Characteristics and pregnancy outcomes across gestational diabetes mellitus subtypes based on insulin resistance.

AIMS/HYPOTHESIS: This study aimed to determine the characteristics and pregnancy outcomes across different subtypes of gestational diabetes mellitus (GDM) based on insulin resistance. METHODS: GDM subtypes were defined in 1813 pregnant women from a multicentre prospective cohort study, stratified according to insulin resistance, based on Matsuda index below the 50th percentile of women with normal glucose tolerance (NGT), during a 75 g OGTT at 24-28 weeks' gestation. GDM was diagnosed in 12.4% (n = 228) of all participants based on the 2013 WHO criteria. RESULTS: Compared with women with NGT (1113 [61.4%] of the total cohort) and insulin-sensitive women with GDM (39 [17.1%] women with GDM), women with GDM and high insulin resistance (189 [82.9%] women with GDM) had a significantly higher BMI, systolic BP, fasting plasma glucose (FPG), fasting total cholesterol, LDL-cholesterol and triacylglycerol levels in early pregnancy. Compared with women with NGT, insulin-sensitive women with GDM had a significantly lower BMI but similar BP, FPG and fasting lipid levels in early pregnancy. Compared with women with NGT, women with GDM and high insulin resistance had higher rates of preterm delivery (8.5% vs 4.7%, p = 0.030), labour induction (42.7% vs 28.1%, p < 0.001), Caesarean section (total Caesarean sections: 28.7% vs 19.4%, p = 0.004; emergency Caesarean sections: 16.0% vs 9.7%, p = 0.010), neonatal hypoglycaemia (15.4% vs 3.5%, p < 0.001) and neonatal intensive care unit admissions (16.0% vs 8.9%, p = 0.003). In multivariable logistic regression analyses using different models to adjust for demographics, BMI, FPG, HbA1c, lipid levels and gestational weight gain in early pregnancy, preterm delivery (OR 2.41 [95% CI 1.08, 5.38]) and neonatal hypoglycaemia (OR 4.86 [95% CI 2.04, 11.53]) remained significantly higher in women with GDM and high insulin resistance compared with women with NGT. Insulin-sensitive women with GDM had similar pregnancy outcomes as women with NGT. The need for insulin treatment during pregnancy and the rate of glucose intolerance in the early postpartum period were not significantly different among the GDM subtypes. CONCLUSIONS/INTERPRETATION: GDM with high insulin resistance represents a more adverse metabolic profile with a greater risk of adverse pregnancy outcomes.

Harmonization of Serum Thyroid-Stimulating Hormone Measurements Paves the Way for the Adoption of a More Uniform Reference Interval.

BACKGROUND: The IFCC Committee for Standardization of Thyroid Function Tests developed a global harmonization approach for thyroid-stimulating hormone measurements. It is based on a multiassay method comparison study with clinical serum samples and target setting with a robust factor analysis method. Here we describe the Phase IV method comparison and reference interval (RI) studies conducted with the objective to recalibrate the participating assays and demonstrate the proof-of-concept. METHODS: Fourteen manufacturers measured the harmonization and RI panel; 4 of them quantified the harmonization and first follow-up panel in parallel. All recalibrated their assays to the statistically inferred targets. For validation, we used desirable specifications from the biological variation for the bias and total error (TE). The RI measurements were done with the assays' current calibrators, but data were also reported after transformation to the new calibration status. We estimated the pre- and postrecalibration RIs with a nonparametric bootstrap procedure. RESULTS: After recalibration, 14 of 15 assays met the bias specification with 95% confidence; 8 assays complied with the TE specification. The CV of the assay means for the harmonization panel was reduced from 9.5% to 4.2%. The RI study showed improved uniformity after recalibration: the ranges (i.e., maximum differences) exhibited by the assay-specific 2.5th, 50th, and 97.5th percentile estimates were reduced from 0.27, 0.89, and 2.13 mIU/L to 0.12, 0.29, and 0.77 mIU/L. CONCLUSIONS: We showed that harmonization increased the agreement of results from the participating immunoassays, and may allow them to adopt a more uniform RI in the future.

Standardization of Free Thyroxine Measurements Allows the Adoption of a More Uniform Reference Interval.

