Inter-observer reproducibility of the 2021 AAGL Endometriosis Classification.

BACKGROUND: Inter-observer agreement for the American Association of Gynecologic Laparoscopists (AAGL) 2021 Endometriosis Classification staging system has not been described. Its predecessor staging system, the revised American Society for Reproductive Medicine (rASRM), has historically demonstrated poor inter-observer agreement. AIMS: We aimed to determine the inter-observer agreement performance of the AAGL 2021 Endometriosis Classification staging system, and compare this with the rASRM staging system. MATERIALS AND METHODS: A database of 317 patients with coded surgical data was retrospectively analysed. Three independent observers allocated AAGL surgical stages (1-4), twice. Observers made their own interpretation of how to apply the tool in the first staging allocation. Consensus rules were then developed for a second staging allocation. RESULTS: First staging allocation: odds ratio (OR) (and 95% CI) for observer 1 to score higher than observer 2 was 8.08 (5.12-12.76). Observer 1 to score higher than observer 3 was 12.98 (7.99-21.11) and observer 2 to score higher than observer 3 was 1.61 (1.03-2.51). This represents poor agreement. Second staging allocation (after consensus): OR for observer 1 to score higher than observer 2 was 1.14 (0.64-2.03), observer 1 to score higher than observer 3 was 1.81 (0.99-3.28) and observer 2 to score higher than observer 3 was 1.59 (0.87-2.89). This represents good agreement. CONCLUSIONS: These findings suggest that in its current format the AAGL 2021 Endometriosis Classification staging system has poor inter-observer agreement, not superior to the rASRM staging system. However, performance improved when additional measures were taken to simplify and clarify areas of ambiguity in interpreting the staging system.

External Validation of the "2021 AAGL Endometriosis Classification": A Retrospective Cohort Study.

STUDY OBJECTIVE: Externally validate the American Association of Gynecologic Laparoscopists (AAGL) staging system against surgical complexity and compare diagnostic accuracy with revised American Society for Reproductive Medicine (rASRM) stage, as was done in original publication. DESIGN: Retrospective, diagnostic accuracy study. SETTING: Multicenter (Sydney, Australia). PATIENTS: A total of 317 patients (January 2016-October 2021) were used in the final analysis. INTERVENTIONS: A database of patients with coded surgical data was analyzed. MEASUREMENTS AND MAIN RESULTS: Three independent observers assigned an AAGL surgical stage (1-4) as the index test and surgical complexity level (A-D) as the reference standard. Results from the most accurate of the 3 observers were used in the final analysis. The weighted kappa score for the overall performance of AAGL stage and rASRM to predict AAGL level was 0.48 and 0.48, respectively (no difference). This represents weaker agreement with AAGL level than was observed in the reference paper, which reported a weighted kappa of 0.62. Diagnostic accuracy (sensitivity, specificity, positive predictive value, and negative predictive value) for stage 1 to predict level A was 98.5%, 64.3%, 66.3%, and 98.3%; stage 2 to predict level B 31.2%, 90.5%, 27.0%, and 92.1 %; stage 3 to predict level C 12.3%, 94.1%, 59.3%, and 60.7%; stage 4 to predict level D 95.65%, 88.10%, 38.60%, and 99.62%. Area under the receiver operating characteristic curve for A vs B/C/D (cut point 9) was 0.87, A/B vs C/D (cut point 16) was 0.78, and A/B/C vs D (cut point 22) was 0.94. CONCLUSION: There was weak to moderate agreement between AAGL stage and AAGL surgical complexity level. Across all key indicators, the AAGL system did not perform as well in this external validation, nor did it outperform rASRM as it did in the reference paper. Results suggest the system is not generalizable.

Maternal Perfluoroalkyl Substances, Thyroid Hormones, and DIO Genes: A Spanish Cross-sectional Study.

Results of studies on perfluoroalkyl substances (PFASs) and thyroid hormones (THs) are heterogeneous, and the mechanisms underlying the action of PFASs to target THs have not been fully characterized. We examined the relation between first-trimester maternal PFAS and TH levels and the role played by polymorphisms in the iodothyronine deiodinase 1 (DIO1) and 2 (DIO2) genes in this association. Our sample comprised 919 pregnant Spanish women (recruitment = 2003-2008) with measurements of perfluorohexanesulfonic acid (PFHxS), perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA), thyroid-stimulating hormone (TSH), total triiodothyronine (TT3), and free thyroxine (FT4), and we genotyped for single-nucleotide polymorphisms in the DIO1 (rs2235544) and DIO2 (rs12885300) genes. We performed multivariate regression analyses between PFASs and THs and included the interaction term PFAS-genotypes in the models. PFHxS was associated with an increase in TSH (% change in outcome [95% CI] per 2-fold PFAS increase = 6.09 [-0.71, 13.4]), and PFOA and PFNA were associated with a decrease in TT3 (-7.17 [-13.5, -0.39] and -6.28 [-12.3, 0.12], respectively). We found stronger associations between PFOA, PFNA, and TT3 for DIO1-CC and DIO2-CT genotypes, although interaction p-values were not significant. In conclusion, this study found evidence of an inverse association between PFOA and TT3 levels. No clear effect modification by DIO enzyme genes was observed.

