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Figure.
Flow of Participants Through the POSTAL Study of Levothyroxine During IVF-ET
Flow of Participants Through the POSTAL Study of Levothyroxine During IVF-ET

BMI indicates body mass index, calculated as weight in kilograms divided by height in meters squared; IVF, in vitro fertilization; ET, embryo transfer.

aAdjuvant treatment includes anticoagulants, glucocorticoids, or other relevant treatments.

bPreterm delivery was defined as a live birth before 37 weeks of gestation.

cOne woman was diagnosed hydatidiform mole after natural conception. This conception was not counted as a clinical pregnancy.

dBiochemical pregnancy was defined as serum β-human chorionic gonadotropin (hCG) level more than 30 IU/L 14 days after ET.

eMiscarriage was defined as pregnancy loss before the 28th week of gestation; prespecified early and late miscarriages are defined in the Methods section.

Table 1.  
Baseline Characteristics of the Participants (Intention-to-Treat Analysis)
Baseline Characteristics of the Participants (Intention-to-Treat Analysis)
Table 2.  
Protocols of Controlled Ovarian Hyperstimulation and Data of In Vitro Fertilization and Embryo Transfer (Intention-to-Treat Analysis)
Protocols of Controlled Ovarian Hyperstimulation and Data of In Vitro Fertilization and Embryo Transfer (Intention-to-Treat Analysis)
Table 3.  
Pregnancy Outcomes of the Participants (Intention-to-Treat analysis)
Pregnancy Outcomes of the Participants (Intention-to-Treat analysis)
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Original Investigation
December 12, 2017

Effect of Levothyroxine on Miscarriage Among Women With Normal Thyroid Function and Thyroid Autoimmunity Undergoing In Vitro Fertilization and Embryo Transfer: A Randomized Clinical Trial

Author Affiliations
  • 1Department of Endocrinology and Metabolism, Center of Reproductive Medicine, Peking University Third Hospital, Beijing, China
  • 2Clinical Epidemiology Research Center, Peking University Third Hospital, Beijing, China
  • 3The Robinson Research Institute, School of Pediatrics and Reproductive Health, University of Adelaide, Australia
  • 4South Australian Health and Medical Research Institute, Adelaide, Australia
JAMA. 2017;318(22):2190-2198. doi:10.1001/jama.2017.18249
Key Points

Question  Does levothyroxine treatment improve outcomes following in vitro fertilization and embryo transfer in women who have tested positive for thyroid autoantibodies but otherwise have normal thyroid function?

Findings  In this randomized clinical trial involving 600 women undergoing in vitro fertilization and embryo transfer who tested positive for antithyroperoxidase antibodies but who had a normal thyroid function, the miscarriage rate before 28 weeks’ gestation was 10.3% among women who received and 10.6% among those who did not receive levothyroxine, a nonsignificant difference.

Meaning  Levothyroxine treatment did not appear to improve pregnancy outcomes among women with thyroid autoantibodies undergoing in vitro fertilization and embryo transfer.

Abstract

Importance  Presence of thyroid autoantibodies in women with normal thyroid function is associated with increased risk of miscarriage. Whether levothyroxine treatment improves pregnancy outcomes among women undergoing in vitro fertilization and embryo transfer (IVF-ET) is unknown.

Objective  To determine the effect of levothyroxine on miscarriage among women undergoing IVF-ET who had normal thyroid function and tested positive for thyroid autoantibodies.

Design, Setting, and Participants  An open-label, randomized clinical trial involving 600 women who tested positive for the antithyroperoxidase antibody and were being treated for infertility at Peking University Third Hospital from September 2012 to March 2017.

Interventions  The intervention group (n = 300) received either a 25-μg/d or 50-μg/d dose of levothyroxine at study initiation that was titrated according to the level of thyroid-stimulating hormone during pregnancy. The women in the control group (n = 300) did not receive levothyroxine. All participants received the same IVF-ET and follow-up protocols.

Main Outcomes and Measures  The primary outcome was the miscarriage rate (pregnancy loss before 28 weeks of gestation, which was calculated among women who became pregnant). The secondary outcomes were clinical intrauterine pregnancy rate (fetal cardiac activity seen at sonography observation on the 30th day after the embryo transfer), and live-birth rate (at least 1 live birth after 28 weeks of gestation).

