too premature. Although further long-term trials are needed to confirm our findings, the present study advances the clinical use of LT4 among pregnant women. Funding This work was supported by the National Natural Science Foundation of China (No. 82100851) and the Natural Science Foundation of Sichuan Province, China (No. 2024NSFSC0583). Registration information This work was registered in PROSPERO (CRD42023395712). Conflicts of interest None.