BACKGROUND: The IFCC Committee for Standardization of Thyroid Function Tests intended to standardize free thyroxine (FT4) immunoassays. We developed a Système International d'Unités traceable conventional reference measurement procedure (RMP) based on equilibrium dialysis and mass spectrometry. We describe here the latest studies intended to recalibrate against the RMP and supply a proof of concept, which should allow continued standardization efforts. METHODS: We used the RMP to target the standardization and reference interval (RI) panels, which were also measured by 13 manufacturers. We validated the suitability of the recalibrated results to meet specifications for bias (3.3%) and total error (8.0%) determined from biological variation. However, because these specifications were stringent, we expanded them to 10% and 13%, respectively. The results for the RI panel were reported as if the assays were recalibrated. We estimated all but 1 RI using parametric statistical procedures and hypothesized that the RI determined by the RMP was suitable for use by the recalibrated assays. RESULTS: Twelve of 13 recalibrated assays had a bias, meeting the 10% specification with 95% confidence; for 7 assays, this applied even for the 3.3% specification. Only 1 assay met the 13% total error specification. Recalibration reduced the CV of the assay means for the standardization panel from 13% to 5%. The proof-of-concept study confirmed our hypothesis regarding the RI but within constraints. CONCLUSIONS: Recalibration to the RMP significantly reduced the FT4 immunoassays' bias, so that the RI determined by the RMP was suitable for common use within a margin of 12.5%.

DICER1 Mutations Define the Landscape of Poorly Differentiated Thyroid Carcinoma in Children and Young Adults: Case Report and Literature Review.

Poorly differentiated thyroid carcinoma (PDTC) is a rare malignancy, representing ~1% of all thyroid tumors. It is characterized by high-grade histologic features without the anaplastic characteristics observed in anaplastic thyroid carcinoma. Although rare in children and young adults, there is emerging evidence of clinical and genetic differences with PDTC in adults. We present a case of a 19-year-old female with a right thyroid lobe nodule classified as an EU-TIRADS 5 lesion. Subsequent FNAC showed a cellular aspirate of solitary cells and scant microfollicles with variable nuclear irregularities, which was designated a Bethesda class IV lesion. Thyroidectomy revealed histopathological features consistent with PDTC, including solid/trabecular growth, increased mitotic activity, central necrosis, and extensive vascular invasion. Molecular analysis identified germline and somatic DICER1 mutations in the absence of other established driver mutations of PDTC. This case report describes the fourth reported patient with a PDTC and germline DICER1 mutation. Our findings contribute to a limited body of literature on pediatric/young adult PDTC cases and highlight the pivotal role of DICER1 mutations. Emerging evidence suggests that pediatric PDTC may exhibit unique clinical and genetic characteristics, prompting further research into its molecular profile.

Fetal size monitoring in women with gestational diabetes and normal glucose tolerance.

AIMS: To monitor fetal size and identify predictors for birthweight in women with gestational diabetes (GDM) and normal glucose tolerance (NGT). METHODS: Cohort study of 1843 women universally screened for GDM, with routine ultrasounds each trimester. Women with GDM and NGT were categorized in subgroups by birthweight centile. RESULTS: Of the total cohort, 231 (12.5%) women were diagnosed with GDM. Fetal size, incidence of large-for-gestational age (LGA: 12.3% of GDM vs. 12.9% of NGT, p = 0.822) and small-for-gestational age (SGA) neonates (4.8% of GDM vs. 5.1% of NGT, p = 0.886) were similar between GDM and NGT. GDM women with LGA neonates were more insulin resistant at baseline and had more often estimated fetal weight (EFW) ≥ P90 on the 28-33 weeks ultrasound (p = 0.033) than those with AGA (appropriate-for-gestational age) neonates. Compared to NGT women with AGA neonates, those with LGA neonates were more often obese and multiparous, had higher fasting glycemia, a worse lipid profile, and higher insulin resistance between 24 -28 weeks, with more often excessive gestational weight gain. On the 28-33 weeks ultrasound, abdominal circumference ≥ P95 had a high positive predictive value for LGA neonates in GDM (100%), whereas, in both GDM and NGT, EFW ≥ P90 and ≤ P10 had a high negative predictive value for LGA and SGA neonates (> 88%), respectively. CONCLUSIONS: There were no differences in fetal size throughout pregnancy nor in LGA incidence between GDM and NGT women. EFW centile at 28-33 weeks correlated well with birthweight. This indicates that GDM treatment is effective and targeted ultrasound follow-up is useful. TRIAL REGISTRATION CLINICALTRIALS.GOV: NCT02036619. Registration date: January 15, 2014. https://clinicaltrials.gov/ct2/show/NCT02036619 .