Results  Among the 600 women (mean [SD] age, 31.6 [3.8] years) randomized in this trial, 567 women (94.5%) underwent IVF-ET and 565 (94.2%) completed the study. Miscarriage rates were 10.3% (11 of 107) in the intervention group and 10.6% (12 of 113) in the control group, with the absolute rate difference (RD) of −0.34% (95% CI, −8.65% to 8.12%) over the 4.5-year study period. Clinical intrauterine pregnancy rates were 35.7% (107 of 300) in the intervention group and 37.7% (113 of 300) in the control group, with an absolute RD of −2.00% (95% CI, −9.65% to 5.69%). Live-birth rates were 31.7% (95 of 300) in the intervention group and 32.3% (97 of 300) in the control group, with an absolute RD of −0.67% (95% CI, −8.09% to 6.77%).

Conclusions and Relevance  Among women in China who had intact thyroid function and tested positive for antithyroperoxidase antibodies and were undergoing IVF-ET, treatment with levothyroxine, compared with no levothyroxine treatment, did not reduce miscarriage rates or increase live-birth rates.

Trial Registration  Chinese Clinical Trial Registry: ChiCTR-TRC-13004097

Introduction

Thyroid hormones are important in regulating metabolism and reproductive health. Overt hypothyroidism has been associated with increased risk of spontaneous miscarriage and preterm delivery.1Thyroid autoimmunity, defined as presence of the thyroid autoantibodies, antithyroperoxidase antibody, or antithyroglobulin antibody, is the most common cause of hypothyroidism among women of childbearing age.2

Quiz Ref IDThe prevalence of thyroid autoimmunity among women of reproductive age is 8% to 14% worldwide.2 Women who test positive for thyroid autoantibodies have been reported to be at 2- to 3-fold higher risk of spontaneous miscarriage than those who test negative.3,4 However, the effect of levothyroxine on miscarriage among women whose thyroid function is intact yet who test positive for thyroid autoantibodies has been documented in limited studies with conflicting results.5,6 The prevalence of thyroid autoimmunity is increased among women who are infertile.7 One of the most frequently applied treatments in infertility is in vitro fertilization and embryo transfer (IVF-ET). Several studies that examined the association between presence of thyroid autoantibodies and IVF-ET outcomes suggested that the miscarriage rate increased with their presence, thus reducing the live-birth rate.8

It is hypothesized that there is underlying subtle hypothyroidism after controlled ovarian hyperstimulation in women with positive thyroid autoantibodies.9 If this were the case, supplementation of levothyroxine before initiation of IVF-ET cycle may improve outcomes. However, limited studies have evaluated the effect of levothyroxine on miscarriage among women undergoing IVF-ET who tested positive for thyroid autoantibodies but had normal thyroid function.10 The 2017 American Thyroid Association guideline concluded that “there is insufficient evidence to determine whether levothyroxine therapy improves the success of pregnancy following assisted reproductive technology in antithyroperoxidase antibody positive, euthyroid women.”11

Therefore, the Pregnancy Outcomes Study in Euthyroid Women With Thyroid Autoimmunity After Levothyroxine (POSTAL) study was conducted to evaluate whether levothyroxine treatment initiated before IVF-ET could decrease the miscarriage rate and improve the live-birth rate among women who tested positive for antithyroperoxidase antibodies but otherwise had normal thyroid function.

Methods
Trial Design and Ethical Approval

This single-center, randomized, open-label, superiority trial was approved by the Reproductive Health Ethics Committee of Peking University Third Hospital. The study protocol and statistical analysis plan are available in Supplement 1. All the eligible participants gave their written informed consent.

Recruitment

Women referred to the reproductive center for their first or second fresh IVF-ET cycle were screened for eligibility. The start date of participant enrollment was September 6, 2012, and June 15, 2016, was the end date. To determine the causes of infertility, all women received a routine examination, including ultrasound for uterus, fallopian tubes, and ovaries and underwent laboratory assays, hysteroscopy, and hysterosalpingography. In addition, a sperm test for the partner was usually also needed. The indications for IVF-ET were oviduct obstruction, ovulation dysfunction, endometriosis, oligospermia, immune infertility, or unexplained infertility.

