TSH and FT4 Reference Interval Recommendations and Prevalence of Gestational Thyroid Dysfunction: Quantification of Current Diagnostic Approaches.

CONTEXT: Guidelines recommend use of population- and trimester-specific thyroid-stimulating hormone (TSH) and free thyroxine (FT4) reference intervals (RIs) in pregnancy. Since these are often unavailable, clinicians frequently rely on alternative diagnostic strategies. We sought to quantify the diagnostic consequences of current recommendations. METHODS: We included cohorts participating in the Consortium on Thyroid and Pregnancy. Different approaches were used to define RIs: a TSH fixed upper limit of 4.0 mU/L (fixed limit approach), a fixed subtraction from the upper limit for TSH of 0.5 mU/L (subtraction approach) and using nonpregnancy RIs. Outcome measures were sensitivity and false discovery rate (FDR) of women for whom levothyroxine treatment was indicated and those for whom treatment would be considered according to international guidelines. RESULTS: The study population comprised 52 496 participants from 18 cohorts. Compared with the use of trimester-specific RIs, alternative approaches had a low sensitivity (0.63-0.82) and high FDR (0.11-0.35) to detect women with a treatment indication or consideration. Sensitivity and FDR to detect a treatment indication in the first trimester were similar between the fixed limit, subtraction, and nonpregnancy approach (0.77-0.11 vs 0.74-0.16 vs 0.60-0.11). The diagnostic performance to detect overt hypothyroidism, isolated hypothyroxinemia, and (sub)clinical hyperthyroidism mainly varied between FT4 RI approaches, while the diagnostic performance to detect subclinical hypothyroidism varied between the applied TSH RI approaches. CONCLUSION: Alternative approaches to define RIs for TSH and FT4 in pregnancy result in considerable overdiagnosis and underdiagnosis compared with population- and trimester-specific RIs. Additional strategies need to be explored to optimize identification of thyroid dysfunction during pregnancy.

Gestation-suppressed serum TSH levels during early pregnancy are not associated with altered maternal and neonatal outcomes.

Objective: The aim of the study was to investigate the impact of suppressed serum TSH levels (sTSH) during early pregnancy on maternal and neonatal outcomes. Methods: In this single-centre, retrospective cohort study 1081 women were screened at 11.8 ± 2.4 weeks of pregnancy for TSH, free T4 (FT4) and TPOAb. Exclusion criteria were twin- and assisted- reproduction pregnancies, women with TSH levels >3.74 mIU/L, severe hyperthyroidism, treated for thyroid dysfunction before or after screening and gestational blood sampling <6 or >16 weeks of pregnancy. The prevalence of adverse pregnancy outcomes was compared between the study group sTSH (TSH: < 0.06 mIU/L; n = 36) and euthyroid controls (TSH: 0.06-3.74 mIU/L; n = 1045), and the impact of sTSH on pregnancy outcomes verified in logistic regression analyses. Results: Median (IQR) serum TSH level in women with sTSH was 0.03 (0.03-0.03) vs 1.25 (0.81-1.82) mIU/L in controls and FT4 levels 18.0 (14.4-20.3) vs 14.2 (12.9-15.4) pmol/L; both P < 0.001. None of the women with sTSH had thyrotropin receptor antibodies. Compared with controls, the prevalence of TPOAb positivity (TAI) was comparable between groups (5.6% vs 6.6%; P = 0.803). The prevalence of maternal and neonatal pregnancy outcomes was comparable between the study and control group. The logistic regression analyses with corrections for TAI, FT4 and demographic parameters confirmed the absence of an association between sTSH, and the following outcomes: iron deficient anaemia (aORs (95% CI)): 1.41 (0.64-2.99); P = 0.385, gestational diabetes: 1.19 (0.44-2.88); P = 0.713, preterm birth: 1.57 (0.23-6.22);P = 0.574 and low Apgar-1' score: 0.71 (0.11-2.67); P = 0.657. Conclusions: Suppressed serum TSH levels during the first to early second trimester of pregnancy were not associated with altered maternal or neonatal outcomes.