Impact of breastfeeding on risk of glucose intolerance in early postpartum after gestational diabetes.

Aims: To determine the impact of breastfeeding on the risk of postpartum glucose intolerance in women with gestational diabetes. Methods: Sub-analysis of two multi-centric prospective cohort studies (BEDIP-N and MELINDA) in 1008 women with gestational diabetes. Data were collected during pregnancy and at a mean of 12 weeks postpartum. Multivariate logistic regression was used to estimate the effect of breastfeeding on glucose intolerance, with adjustment for ethnicity, education, income, professional activity and BMI. Results: Of all participants, 56.3% (567) breastfed exclusively, 10.1% (102) gave mixed milk feeding and 33.6% (339) did not breastfeed. Mean breastfeeding duration was 3.8 ± 2.4 and 3.7 ± 2.1 months in the breastfeeding and mixed milk feeding groups (p=0.496). The rate of glucose intolerance was lower in both the breastfeeding [22.3% (126)] and mixed milk feeding [25.5% (26)] groups compared to the no breastfeeding group [29.5% (100)], with an adjusted OR of 0.7 (95% CI 0.5-1.0) for glucose intolerance in the breastfeeding group compared to no breastfeeding group and an adjusted OR of 0.7 (95% CI 0.4-1.2) for the mixed milk feeding group compared to the no breastfeeding group. Postpartum, breastfeeding women had a lower BMI, less often postpartum weight retention, lower fasting triglycerides, less insulin resistance and a higher insulin secretion-sensitivity index-2 than the mixed milk feeding and no breastfeeding group. The mixed milk feeding group was more often from an non-White background, had a lower blood pressure and lower fasting triglycerides compared to the no breastfeeding group. Conclusions: Breastfeeding (exclusive and mixed milk feeding) is associated with less glucose intolerance and a better metabolic profile in early postpartum in women with gestational diabetes.

Preoperative imaging for hyperparathyroidism often takes upper parathyroid adenomas for lower adenomas.

We retrospectively evaluated how accurately preoperative imaging localizes parathyroid adenoma in superior versus inferior parathyroids. Over 6 years, 104 patients with primary hyperparathyroidism underwent parathyroid surgery in a single centre. Of these, 103 underwent ultrasound, 97 [99mTc]pertechnetate/MIBI SPECT/CT and 30 [18F]fluorocholine (FCH) PET/CT. One patient with a unilateral double adenoma was excluded from the analysis. Surgical findings with histopathologic confirmation of adenoma were used as the standard. Ultrasound misjudged 5 of 48 detected lower adenomas as upper, but 14 of 29 upper adenomas as lower (error rate 10 vs 48%, p = 0.0002). The corresponding error rates for [99mTc]pertechnetate/MIBI SPECT/CT were 3 versus 55% (p = 0.000014), and for [18F]FCH PET/CT 17 versus 36% (p = 0.26). Our results suggest that about half of the superior parathyroid adenomas which are detected, are erroneously assigned to the inferior position by both ultrasound and SPECT/CT imaging whereas the opposite mistake is significantly less frequent with ultrasound and SPECT/CT.

Parathyroid adenoma apoplexy mimicking a thyroid bleeding cyst: a seemingly innocent condition that can be life-threatening.

Summary: Primary hyperparathyroidism most commonly presents with hypercalcaemia. Rarely, parathyroid apoplexy or haemorrhage mimicking a thyroid bleeding cyst is the first presentation of a parathyroid adenoma. A woman presented with a sudden-onset painful 'goitre'. Ultrasound showed a cystic nodule located posterior to rather than in the right thyroid lobe, suggesting parathyroid adenoma bleeding. Biochemistry showed mild primary hyperparathyroidism. 99mTc-pertechnetate/sestamibi showed no uptake in the nodule, which was interpreted as a cold thyroid nodule. 18F-fluorocholine PET/CT showed uptake in the nodule, suggestive of a parathyroid adenoma. Persistent mild primary hyperparathyroidism complicated by nephrolithiasis and osteopenia favoured parathyroidectomy over a wait-and-see approach. The patient was referred for parathyroidectomy along with right thyroid lobectomy. Pathology showed an adenoma, with an eccentrically located cystic structure filled with red blood cells surrounded by a thickened fibrous capsule. In conclusion, cervical pain/haemorrhage with hypercalcaemia points to the diagnosis of parathyroid apoplexy, mimicking a thyroid bleeding cyst. Workup with ultrasound and, if available, 18F-choline PET/CT allows for timely surgery, minimizing the risk of recurrent and severe bleeding. Learning points: A bleeding cyst may be located posterior to rather than in the thyroid, suggesting a parathyroid haemorrhage. Neck pain and/or haemorrhage along with primary hyperparathyroidism point to parathyroid apoplexy. A two-step presentation has been described, with a first phase of local symptoms to be followed by visible and possibly life-threatening compressing bleeding. Therefore, an expedited workup is needed, allowing for timely surgery.