To be eligible, participants had to be between the ages of 23 years and 40 years and a body mass index (calculated as weight in kilograms divided by height in meters squared) of 35 or less. Women taking a thyroid hormone or antithyroid medication or who had undergone thyroid surgery or radioiodine treatment were excluded from the trial. Women were not eligible if they had 2 or more spontaneous miscarriages; had known diabetes mellitus or other endocrinologic or metabolic diseases; had tested positive for the anticardiolipin antibody, antinuclear antibody, or lupus anticoagulants; had serum alanine aminotransferase and aspartate aminotransferase levels more than 2 times the upper limit of normal; had a serum creatinine concentration of more than 1.47 mg/dL (to convert from mg/dL to μmol/L, multiply by 88.4); or were taking adjuvant treatments, such as anticoagulants, glucocorticoids, or other relevant treatments.

All women scheduled for their first or second IVF-ET cycle were tested for antithyroperoxidase antibodies, antithyroglobulin antibodies, total thyroxine, free thyroxine, thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), luteinizing hormone, prolactin, estradiol, and testosterone by commercial kits (Siemens Healthcare Diagnostics) using a fully automatic chemiluminescence immunoassay analyzer (ADVIA Centaur XP, Siemens Healthcare Diagnostics). Serum anticardiolipin antibodies were measured by a commercial kit (Inova Diagnostics) using chemiluminescence immunoassay (Bio-Flash, Inova Diagnostics). Serum antinuclear antibodies were detected by a commercial kit (EUROIMMUN Service) using an immunofluorescent method (Olympus BX61). The immunoturbidimetry method (ACL TOP700, Instrumentation Laboratory) was used to test the silica clot time and dilute Russell viper venom time for screening of lupus anticoagulants. Quiz Ref IDWomen with normal thyroid function, defined as the TSH level within the reference range of 0.50 to 4.78 mIU/L12 but tested positive for antithyroperoxidase antibody (≥60 IU/mL) with or without positive antithyroglobulin antibody (≥60 IU/mL) were potentially eligible for the study.

Randomization, Intervention, and Follow-up

Eligible women were informed about the study by one of the investigators. Thereafter, participants were randomized to receive either the intervention (levothyroxine treatment) or the blank control (no levothyroxine treatment). Randomization was performed by an independent data manager. The randomization sequence was generated in a 1:1 ratio by producing a 600 unique random–number list using EpiCalc 2000 software (http://www.brixtonhealth.com/epicalc.html), in which the even number was assigned to the intervention and the odd number to the control.

Quiz Ref IDWomen randomized to the intervention group began levothyroxine treatment between 2 and 4 weeks before the controlled ovarian hyperstimulation and continued through the end of pregnancy. For individuals with a TSH level of 2.5 mIU/L or higher, the starting dose was 50 μg/d; for those with a TSH level of less than 2.5 mIU/L, the starting dose was 25 μg/d. For individuals with body weight less than 50 kg, the starting dose was decreased by 50%. The levothyroxine dose was titrated to keep the TSH level within 0.1 to 2.5 mIU/L in the first trimester, 0.2 to 3.0 mIU/L in the second trimester, and 0.3 to 3.0 mIU/L in the third trimester. Medication was continued if the participants achieved clinical pregnancy. During pregnancy, levothyroxine was dosed according to their TSH level monitored routinely in local hospitals. Adherence to medication was monitored by interviews during the IVF-ET cycle (the day before controlled ovarian hyperstimulation, the day of human chorionic gonadotropin (hCG) administration, and the 14th day after ET). The medication and follow-up ceased when a pregnancy did not occur during the IVF-ET cycle. Telephone follow-up calls recording levothyroxine therapy and pregnancy outcomes were performed by one of the trained physicians at 12th and 24th week of gestational age and after birth. The care of women randomized to the control group followed the same pattern as the intervention group. For participants whose TSH levels exceeded the upper limit of the normal range during pregnancy, levothyroxine was prescribed and recorded (eMethods in Supplement 2). The end date of participant follow-up was March 20, 2017.