Impact of thyroid hormone treatment on maternal pregnancy outcomes in women with subclinical hypothyroidism without TPOAb: a retrospective cross-sectional study.

BACKGROUND: Evidence on the impact of thyroid hormone treatment (LT4) on maternal pregnancy outcomes in women with subclinical hypothyroidism (SCH) without thyroid peroxidase antibodies (TPOAb) positivity is scarce. METHODS: Single centre, cross-sectional study in 1460 women screened for TSH, free T4 and TPOAb at median 13 (11-17) weeks of gestation during the period 2013-2014. Exclusion criteria were twin- and assisted reproduction pregnancies, TPO positivity, overt thyroid dysfunction, and treatment with LT4 before screening. The impact of LT4 on maternal pregnancy outcomes was investigated in a group of 53 women with SCH (TSH > 3.74 mIU/L) in which LT4 was initiated at median 13 (10-22) weeks (treated group). The control group included 18 women with SCH (TSH > 3.74 mIU/L). The prevalence of pregnancy complications in these two groups was compared with that in a euthyroid reference (REF) group of 1389 women (TSH ≤ 3.74 mIU/L). RESULTS: The prevalence of pre-eclampsia and gestational diabetes (GDM) was higher in the control group vs the REF group (16.7% vs 5.0% and 27.8% vs 18.9%; p = 0.017 and p = 0.016, respectively), but comparable in the treated group vs the REF group (7.6% vs 5.0% and 22.6% vs 18.9%; p = 0.918 and 0.676, respectively). The prevalence of iron-deficiency anaemia was lower in the treated vs the REF group (17.0% vs 32.5%; p = 0.017). CONCLUSION: Pregnant women with untreated SCH and without TPOAb positivity had a higher prevalence of pre-eclampsia and GDM compared with euthyroid women, while this was not the case in women with treated SCH, even when it was initiated after the first trimester.

Association between thyroid autoimmunity and gestational diabetes mellitus in euthyroid women.

Objective: Pregnant women with autoimmune (subclinical) hypothyroidism have an increased risk of developing gestational diabetes mellitus (GDM). However, this association remains controversial in euthyroid women with thyroid autoimmunity (TAI). Therefore, the aim of the study was to determine the association between TAI and GDM in euthyroid women in a logistic regression analysis with adjustments for baseline/demographic parameters. Methods: Cross-sectional study in 1447 euthyroid women who performed their entire clinical/biological workup and oral glucose tolerance test (OGTT) in our center. At median 13 (11-17) weeks of gestation, thyroid-stimulating hormone, free T4, and thyroid peroxidase antibodies (TPOAb) were measured, baseline characteristics were recorded, and an OGTT was performed between 24 and 28 weeks of pregnancy. Exclusion criteria were pre-pregnancy diabetes, assisted pregnancies, and women with (treated) thyroid dysfunction before or after screening. The diagnosis of GDM was based on 2013 World Health Organization criteria, and TAI was defined as TPOAb levels ≥60 kIU/L. Results: Two hundred eighty women were diagnosed with GDM (19.4%), 26.1% in women with TAI, and 18.9% in women without TAI (P = 0.096). In the logistic regression analysis, TAI was associated with GDM in women older than 30 years (adjusted odds ratio 1.68 (95% CI, 1.01-2.78); P = 0.048). Maternal age >30 years, pre-pregnancy BMI ≥30 kg/m2, and other than Caucasian background were also associated with GDM; aOR 1.93 (95% CI, 1.46-2.56); P < 0.001, 2.03 (95% CI, 1.46-2.81); P < 0.001 and 1.46 (95% CI, 1.03-2.06); P = 0.034, respectively. Conclusions: In older pregnant women, the presence of TAI in euthyroid women was associated with GDM. In line with the literature data, (higher) age and BMI were strongly associated with GDM. Future investigations should focus on treatments that might prevent the development of GDM in euthyroid women with TAI.

Does foetal gender influence maternal thyroid parameters in pregnancy?