Low Gestational Weight Gain in Women With Gestational Diabetes Is Safe With Better Metabolic Profile Postpartum.

CONTEXT: More data are needed on the potential benefits and risks of gestational weight gain (GWG) less than recommended and excessive GWG in women with gestational diabetes (GDM) compared to women with normal glucose tolerance (NGT) during pregnancy. OBJECTIVE: This work aimed to evaluate association of gestational weight gain (GWG) as low, within, or above (excessive) according to Institute of Medicine (IOM) guidelines, with pregnancy outcomes in women with gestational diabetes (GDM) and normal glucose tolerance (NGT). METHODS: This prospective cohort study included 7 Belgian hospitals and 1843 women receiving universal GDM screening with a 75-g oral glucose tolerance test. Pregnancy outcomes and postpartum characteristics were the main outcome measures. RESULTS: Women with GDM and low GWG (n = 97, 52.4%) had similar rates of small-for-gestational age infants and preterm delivery, were less often overweight or obese postpartum (35.7% [30] vs 56.5% [26]; P < .022) and less often had postpartum weight retention (PPWR) (48.8% [41] vs 87.9% [40]; P < .001) compared to GWG within range (n = 58, 31.3%). GDM with excessive GWG (n = 30, 16.2%) more often had neonatal hypoglycemia (30.8% (8) vs 5.9% [3], aOR 7.15; 95% CI, 1.52-33.63; P = .013) compared to GWG within range. NGT with excessive GWG (28.3% [383]) more often had instrumental delivery (15.9% [61] vs 11.9% [64], aOR 1.53; 95% CI, 1.03-2.27; P = .035) and more large-for-gestational age infants (19.3% [74] vs 10.4% [56], aOR 1.67; 95% CI, 1.13-2.47; P = .012) compared to GWG within range. CONCLUSION: GWG below IOM guidelines occurred frequently in GDM women, without increased risk for adverse pregnancy outcomes and with better metabolic profile postpartum. Excessive GWG was associated with increased risk for neonatal hypoglycemia and worse metabolic profile postpartum in women with GDM, and with higher rates of LGA and instrumental delivery in NGT women.

Normal glucose tolerant women with low glycemia during the oral glucose tolerance test have a higher risk to deliver a low birth weight infant.

Background: Data are limited on pregnancy outcomes of normal glucose tolerant (NGT) women with a low glycemic value measured during the 75g oral glucose tolerance test (OGTT). Our aim was to evaluate maternal characteristics and pregnancy outcomes of NGT women with low glycemia measured at fasting, 1-hour or 2-hour OGTT. Methods: The Belgian Diabetes in Pregnancy-N study was a multicentric prospective cohort study with 1841 pregnant women receiving an OGTT to screen for gestational diabetes (GDM). We compared the characteristics and pregnancy outcomes in NGT women according to different groups [(<3.9mmol/L), (3.9-4.2mmol/L), (4.25-4.4mmol/L) and (>4.4mmol/L)] of lowest glycemia measured during the OGTT. Pregnancy outcomes were adjusted for confounding factors such as body mass index (BMI) and gestational weight gain. Results: Of all NGT women, 10.7% (172) had low glycemia (<3.9 mmol/L) during the OGTT. Women in the lowest glycemic group (<3.9mmol/L) during the OGTT had compared to women in highest glycemic group (>4.4mmol/L, 29.9%, n=482), a better metabolic profile with a lower BMI, less insulin resistance and better beta-cell function. However, women in the lowest glycemic group had more often inadequate gestational weight gain [51.1% (67) vs. 29.5% (123); p<0.001]. Compared to the highest glycemia group, women in the lowest group had more often a birth weight <2.5Kg [adjusted OR 3.41, 95% CI (1.17-9.92); p=0.025]. Conclusion: Women with a glycemic value <3.9 mmol/L during the OGTT have a higher risk for a neonate with birth weight < 2.5Kg, which remained significant after adjustment for BMI and gestational weight gain.

