Thyroid function and IVF outcome for different indications of subfertility.

ABSTRACT: Studies evaluating pregnancy outcomes after assisted reproductive treatment (ART) in women with high-normal (2.5-4.5 mIU/L) thyroid-stimulating hormone (TSH) levels are conflicting, possibly due to different patient charactistics and subfertility indications. The aim of this study was to examine the hypothesis that high-normal compared to low-normal TSH levels are associated with adverse implications for pregnancy outcomes in conventional in vitro fertilization (IVF)-treated women. Therefore, we analyzed retrospectively the characteristics and pregnancy outcomes of 949 subfertile women with TSH 0.3-4.5 mIU/L, treated with conventional IVF between January 2008 and March 2012. Demographic and baseline characteristics were compared between groups of patients based on TSH quartiles, using one-way Anova, Kruskal-Wallis ANOVA and chi-square test. Women with high-normal quartile TSH were significantly more likely to be primary subfertile (P = 0.01), with a higher prevalence of unexplained subfertility and with 15% fewer live births after IVF compared to lower TSH quartiles (P = 0.02). In secondary subfertile women with high-normal TSH, male factor subfertility prevailed (P = 0.01), with more live births (P = 0.01). When analyzing primary and secondary subfertile women as one group, these differences failed to be observed, showing no differences in cumulative pregnancy outcomes of IVF between TSH quartiles (I: 0.3-1.21 mIU/L; II: 1.22-1.68 mIU/L; III: 1.69-2.31 mIU/L; IV: 2.32-4.5 mIU/L). In conclusion, primary subfertile women predominate in the high-normal TSH quartile, associated with significantly fewer live births in a subgroup of primary unexplained subfertile women (9%; n = 87/949), while in secondary subfertile women, dominated by male factor subfertility, high-normal TSH is associated with more live births. LAY SUMMARY: Thyroid hormones are required for all cell processes in the body. An underactive thyroid gland, in which insufficient thyroid hormones are produced and thyroid-stimulating hormone (TSH) rises, is associated with a lower chance of pregnancy. It is not yet clear above which TSH level, 4.5 or also 2.5 mIU/L, this lower probability occurs. Therefore, in 949 couples treated with conventional IVF, we examined whether high-normal TSH levels (TSH: 2.5-4.5 mIU/L) compared to low normal TSH levels (0.3-2.5 mIU/L) affect the live birth rate. We found that women who were trying to become pregnant for the first time, especially without any other cause, that is unexplained subfertility, were more likely to have higher TSH levels. These women had a much lower chance of having a baby compared to women with low-normal TSH levels.

Live birth rate after intrauterine insemination is not different between women with lower quartile versus higher quartile normal range thyroid stimulating hormone levels.

STUDY QUESTION: Does lower quartile normal range thyroid stimulating hormone (TSH) compared to higher quartile normal range in women without thyroid hormone substitution affect live birth rate after a complete IUI treatment series? SUMMARY ANSWER: Lower quartile normal range TSH, in women without thyroid hormone substitution, does not affect live birth rate after a complete intrauterine insemination treatment series compared to higher quartile normal range TSH. WHAT IS KNOWN ALREADY: TSH is historically seen as the most sensitive test for thyroid function. Its distribution is right-skewed. Whether the preconceptional upper reference TSH values in subfertile women should be 2.5 or 4.5 mIU/L is under debate. Studies have shown that IUI patients treated with levothyroxine for TSH levels above 2.5 mIU/L show higher pregnancy rates. However, no adverse outcome is associated with untreated high normal TSH levels studied in first IUI cycles. Thyroid peroxidase antibodies have also impaired outcomes in some studies whereas others have shown an effect only in combination with high normal TSH levels. As a subgroup, patients with unexplained infertility showed increased levels of TSH. This article adds to the value of TSH evaluation and fertility outcome in four quartiles and in the context of a completed IUI treatment modus of a maximum of six inseminations. STUDY DESIGN SIZE DURATION: This is a retrospective cohort study in 909 women undergoing 3588 IUI cycles starting treatment between the first of January 2008 and the first of March 2012. PARTICIPANTS/MATERIALS SETTING METHODS: Women aged 22-45 years with TSH 0.3-4.5 mIU/L without thyroid hormone substitution were included at Amsterdam UMC, Vrije Universiteit, Amsterdam, the Netherlands, an Iodine-sufficient area. The primary endpoint was live birth. Clinical pregnancy, pregnancy loss and ongoing pregnancy were secondary endpoints. Logistic regression was used with the natural logarithm of TSH as a continuous predictor. Chi-square tests and logistic regression were used to compare groups of patients based on TSH values in four quartile TSH groups (0.3-1.21 mIU/L; 1.22-1.75 mIU/L; 1.76-2.34 mIU/L; 2.35-4.5 mIU/L) on basic characteristics and on the endpoints while adjusting for confounders. MAIN RESULTS AND THE ROLE OF CHANCE: Analysis with the natural logarithm of TSH as a continuous variable showed no association with live birth, pregnancy chance or pregnancy loss. There were no differences in any of the outcomes across the quartile TSH level ranges after regression analysis before and after adjusting for age, BMI, use of alcohol, tobacco, use or gonadotrophins, sperm count, diminished ovarian reserve, unexplained infertility and primary or secondary subfertility.The distribution of primary and secondary subfertility and smoking characteristics were remarkably different across the four groups, with proportionally the lowest prevalence of primary subfertility and the highest rate of smoking in the lowest TSH group (0.3-1.20 mIU/L). LIMITATIONS REASONS FOR CAUTION: Unknown values of free thyroxine and thyroid peroxidase antibodies, as well as the retrospective character of the study, limit the clinical interpretability. WIDER IMPLICATIONS OF THE FINDINGS: TSH in the highest quartile range (2.35-4.5 mIU/L) in subfertile women preceding IUI is not associated with a lower live birth rate or rate of clinical and ongoing pregnancy, or with loss of pregnancies, compared to subfertile women with TSH in the lower three quartile groups after complete intrauterine insemination treatment. STUDY FUNDING/COMPETING INTERESTS: The department of Obstetrics and Gynaecology, division of Reproductive Medicine, and of Internal Medicine, division of Endocrinology provided support. There are no competing interests. TRIAL REGISTRATION NUMBER: N/A.