Objective: It is unknown if foetal gender influences maternal thyroid function during pregnancy. We therefore investigated the prevalence of thyroid disorders and determined first-trimester TSH reference ranges according to gender. Methods: A cross-sectional study involving 1663 women with an ongoing pregnancy was conducted. Twin and assisted pregnancies and l-thyroxine or antithyroid treatment before pregnancy were exclusion criteria. Serum TSH, free T4 (FT4) and thyroid peroxidase antibodies (TPOAb) were measured at median (interquartile range; IQR) 13 (11-17) weeks of gestation. Subclinical hypothyroidism (SCH) was present when serum TSH levels were >3.74 mIU/L with normal FT4 levels (10.29-18.02 pmol/L), and thyroid autoimmunity (TAI) was present when TPOAb were ≥60 kIU/L. Results: Eight hundred and forty-seven women were pregnant with a female foetus (FF) and 816 with a male foetus (MF). In women without TAI and during the gestational age period between 9 and 13 weeks (with presumed high-serum hCG levels), median (IQR range) serum TSH in the FF group was lower than that in the MF group: 1.13 (0.72-1.74) vs 1.24 (0.71-1.98) mIU/L; P = 0.021. First-trimester gender-specific TSH reference range was 0.03-3.53 mIU/L in the FF group and 0.03-3.89 mIU/L in the MF group. The prevalence of SCH and TAI was comparable between the FF and MF group: 4.4% vs 5.4%; P = 0.345 and 4.9% vs 7.5%; P = 0.079, respectively. Conclusions: Women pregnant with an MF have slightly but significantly higher TSH levels and a higher upper limit of the first-trimester TSH reference range, compared with pregnancies with a FF. We hypothesise that this difference may be related to higher hCG levels in women pregnant with a FF, although we were unable to measure hCG in this study. Further studies are required to investigate if this difference has any clinical relevance.

Thyroid Disorders and In Vitro Outcomes of Assisted Reproductive Technology: An Unfortunate Combination?

Background: The impact of thyroid disorders on in vitro outcomes of assisted reproductive technology (ART) remains controversial. Therefore, the aim of our study was to investigate whether thyroid peroxidase antibodies (TPO-Abs)/thyroid autoimmunity (TAI) or thyroid function (serum thyrotropin [TSH])/subclinical hypothyroidism are associated with an altered number of oocyte retrieval (NOR), fertilization rate (FR), and embryo quality (EQ). Methods: Cross-sectional study in 279 women in a single center, comprising 297 cycles and 1168 embryos. In vitro data (NOR, FR, and EQ) were documented in two groups; one according to thyroid function in women without TAI (TSH ≤2.5 and >2.5 mIU/L) and one according to the presence/absence of TAI (determined by TPO-Abs). EQ was evaluated according to international criteria and classified as excellent/good and poor. Women treated with levothyroxine (LT4) were excluded. Furthermore, the impact of thyroid parameters on outcomes, normal NOR (>6 or 8) and high FR (>60%), was verified in a multivariable logistic regression model. Results: In women without TAI, 27% had TSH levels >2.5 mIU/L, the prevalence of TAI was 8%, and overall, 6% of women had TSH levels >4.2 mIU/L. NOR, FR, and EQ were comparable between study groups. In the regression analysis, women aged ≥30 years and receiving a high ovarian stimulation dosage (>2300 IU/cycle) had lower rates of normal NOR (odds ratio [OR] 0.18 [95% confidence interval, CI 0.04-0.72]; p = 0.016 and OR 0.17 [CI 0.06-0.48]; p < 0.001, respectively). Conclusions: Our results do not suggest an impact of thyroid antibodies/autoimmunity and (dys)function on ART in vitro outcomes.

The Impact of Thyroid Disorders on Clinical Pregnancy Outcomes in a Real-World Study Setting.