Atypical neurofibromas in neurofibromatosis type 1 are premalignant tumors.

Benign peripheral nerve sheath tumors (PNSTs) are a characteristic feature of neurofibromatosis type I (NF1) patients. NF1 individuals have an 8-13% lifetime risk of developing a malignant PNST (MPNST). Atypical neurofibromas are symptomatic, hypercellular PNSTs, composed of cells with hyperchromatic nuclei in the absence of mitoses. Little is known about the origin and nature of atypical neurofibromas in NF1 patients. In this study, we classified the atypical neurofibromas in the spectrum of NF1-associated PNSTs by analyzing 65 tumor samples from 48 NF1 patients. We compared tumor-specific chromosomal copy number alterations between benign neurofibromas, atypical neurofibromas, and MPNSTs (low-, intermediate-, and high-grade) by karyotyping and microarray-based comparative genome hybridization (aCGH). In 15 benign neurofibromas (4 subcutaneous and 11 plexiform), no copy number alterations were found, except a single event in a plexiform neurofibroma. One highly significant recurrent aberration (15/16) was identified in the atypical neurofibromas, namely a deletion with a minimal overlapping region (MOR) in chromosome band 9p21.3, including CDKN2A and CDKN2B. Copy number loss of the CDKN2A/B gene locus was one of the most common events in the group of MPNSTs, with deletions in low-, intermediate-, and high-grade MPNSTs. In one tumor, we observed a clear transition from a benign-atypical neurofibroma toward an intermediate-grade MPNST, confirmed by both histopathology and aCGH analysis. These data support the hypothesis that atypical neurofibromas are premalignant tumors, with the CDKN2A/B deletion as the first step in the progression toward MPNST.

TPO antibody status prior to first radioactive iodine therapy as a predictive parameter for hypothyroidism in Graves' disease.

Objective: We investigated whether a positive thyroid peroxidase antibody (TPO Ab) status before radioactive iodine (RAI) therapy in patients with Graves' hyperthyroidism is a predictive factor for developing hypothyroidism post RAI. Methods: We performed a retrospective study of patients with Graves' hyperthyroidism with known TPO Ab status, receiving the first administration of RAI. Patients from four thyroid outpatient centres in Belgium receiving their first RAI therapy between the years 2011 and 2019 were studied. Clinical, laboratory, imaging, and treatment data were recorded from medical charts. Hypothyroidism and cure (defined as combined hypo- and euthyroidism) were evaluated in period 1 (≥2 and ≤9 months, closest to 6 months post RAI) and period 2 (>9 months and ≤24 months post RAI, closest to 12 months post RAI). Results: A total of 152 patients were included of which 105 (69%) were TPO Ab-positive. Compared to TPO Ab-negative patients, TPO Ab-positive patients were younger, had a larger thyroid gland, and had more previous episodes of hyperthyroidism. In period 1, 89% of the TPO Ab-positive group developed hypothyroidism and 72% in the TPO Ab-negative group (P = 0.007). In period 2, the observation was similar: 88% vs 72% (P = 0.019). In the multivariate logistic regression analysis, a positive TPO Ab status was associated with hypothyroidism in period 2 (adjusted OR: 4.78; 95% CI: 1.27-20.18; P = 0.024). In period 1, the aOR was 4.16 (95% CI: 1.0-18.83; P = 0.052). Conclusion: A positive TPO Ab status in patients with Graves' hyperthyroidism receiving the first administration of RAI is associated with a higher risk of early hypothyroidism.

Combining data to perform population-based observational studies: know your sources. The case of thyroid cancer in Belgium.