IVF-ET Protocols

All the eligible participants underwent IVF-ET according to 1 of 4 conventional protocols.13 In the IVF-ET long protocol, patients underwent pituitary downregulation by midluteal administration of a gonadotropin-releasing hormone (GnRH) agonist, 0.1 mg triptorelin acetate (Ipsen Pharma Biotech). In the short protocol, patients received a GnRH agonist from day 2 of their menstrual cycle onward. Controlled ovarian hyperstimulation was achieved in these patients by using either recombinant FSH (rFSH; Gonal-F, Merck Serono) or human menopausal gonadotropin (Livzon) in various flexible protocols. In the ultralong protocol, patients underwent ovarian stimulation that was induced by a rFSH protocol starting between day 28 and day 30 of their menstrual cycle after pituitary downregulation by 3.75 mg of triptorelin acetate on the first day of that cycle. In the antagonist protocol, patients who received the IVF-ET protocol started rFSH treatment on the second day of the cycle by once-daily injection. After 5 days of this treatment, the antagonist cetrorelix acetate (Merck Serono) was administered daily. The rFSH dose was adjusted according to individual ovarian response, which was assessed by daily ultrasound. The antagonist treatment continued up to, and including, the hCG day.

In all treatment protocols, when at least 2 leading follicles reached 18 mm in size, ovulation was induced by between 5000 and 10 000 IU hCG (Livzon), and ovum collection was performed between 36 and 38 hours later. Oocytes were fertilized by either conventional IVF or intracytoplasmic sperm injection. One to 3 embryos were transferred on the third day of the cycle according to the Code of Practice for Assisted Reproductive Technology developed by the Ministry of Health of the People’s Republic of China. Embryo transfers were performed by specified gynecologists with the same standard ET protocol.13

The luteal phase was supported by a 60-mg progesterone (Shanghai General Pharmaceutical) injection from the day of ET to maintain lutein function through the 10th week of pregnancy.13

Primary and Secondary Outcomes

The primary outcome was miscarriage, defined as a pregnancy loss before 28 weeks of gestation (calculated among women who became pregnant). Miscarriage was prespecified as early miscarriage, termination within the first 12 weeks of gestation, and late miscarriage, miscarriage between 13 and 28 weeks of gestation.14

Secondary outcomes were clinical intrauterine pregnancy and live birth. Clinical intrauterine pregnancy was defined as fetal cardiac activity 30 days after the ET procedure as observed through sonograph.15 Live birth was defined as a delivery of a living fetus (or living fetuses) beyond 28 weeks of gestation. Exploratory analysis of the end points, twin pregnancy (confirmed by the ultrasound observation) and preterm delivery (defined as delivery of a live neonate before 37 weeks of gestation), was also performed. To assess pregnancy outcome, all pregnant women were followed up by telephone interview.

Sample-Size Calculations

Previous meta-analysis showed that the miscarriage rate among women with thyroid autoimmunity was 30% and that levothyroxine intervention could reduce the risk of miscarriage by 50%.3 To detect a 50% decrease in miscarriage rate from 30% to 15%, 120 clinical pregnancies per group were needed (α error, .05; β error, .2). Because the retrospective 2008-2009 data of the Center of Reproductive Medicine of Peking University Third Hospital showed the clinical pregnancy rate was 42%,15 285 fresh cycles for each group were needed. Anticipating a 5% dropout rate, the total number of women required for randomization was 300 for each group.