Background: Subclinical hypothyroidism (SCH) and thyroid autoimmunity (TAI) have been associated with poor clinical pregnancy outcomes. However, these outcomes also depend on a number of demographic and obstetric variables. Therefore, the aim of this study was to investigate the impact of thyroid disorders on these outcomes, after adjustment for associated demographic and obstetrical parameters. Methods: This is cross-sectional study including 1521 pregnant women who underwent work-up and follow-up in the Centre Hospitalier Universitaire (CHU) Saint-Pierre, Brussels, and had ongoing pregnancies. Thyroid function (thyrotropin [TSH], free thyroxine [fT4]) and TAI (thyroid peroxidase antibodies) was determined at median (Q1-Q3) 13 (11-17) weeks. Baseline parameters and the prevalence of poor clinical pregnancy outcomes were compared between controls (no TAI and TSH <2.51 mIU/L) and three study groups (isolated TAI [TSH <2.51 mIU/L], SCH1 [TSH 2.51-3.7 mIU/L], SCH2 [TSH >3.7 mIU/L]). The impact of the different thyroid groups and demographic/obstetric independent variables on six poor clinical pregnancy outcomes (preeclampsia, intrauterine growth restriction [IUGR], preterm birth, neonatal intensive care unit [NICU] admission, low birth weight, and macrosomia) was investigated in a logistic regression model. Treatment with thyroid hormone before and during pregnancy and assisted and multiple pregnancies were exclusion criteria. Results: In total, 79 preeclampsias (5.2%), 40 IUGRs (2.6%), 79 preterm births (5.2%), 10 admissions to NICU (0.66%), 74 low birth weights (4.9%), and 94 babies with macrosomia (6.2%) were documented. TAI was independently associated with NICU admission (adjusted odds ratio [aOR] 16.92 confidence interval [CI 3.36-85.29]; p < 0.001) and TSH, as a continuous variable in the whole range, with preeclampsia (aOR 1.97 [CI 1.18-3.31]; p = 0.010). Trends were present for an association between SCH2 and preeclampsia (aOR 16.73 [CI 1.43-196.42]; p = 0.025), and for SCH1with NICU admission and low birth weight (aOR 19.36 [CI 1.18-316.97]; p = 0.038 and 21.38 [CI 1.29-353.39]; p = 0.032, respectively). Conclusions: Pregnant women with TAI had a significantly higher risk of an admission of the baby to the NICU, and SCH tended to be associated with a higher risk of preeclampsia and low birth weight. Other poor clinical pregnancy outcomes were not associated with thyroid disorders, but with demographic and obstetric parameters.

Screening for Thyroid Dysfunction in Pregnancy With Targeted High-Risk Case Finding: Can It Be Improved?

CONTEXT AND OBJECTIVE: Targeted screening is proposed for the detection of thyroid dysfunction in pregnant women rather than universal screening (US). We aimed to determine the detection rate of subclinical hypothyroidism (SCH) and overt hypothyroidism (OH) based on American Thyroid Association guidelines (ATA-GL) and whether it could be improved. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study of 1832 pregnant women in a single center. Thyroid function (TSH and free T4) and iron status were determined. The high-risk group (HRG) included women with one or more ATA-GL risk factors and the low-risk group (LRG) included women without. Participants with other risk factors [body mass index (BMI) 30 to 39.9 kg/m2, Caucasian background] were classified as HRG+ and those with iron deficiency as HRG++. RESULTS: The HRG included 64% of women and the LRG included 36% (P < 0.001). Of all participants, 4.5% had SCH and 0.5% OH. The detection rate of SCH and OH was comparable between the LRG and HRG (46% vs 54% and 25% vs 75%; P = 0.560 and 0.157, respectively). In the HRG, the detection rate of SCH was lower than that of US (54% vs 100%; P < 0.001), but that of OH was comparable (75%; P = 0.596). The detection rate of SCH in the HRG+ and HRG++ was comparable to that in the US group (81% and 88% vs 100%; P = 0.220 and 0.439, respectively). CONCLUSIONS: Targeted high-risk case finding screening was not effective for the detection of SCH but performed better for OH. When obesity in the range BMI 30 to 39.9 kg/m2 and a Caucasian background were included as risk factors, the detection rate of SCH became comparable with that of US.