BACKGROUND: Large scale observational studies are crucial to study thyroid cancer incidence and management, known to vary in time and place. Combining cancer registry data with other data sources enables execution of population-based studies, provided data sources are accurate. The objective was to compare thyroid tumour and treatment information between the available data sources in Belgium. METHODS: We performed a retrospective national population-based cohort study. All patients with thyroid cancer diagnosis in Belgium between 2009 and 2011 (N = 2659 patients) were retrieved from the Belgian Cancer Registry database, containing standard patient and tumour characteristics. Additionally, information was obtained from the following sources: a) detailed pathology reports b) the health insurance company database for reimbursed performed therapeutic acts (both available for N = 2400 patients) c) registration forms for performed and/or planned treatments at the time of the multidisciplinary team meeting (available for N = 1819 patients). More precisely, information was retrieved regarding characteristics of the tumour (histologic subtype, tumour size, lymph node status (source a)) and the treatment (thyroid surgery (a,b,c), lymph node dissection (a,b), postoperative administration of radioactive iodine (b,c)). RESULTS: High concordance in histological cancer subtype (> 90%), tumour size (96.2%) and lymph node involvement (89.2%) categories was found between the cancer registry database and the pathology reports. Tumour subcategories (such as microcarcinoma, tumor ≤1 cm diameter) were more specified in the pathology reports. The therapeutic act of thyroid surgery as mentioned in the pathology reports and health insurance company database was concordant in 92.7%, while reports from multidisciplinary team meetings showed 88.5% of concordance with pathology reports and 86.1% with health insurance data. With regard to postoperative radioiodine administration, reports from multidisciplinary teams and health insurance data were concordant in 76.8%. CONCLUSION: Combining registered and/or administrative data results in sufficiently accurate information to perform large scale observational studies on thyroid cancer in Belgium. However, thorough and continuous quality control and insight in strengths and limitations of each cancer data source is crucial.

Retrospective real-life study on preoperative imaging for minimally invasive parathyroidectomy in primary hyperparathyroidism.

The objective of this study was to retrospectively evaluate preoperative imaging modalities for localization of parathyroid adenomas with a view to enable minimally invasive parathyroidectomy and in particular, to consider the contribution of 18F-fluorocholine-PET/CT. 104 patients with primary hyperparathyroidism, who underwent parathyroid surgery in a single centre during a 6-year period were included. Of these, 103 underwent ultrasound, 97 99mTc-Pertechnetate/SestaMIBI-SPECT, 20 MRI and 30 18F-fluorocholine-PET/CT. Based on surgical findings, sensitivities and specificities for correct lateralisation in orthotopic locations were: for ultrasound 0.75 (0.65-0.83) and 0.89 (0.81-0.94), for 99mTc-MIBI-SPECT 0.57 (0.46-0.67) and 0.97 (0.91-0.99), for MRI 0.60 (0.36-0.81) and 0.83 (0.59-0.96) and for 18F-fluorocholine-PET/CT 0.90 (0.73-0.98) and 0.90 (0.73-0.98). Correctly lateralized adenomas were significantly larger than those not found with ultrasound (p = 0.03) and SPECT (p = 0.002). Pre-operative PTH-levels were higher in single adenomas detected by scintigraphy than in those not (p = 0.02). 64 patients could be treated with a minimally invasive procedure. Cure after parathyroidectomy was obtained in 94% of patients. 18F-Fluorocholine-PET/CT could be shown to be a highly accurate modality to localize parathyroid adenomas preoperatively, obviating the need for total exploration in the majority of patients in whom ultrasound and scintigraphic results are discordant or both negative.

Use of thyroid hormones in hypothyroid and euthyroid patients: a THESIS* survey of Belgian specialists *THESIS: treatment of hypothyroidism in Europe by specialists: an international survey.

BACKGROUND: Hypothyroidism is a topic that continues to provoke debate and controversy with regards to specific indications, type of thyroid hormone substitution and efficacy. We investigated the use of thyroid hormones in clinical practice in Belgium, a country where currently only levothyroxine (LT4) tablet formulations are available. METHOD: Members of the Belgian Endocrine Society were invited to respond to an online questionnaire. Results were compared with those from other THESIS surveys. RESULTS: Eighty (50%) of the invited 160 individuals, completed the questionnaire. LT4 was the first treatment of choice for all respondents. As secondary choice, some also prescribed liothyronine (LT3) and LT4 + LT3 combinations (2 and 7 respondents, respectively). Besides hypothyroidism, 34 and 50% of respondents used thyroid hormones for infertile euthyroid TPOAb positive women and the treatment of a growing non-toxic goiter, respectively. Had alternative formulations of LT4 to tablets been available (soft gel or liquid L-T4), 2 out of 80 (2.5%) participants would consider them for patients achieving biochemical euthyroidism but remaining symptomatic. This proportion was higher in case of unexplained poor biochemical control of hypothyroidism (13.5%) and in patients with celiac disease or malabsorption or interfering drugs (10%). In symptomatic euthyroid patients, 20% of respondents would try combined LT4 + LT3 treatment. Psychosocial factors were highlighted as the main contributors to persistent symptoms. CONCLUSIONS: LT4 tablets is the preferred treatment for hypothyroidism in Belgium. A minority of the respondents would try combined LT4 + LT3 in symptomatic but biochemically euthyroid patients. Thyroid hormones are prescribed for euthyroid infertile women with thyroid autoimmunity and patients with non-toxic goiter, a tendency noted in other European countries, despite current evidence of lack of benefit.