Statistical Analysis

The statistician who conducted the analysis was blinded to group allocation. The intention-to-treat analysis was performed to evaluate the effect of levothyroxine treatment on pregnancy outcomes. The per-protocol analysis was also performed. The absolute rate difference (RD) and relative risks (RRs) with 95% CIs were estimated for the primary and secondary outcomes. The 95% CIs of absolute RDs were calculated using the Newcombe-Wilson score method.16

Comparison between groups was performed using the independent sample t test or Pearson χ2 test or Fisher exact test as appropriate. When continuous variables did not follow a Gaussian distribution, they were presented as median (interquartile range) and comparisons between groups were carried out using the Mann-Whitney U test. Given the complexity of the process of implantation and pregnancy, many factors might affect the pregnancy outcomes, so post hoc subgroup analyses on several known or presumable risk factors were performed. Effects of TSH levels on IVF-ET outcomes were analyzed in the subgroup analysis. According to the 2015 American Society for Reproductive Medicine guideline,17 the optimal TSH level before IVF-ET for women with thyroid autoimmunity is less than 2.5 mIU/L and a TSH level of less than 4.0 mIU/L is preferable for women without thyroid autoimmunity undergoing IVF-ET. Subgroup analyses were performed using the RR for the stratification factors. Interactions of the intervention with the stratification factors were analyzed using binary logistic regression.

Missing data were treated as missing at random and were imputed using the last-observation-carried-forward method. For the missing values (0.83%), a post hoc sensitivity analysis was conducted under the hypothesis of the worst outcomes (missing values were imputed as miscarriages) and the best outcomes (missing values were imputed as live births). No adjustment was made for multiple comparisons. Therefore, all secondary outcomes and subgroup analyses should be considered exploratory.

All statistical analyses were conducted using the statistical package SPSS, version 18.0 (SPSS Inc). Statistical significance was defined as P < .05 with 2-sided testing.

Results
Enrollment and Baseline Characteristics of Participants Scheduled for IVF-ET

Between September 6, 2012, and June 15, 2016, a total of 32 157 women referred to the Reproductive Center were screened for positive antithyroperoxidase antibody. A total of 1035 women tested positive for antithyroperoxidase antibodies in the presence or absence of positive antithyroglobulin antibodies. Four hundred seventeen women did not meet the inclusion criteria, and 18 women declined to participate in the trial (Figure). Of the 600 eligible women (mean age, 31.6 years), 300 were randomly assigned to the levothyroxine group and 300 to the control group. The baseline characteristics were comparable between the groups except for their serum TSH levels (intention-to-treat set, Table 1). In addition, the values of sperm parameters including density and activity in the participant’s partners did not differ between the groups. After randomization, 282 women in the intervention group and 285 women in the control group underwent their first or second fresh IVF-ET cycle (per-protocol set, eTable 1 in Supplement 2).

Protocols and Data of IVF-ET in Participants

In the intervention group, 18 women did not undergo IVF-ET, 8 of whom conceived spontaneously, 8 did not start controlled ovarian hyperstimulation, and 2 were lost to follow-up. In the control group, 15 women did not undergo IVF-ET, 6 of whom became pregnant spontaneously, 7 did not start controlled ovarian hyperstimulation, 1 had a hydatidiform mole, and 1 was lost to follow-up (Figure). The percentage of first fresh IVF-ET cycles, distribution of protocols for controlled ovarian hyperstimulation, number of retrieved oocytes, rate of intracytoplasmic sperm injection, number of good-quality embryos, and number of transferred embryos did not significantly differ between groups (Table 2; and eTable 2 in Supplement 2).

Compliance and Dosage of Levothyroxine Intervention

All the women in the intervention group took the medication as planned, of whom 3 discontinued medication due to their TSH level decreasing to less than 0.01 mIU/L with normal free thyroxine and free triiodothyronine levels (all delivered at term). In the control group, 8 women started levothyroxine treatment after controlled ovarian hyperstimulation (1 biochemical pregnancy only, 2 miscarriages, 2 preterm live births, and 3 delivered at term), and 2 women took levothyroxine after spontaneous pregnancies (both delivered at term).

In the intervention group, the mean (SD) dose of levothyroxine at the beginning of controlled ovarian hyperstimulation was 30.1 (12.1) μg/d and was 32.5 (14.1) μg/d on the day hCG was administered. The dosages of levothyroxine increased to 33.6 (15.5) μg/d on day 14 and to 45.0 (24.7) μg/d on day 30 after ET. No levothyroxine-related adverse events were reported.