A Multicenter International Temporal and External Validation Study of the Ultrasound-based Endometriosis Staging System.

STUDY OBJECTIVE: The aim of this study was to validate temporally and externally the ultrasound-based endometriosis staging system (UBESS) to predict the level of complexity of laparoscopic surgery for endometriosis. DESIGN: A multicenter, international, retrospective, diagnostic accuracy study was carried out between January 2016 and April 2018 on women with suspected pelvic endometriosis. SETTING: Four different centers with advanced ultrasound and laparoscopic services were recruited (1 for temporal validation and 3 for external validation). PATIENTS: Women with pelvic pain and suspected endometriosis. INTERVENTIONS: All women underwent a systematic transvaginal ultrasound and were staged according to the UBESS system, followed by classification of laparoscopic level of complexity according to the Royal College of Obstetricians and Gynaecologists (RCOG) levels 1 to 3. MEASUREMENTS AND MAIN RESULTS: UBESS I, II, and III were then correlated with RCOG levels 1, 2, and 3, respectively. A comparison between temporal and external sites (skipping "A") and between each site was performed in terms of the diagnostic accuracy of UBESS to predict RCOG laparoscopic skill level. A total of 317 consecutive women who underwent laparoscopy with suspected endometriosis were included. Complete transvaginal ultrasound and laparoscopic surgical outcomes were available for 293/317 (92.4%). At the temporal site, the accuracy, sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio of UBESS I to predict RCOG level 1 were 80.0%,73.8%, 94.9%, 97.2%, 60.2%, 14.5%, and 0.3%, respectively; of UBESS II to predict RCOG level 2 were 81.0%, 70.6%, 82.0%, 26.7%, 96.8%, 3.9%, and 0.3%, respectively; of UBESS III to predict RCOG level 3 were 91.0%, 85.7%, 92.4%, 75.0%, 96.1%, 11.3%, and 0.2%, respectively. At the external sites, the results of UBESS I to predict RCOG level 1 were 90.3%, 92.0%, 88.4%, 90.2%, 90.5%, 7.9%, and 0.1% respectively; UBESS II to predict RCOG level 2 were 89.2%, 100.0%, 88.5%, 37.5%, 100.0%, 8.7%, and 0.0%, respectively; and UBESS III to predict RCOG level 3 were 86.0%, 67.6%, 98.2%, 96.2%, 82.1%, 37.8%, and 0.3%, respectively. When patients requiring ureterolysis (i.e., RCOG level 3) in the absence of bowel endometriosis were excluded (n = 54), the sensitivity of UBESS III to correctly classify RCOG level 3 increased from 85.7% to 96.7% at the temporal site (n = 42) and from 67.6% to 96.0% at the external sites (n = 12) (p <.005). CONCLUSION: The results from this external validation study suggest that UBESS in its current form is not generalizable unless there is either or both bowel deep endometriosis and cul-de-sac obliteration present. The major limitation appears to be the misclassification of women who require surgical ureterolysis in the absence of bowel endometriosis.

Endometriosis and the Urinary Tract: From Diagnosis to Surgical Treatment.

We aim to describe the diagnosis and surgical management of urinary tract endometriosis (UTE). We detail current diagnostic tools, including advanced transvaginal ultrasound, magnetic resonance imaging, and surgical diagnostic tools such as cystourethroscopy. While discussing surgical treatment options, we emphasize the importance of an interdisciplinary team for complex cases that involve the urinary tract. While bladder deep endometriosis (DE) is more straightforward in its surgical treatment, ureteral DE requires a high level of surgical skill. Specialists should be aware of the important entity of UTE, due to the serious health implications for women. When UTE exists, it is important to work within an interdisciplinary radiological and surgical team.

One-Size-Fits-All Approach Does Not Work for Gynecology Trainees Learning Endometriosis Ultrasound Skills.