Fasting plasma glucose level to guide the need for an OGTT to screen for gestational diabetes mellitus.

AIMS: To determine the fasting plasma glucose (FPG) level at which an oral glucose tolerance test (OGTT) could be avoided to screen for gestational diabetes (GDM) and to evaluate the characteristics of women across this FPG threshold. METHODS: A multi-centric prospective cohort study with 1843 women receiving universal screening for GDM with a 75 g OGTT. RESULTS: In the total population, GDM prevalence was 12.5% (231). A FPG < 78 mg/dL was the cut-off with best trade-off to limit the number of missed GDM cases [44 (19.0%)] with a negative predictive value of 97.3% (95% CI 96.5-98.0) for GDM, while avoiding 52.2% OGTTs. Compared to GDM with FPG ≥ 78 mg/dL [187 (81.0%)], GDM women with FPG < 78 mg/dL had a significantly lower BMI (27.1 ± 4.5 vs. 29.6 ± 5.2 kg/m2, p = 0.003), less insulin resistance [Matsuda: 0.4 (0.4-0.7) vs. 0.3 (0.2-0.5), p < 0.001] and better ß-cell function [ISSI-2: 0.13 (0.08-0.25) vs. 0.09 (0.04-0.15), p = 0.004]. Compared to NGT women (1612) with FPG ≥ 78 mg/dL [846 (52.5%)], NGT with FPG < 78 mg/dL [766 (47.5%)] had a significantly lower BMI (26.0 ± 3.9 vs. 27.8 ± 4.7 kg/m2, p < 0.001), less insulin resistance [Matsuda: 0.7 (0.5-0.9) vs. 0.5 (0.4-0.7), p < 0.001], better ß-cell function [ISSI-2: 0.17 (0.10-0.30) vs. 0.12 (0.07-0.21), p < 0.001], and less often large-for-gestational age infants [9.2 (70) vs. 16.2% (136), p < 0.001]. CONCLUSIONS: FPG < 78 mg/dL can be used to limit the number of OGTTs when screening for GDM. Women with FPG < 78 mg/dL had a better metabolic profile and in NGT women also less fetal overgrowth.

Type 1 diabetes-related autoimmune antibodies in women with gestational diabetes mellitus and the long-term risk for glucose intolerance.

Aims: To characterize women with gestational diabetes mellitus (GDM) positive for type 1 diabetes-related autoimmune antibodies (T1D-related autoantibodies) in pregnancy and to evaluate their risk for long-term glucose intolerance. Methods: In a multi-centric prospective cohort study with 1843 women receiving universal screening for GDM with a 75 g oral glucose tolerance test (OGTT), autoantibodies were measured in women with GDM: insulin autoantibodies (IAA), islet cell antibodies (ICA), insulinoma-associated protein-2 antibodies (IA-2A) and glutamic acid decarboxylase antibodies (GADA). Long-term follow-up ( ± 4.6 years after delivery) with a 75 g OGTT and re-measurement of autoantibodies was done in women with a history of GDM and autoantibody positivity in pregnancy. Results: Of all women with GDM (231), 80.5% (186) received autoantibody measurement at a mean of 26.2 weeks in pregnancy, of which 8.1% (15) had one positive antibody (seven with IAA, two with ICA, four with IA-2A and two with GADA). Characteristics in pregnancy were similar but compared to women without autoantibodies, women with autoantibodies had more often gestational hypertension [33.3% (5) vs. 1.7% (3), p<0.001] and more often neonatal hypoglycemia [40.0% (6) vs. 12.5% (19), p=0.012]. Among 14 of the 15 autoantibody positive women with an early postpartum OGTT, two had impaired fasting glucose (IFG). Of the 12 women with long-term follow-up data, four tested again positive for T1D-related autoantibodies (three positive for IA-2A and one positive for ICA and IAA). Five women were glucose intolerant at the long-term follow-up of which two had IA-2A (one had IFG and one had T1D) and three without autoantibodies. There were no significant differences in long-term characteristics between women with and without autoantibodies postpartum. Conclusions: Systematic screening for T1D-related autoantibodies in GDM does not seem warranted since the low positivity rate for autoantibodies in pregnancy and postpartum. At 4.6 years postpartum, five out of 12 women were glucose intolerant but only two still had autoantibodies. In women with clinically significant increased autoantibody levels during pregnancy, postpartum autoantibody re-measurement seems useful since the high risk for further increase of autoantibody levels.