Outcomes of the Participants

Quiz Ref IDThe intention-to-treat analysis showed that the miscarriage rate in the intervention group was 10.3% (11 of 107) and was 10.6% (12 of 113) in the control group for an absolute RD of −0.34% (95% CI, −8.65% to 8.12%) over the 4.5-year study period.Quiz Ref ID The clinical intrauterine pregnancy rates were 35.7% (107 of 300) for the intervention group and 37.7% (113 of 300) for the control group, for an absolute RD of −2.00% (95% CI, −9.65% to 5.69%); the twin pregnancy rates, 36.4% (39 of 107) and 28.3% (32 of 113) for an absolute RD of 8.13% (95% CI, −4.19% to 20.18%); live-birth rates, 31.7% (95/300) and 32.3% (97/300) for an absolute RD of −0.67% (95% CI, −8.09% to 6.77%). Among the women who had a live birth, preterm delivery rates were 22.1% (21 of 95) in the intervention group and 19.6% (19 of 97) in the control group for an absolute RD of 2.52% (95% CI, −8.98% to 13.99%; Table 3).

The post hoc per-protocol analysis was consistent with the intention-to-treat analysis (eTable 3 in Supplement 2). Moreover, sensitivity analyses for the missing values in both intention-to-treat and per-protocol sets were concordant (eTable 4 and eTable 5 in Supplement 2).

To detect other clinical parameters that may affect pregnancy outcomes, post hoc subgroup analysis of miscarriage, clinical intrauterine pregnancy, and live-birth outcomes were performed for women with IVF-ET cycles. Effects of TSH level on IVF-ET outcomes were analyzed in the subgroup analysis. No significant interaction was found. Specifically, there was no interaction effect between the intervention and the stratified factors, such as TSH, antithyroperoxidase antibody, or controlled ovarian hyperstimulation protocols (eFigure 1-3 in Supplement 2).

Discussion

This randomized clinical trial investigating whether levothyroxine treatment affected pregnancy outcomes among women undergoing IVF-ET who had normal thyroid function and had tested positive for antithyroperoxidase antibody found that levothyroxine treatment did not reduce miscarriage rate or improve the live-birth rate compared with usual care.

Stagnaro-Green and Glinoer18 first reported that women with thyroid autoimmunity had a 2-fold increased risk of miscarriage (17% vs 8.4%, P = .01) and that the risk of miscarriage was not associated with maternal age, thyroid hormone levels, or previous obstetrical history in a prospective cohort study. Since then, many small-scale clinical studies have indicated that the miscarriage rate and preterm delivery rate among women with thyroid autoimmunity who had conceived naturally were significantly higher than those without thyroid autoimmunity.19,20 An adverse association between presence of thyroid autoantibodies and IVF-ET outcomes was first described by Geva et al,21 but subsequent studies on IVF-ET outcomes provided contradictory results.22-24 A recent meta-analysis25 investigating the effect of thyroid autoantibodies on IVF-ET outcomes showed that presence of thyroid autoantibodies did not affect fertilization, implantation, or clinical pregnancy rate but may have a detrimental effect on the course of a pregnancy, determining an increased miscarriage rate and a decreased live-birth rate. However, the authors also pointed out that age and TSH level were not comparable between the groups, suggesting that further evidence is warranted prior to drawing inferences on causality.

Given that pregnancy may trigger progression to subclinical or overt hypothyroidism in women who otherwise have normal thyroid function but have tested positive for thyroid autoantibodies,26 it was hypothesized that they would benefit from levothyroxine treatment in pregnancy. In a retrospective cohort study assessing the effectiveness of levothyroxine intervention initiated before starting controlled ovarian hyperstimulation among this population of women undergoing IVF-ET, a fixed dose of 50 μg/d of levothyroxine treatment alone did not reduce the miscarriage rate.27 A pooled analysis of 3 randomized clinical trials evaluating the effectiveness of levothyroxine treatment on pregnancy outcomes among women with thyroid autoimmunity but had normal thyroid function who were undergoing IVF-ET showed that levothyroxine treatment was associated with a significant decrease in the miscarriage rate (RR, 0.45; 95% CI, 0.24-0.82) and an increase in the live-delivery rate (RR, 2.76; 95% CI, 1.20-6.44). However, these 3 trials were heterogeneous in many aspects and the sample size of each trial was rather small, which may weaken the quality of the evidence.28 Therefore, the 2011 American Thyroid Association29 and the 2012 Endocrine Society30 guidelines for the diagnosis and treatment of thyroid disease during pregnancy both declared that there was insufficient evidence to recommend for or against treating women with normal thyroid function experiencing sporadic or recurrent miscarriage or undergoing IVF-ET with levothyroxine. Furthermore, the American Thyroid Association took a similar position in its 2017 guideline.11