Higher Thyroid fT3-to-fT4 Ratio Is Associated with Gestational Diabetes Mellitus and Adverse Pregnancy Outcomes.

Aim: To determine the association between thyroid function and the risk of developing gestational diabetes mellitus (GDM) and adverse pregnancy outcomes. Methods: This case−control study was a sub-analysis of the BEDIP-N study, in which 199 GDM women were matched for age and body mass index with 398 controls. Thyroid-stimulating hormone (TSH), free thyroxine (fT4), free triiodothyronine (fT3), and thyroid peroxidase (TPO) antibodies were measured at 6−14 weeks and 26−28 weeks during pregnancy. TSH and fT4 were also measured in early postpartum in GDM women. Results: The fT3-to-fT4 ratio at 26−28 weeks was positively associated with GDM risk with an adjusted odds ratio (aOR for smoking, education, parity, ethnicity, gestational weight gain, and (family) history of diabetes or GDM) of 2.12 (95% CI 1.07; 4.23), comparing the highest with the lowest tertile. Higher fT3 levels and a higher fT3-to-fT4 ratio were associated with a less favorable metabolic profile with higher BMI and more insulin resistance during pregnancy and postpartum. Women in the upper fT3 tertile and the upper fT3-to-fT4 ratio had a higher rate of preeclampsia [4.6% (10) vs. 1.0% (2), p = 0.040, and 4.4% (9) vs. 0.5% (1), p = 0.020], gestational hypertension [8.3% (18) vs. 3.1% (6), p = 0.034 and 8.9% (18) vs. 2.0% (4), p = 0.003], and caesarean sections [29.4% (63) vs. 16.1% (31), p = 0.002 and 32.2% (65) vs. 12.7% (25), p < 0.001]. Conclusion: A higher fT3-to-fT4 ratio late into pregnancy was associated with GDM, adverse pregnancy outcomes, and an adverse metabolic profile in early postpartum.

Women with Mild Fasting Hyperglycemia in Early Pregnancy Have More Neonatal Intensive Care Admissions.

AIMS: To determine impact of mild fasting hyperglycemia in early pregnancy (fasting plasma glucose [FPG] 5.1-5.5 mmol/L) on pregnancy outcomes. METHODS: We measured FPG at 11.9 ± 1.8 weeks in 2006 women from a prospective cohort study. Women with FPG ≥5.6 mmol/L (19) received treatment and were excluded from further analyses. A total of 1838 women with FPG <5.6 mmol/L received a 75 g oral glucose tolerance test (OGTT) between 24 and 28 weeks of pregnancy. RESULTS: Of all participants, 78 (4.2%) had FPG 5.1 to 5.5 mmol/L in early pregnancy, of which 49 had a normal OGTT later in pregnancy (high fasting normal glucose tolerance [NGT] group). Compared with the NGT group with FPG <5.1 mmol/L in early pregnancy (low fasting NGT group, n = 1560), the high fasting NGT group had a higher body mass index (BMI), higher insulin resistance with more impaired insulin secretion and higher FPG and 30 minute glucose levels on the OGTT. The admission rate to neonatal intensive care unit (NICU) was significantly higher in the high fasting NGT group than in the low fasting NGT group (20.4% [10] vs 9.3% [143], P = .009), with no difference in duration (7.0 ± 8.6 vs 8.4 ± 14.3 days, P = .849) or indication for NICU admission between both groups. The admission rate to NICU remained significantly higher (odds ratio 2.47; 95% confidence interval 1.18-5.19, P = .017) after adjustment for age, BMI, and glucose levels at the OGTT. CONCLUSIONS: When provision of an OGTT is limited such as in the Covid-19 pandemic, using FPG in early pregnancy could be an easy alternative to determine who is at increased risk for adverse pregnancy outcomes.