Our study showed that levothyroxine treatment did not affect pregnancy outcomes among participating women. Because the sample size of this trial was much larger, the finding that a levothyroxine supplement was not associated with any beneficial effect on pregnancy outcomes regardless of miscarriage rate, clinical pregnancy rate, or live-birth rate among women undergoing IVF-ET who tested positive for antithyroperoxidase antibody but had normal thyroid function was robust. In 2016, Negro et al31 reported that the levothyroxine intervention showed no beneficial effect on the rate of miscarriage or preterm delivery in unselected pregnancy of women with normal thyroid function who tested positive for thyroid autoantibodies and whose TSH values were less than 2.5 mIU/L.

Whether TSH levels of 2.5 mIU/L or higher affects IVF-ET outcomes is of great concern for obstetricians and endocrinologists. To address those concerns, we performed a subgroup analysis to identify specific subgroups of women who might benefit from levothyroxine treatment. We used TSH concentrations of 2.5 mIU/L or higher and 4.0 mIU/L or higher as cut points based on the recommendation of the 2015 American Society for Reproductive Medicine guideline.17 However, no beneficial effect in any specific subgroups was found. Our finding is congruent with the observations from 2 recent cohort studies on the association of TSH levels with IVF-ET outcomes. One cohort study that evaluated the optimal TSH range before IVF-ET did not find any detrimental effect of TSH levels ranging between 2.5 mIU/L and 4.2 mIU/L on pregnancy outcomes compared with levels that were less than 2.5 mIU/L.32 The other study showed that the miscarriage rate was not associated with TSH levels in women with intact thyroid function undergoing IVF-ET.33 Moreover, a large observational study showed that levothyroxine treatment did not decrease pregnancy loss in women with baseline TSH levels ranging between 2.5 mIU/L and 4.1 mIU/L in unselected pregnancy.34 Those data are consistent with the results of this trial.

Our study has several strengths. First, to our knowledge, it represents the largest sample of participants to assess the effectiveness of levothyroxine treatment for this population. Second, only participants in their first- or second-fresh IVF-ET cycle were included, thus excluding an effect of multiple IVF-ET failure cycles on the titer of antithyroperoxidase antibody.35 Third, our trial excluded women with recurrent miscarriage or other autoimmune diseases, which frequently are comorbidities among women with thyroid autoimmunity, thus excluding confounding effects that might be associated with adverse pregnancy outcomes.36,37

Limitations

Our study has several limitations. First, this study was an open-label trial without placebo. In an open-label study, the unblinded treatment and assessment might theoretically influence reporting or measurement of the outcomes, thus introducing bias. However, this study was an independent investigator-initiated trial and the primary outcome of this trial was miscarriage after IVF-ET. It is an objective event that can hardly be biased by the nonblinding assessment. The adherence rate of participants was high. Only 10 of 300 women in the control group received levothyroxine treatment, and 3 of 300 in the intervention group ceased the treatment. In addition, given that the placebo effect is more important for a study with positive results than a study with negative results like this trial, it was acceptable to consider that the open-label design without placebo would not undermine the results of this trial substantially. Second, this study was a single-center randomized clinical trial. Caution should be used when extending this result to other patient populations. However, a single-center trial might be helpful in several aspects: the quality of IVF-ET procedure and laboratory examination was better controlled in a single center than multiple centers; the Center of Reproductive Medicine of Peking University Third Hospital performs more than 10 000 cycles of IVF-ET per year, providing us with enough potential participants for this trial; moreover, the participants were from all over the country, so the population in this trial was representative. Third, despite randomization, the TSH distribution was skewed with a little higher median value in the intervention group. However, stratified analysis by TSH level did not change the conclusion. Fourth, although controlled ovarian hyperstimulation protocols were nonuniform, the various protocols were distributed similarly between the groups. Fifth, the levothyroxine dosage was relatively low, which might weaken the effect of levothyroxine. In addition, the miscarriage rate was lower than expected, which reduced the power of the study. This lower miscarriage rate might be explained by the fact that women with known comorbidities related to miscarriage—including recurrent miscarriage, known history of autoimmune diseases or presence of their markers (such as antinuclear antibody, anticardiolipin antibody and lupus anticoagulants)—were excluded from this trial. Therefore, our findings might not be applicable to women at increased risk of miscarriage.

Although our trial showed that levothyroxine treatment did not benefit this population, 2 other ongoing trials are investigating its effect on other populations. The TABLET trial (ISRCTN 15948785; http://www.birmingham.ac.uk/research/activity/mds/trials/bctu/trials/womens/tablet/index.aspx ) investigates the effect of daily administration of 50 μg of thyroxine to women with intact thyroid function who tested positive for thyroidperoxidase vs placebo on live-birth outcomes. The T4-LIFE study (NTR 3364) investigates the benefits of levothyroxine treatment of women with intact thyroid function who have experienced recurrent miscarriages and have tested positive for the antithyroperoxidase antibody.38 Nevertheless, it should be worth noting that the 2 ongoing trials did not focus on women undergoing infertility treatments.

Conclusions

Among women in China who had intact thyroid function and tested positive for anti-thyroperoxidase antibodies and were undergoing IVF-ET, treatment with levothyroxine, compared with no levothyroxine treatment, did not reduce miscarriage rates or increase live-birth rates.

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Article Information

Corresponding Authors: Jie Qiao, MD, PhD, Center of Reproductive Medicine, and Tianpei Hong, MD, PhD, Department of Endocrinology and Metabolism, Peking University Third Hospital, 49 N Garden Rd, Haidian District, Beijing 100191, China (jie.qiao@263.net and tpho66@bjmu.edu.cn).

Accepted for Publication: November 1, 2017.

Author Contributions: Drs H. Wang and Chi had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs H. Wang, Gao, Chi, and Zeng contributed equally as first authors to this work. Drs Qiao and Hong jointly directed this work and contributed equally as corresponding authors.

Concept and design: H. Wang, Gao, Chi, Zeng, Xiao, Y. Wang, Li, Zhou, Hong, Qiao.

Acquisition, analysis, or interpretation of data: H. Wang, Gao, Chi, Zeng, Li, P. Liu, C. Wang, Tian, Yang, Y. Liu, Wei, Mol, Hong, Qiao.

Drafting of the manuscript: H. Wang, Gao, Chi, Zeng, Xiao, Li, Zhou.

Critical revision of the manuscript for important intellectual content: H. Wang, Gao, Chi, Y. Wang, Li, P. Liu, C. Wang, Tian, Yang, Y. Liu, Wei, Mol, Hong, Qiao.

Statistical analysis: H. Wang, Gao, Zeng.

Obtained funding: Hong, Qiao.

Administrative, technical, or material support: H. Wang, Gao, Chi, Xiao, Li, C. Wang, Tian, Zhou, Yang, Y. Liu, Wei, Mol, Hong, Qiao.

Supervision: Gao, Zeng, Hong, Qiao.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Mol reported that he received grant support from the National Health and Medical Research Council (GNT1082548) and has served as a consultant for ObsEva, Merck, and Guerbet. No other financial conflicts were reported.

Funding/Support: This study was supported by grants 2015BAI13B06 from the National Key Technology R&D Program and 2012CB517502 and from the Chinese National 973 Program, both from the Ministry of Science and Technology of China.

Role of the Funder/Sponsor: The Ministry of Science and Technology of China had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank Jinlan Dong, BS; Lin Zhang, MD; Li Chen, BS; Xin Wang, BS; Qun Wang, BS; Zheng Ma, BS, who collected and tested all samples throughout the trial. They are all from Department of Endocrinology and Metabolism, Peking University Third Hospital. They received no compensation for their contributions. We thank all the women whose participation made this study possible. None of those participants were compensated for their contribution.

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