OBJECTIVES: To evaluate whether gynecologic surgical trainees (fellows) can become competent in the real-time classification of the pouch of Douglas (POD) obliteration state and direct visualization of bowel deep endometriosis (DE) during a program with a prespecified number of transvaginal ultrasound (TVUS) examinations. METHODS: We performed a prospective study between December 2017 and December 2018. Three fellows (F1-F3) performed 50 scans each, which were all supervised by an expert sonologist, who performed the reference standard TVUS examination. The fellows performed a focused TVUS examination to assess the bowel and POD state, having been blinded to the patient's clinical history and reference standard findings. Immediate feedback and hands-on teaching were provided after each of the fellow's official classifications. To evaluate the number of scans needed to gain competency, the cumulative summation test for the learning curve was used. RESULTS: A total of 150 examinations were performed on 145 patients. Twenty-six (17.9%) patients had a diagnosis of bowel DE, and 34 (23.4%) were classified as having a negative sliding sign by the reference standard. The overall accuracy of the presence/absence of bowel DE was 90% (range, 82%-94%). The overall accuracy of POD state classification was 93% (range, 90%-96%). The cumulative summation test for the learning curve for bowel DE showed that F1 did not reach competency by 50 scans, whereas F2 and F3 required 21 and 25 scans, respectively. For POD obliteration, F2 did not reach competency, whereas F1 and F3 required 40 and 22 scans. CONCLUSIONS: Not all trainees can reach competency for TVUS evaluations of POD obliteration and bowel DE in a predefined number of scans.

Ureter Visualization With Transvaginal Ultrasound: A Learning Curve Study.

OBJECTIVES: To evaluate the learning curve of gynecologic surgical fellows (ie, in training) to properly identify the ureters in real time while simultaneously performing and interpreting transvaginal ultrasound (TVUS) examinations. METHODS: We performed a prospective study, which took place at 2 centers in Sydney, Australia, from December 2017 to December 2018. Three fellows (F1-F3), of varying prestudy ultrasound (US) experience, were recruited to participate. One hundred fifty predetermined examinations were planned. A TVUS examination was performed by the study reference standard (an expert in gynecologic US). Subsequently, the fellows performed a focused component to identify bilateral ureters, having been blinded to the patient's clinical history and reference standard findings. Immediate feedback and hands-on teaching were provided after each of the fellow's evaluations were complete. To evaluate the number of scans needed to gain competency, the cumulative summation test for the learning curve was used. RESULTS: A total of 150 examinations were performed on 145 patients. One patient had a single ureter, and 1 patient had US evidence of hydroureter. The cumulative summation test for the learning curve for bilateral ureter identification showed that F1 did not reach competency by 50 TVUS examinations, whereas F2 and F3 required 41 and 31 TVUS examinations to reach competency, respectively. CONCLUSIONS: Contrary to other studies on the topic, this study suggests that although it is feasible for surgical fellows to learn TVUS identification of bilateral ureters, not all fellows can reach competency during a program based on a predefined number of scans. We advocate for an individualized, competency-based medical education model in learning US for identifying the ureters.

Change over time in the iodine nutritional status of pregnant women from the Pamplona healthcare region. / Evolución del estado de nutrición de yodo en gestantes del area sanitaria de Pamplona.

INTRODUCTION: Adequate iodine intake is essential during pregnancy. A previous study of pregnant women from the Pamplona healthcare region showed mild iodine deficiency (mean urinary iodine level, 125 mcg/L). This study was intended to ascertain the iodine intake of pregnant women in our region and to analyze the change over time in their iodine nutritional status. METHODS: An observational study of 400 women in their first trimester of pregnancy. An iodine intake questionnaire was administered. To assess iodine status, urinary iodine concentration (UIC) was measured in a simple urine sample, and serum thyroglobulin levels were determined. In addition, thyroid volume was measured by cervical ultrasound examination. RESULTS: Iodized salt was used by 70.5% of all participants (55.3% since the pre-gestational period) and 98.5% of them received iodine-containing supplements (mean dose, 202.6±30.1 mcg/day). Mean urinary iodine concentration was 242 mcg/L (138.5-415.5 mcg/L) and the mean serum thyroglobulin level was 12.3 mcg/L (8.3-9 mcg/L). Iodized salt intake was associated with higher UICs and lower thyroid volume. No differences were found in any of the tested parameters regarding the intake of dairy products, fish, or eggs. CONCLUSIONS: Iodine intake by pregnant women in Pamplona has increased due to a greater use of iodized salt and to higher doses of iodine supplements. As a result of this, an adequate iodine status has been achieved in the last decade.

Transvaginal Ultrasound Can Accurately Predict the American Society of Reproductive Medicine Stage of Endometriosis Assigned at Laparoscopy.

STUDY OBJECTIVE: To evaluate the diagnostic accuracy of transvaginal ultrasound in predicting a laparoscopic, surgically assigned, revised American Society of Reproductive Medicine (ASRM) endometriosis stage. DESIGN: A multicenter, retrospective, diagnostic accuracy study. SETTING: The patients visited 1 of 2 academic gynecologic ultrasound units and underwent laparoscopy led by 1 of 6 surgeons in metropolitan Sydney, Australia, between 2016 and 2018. PATIENTS: Patients with suspected endometriosis (n = 204). INTERVENTIONS: Ultrasound followed by laparoscopy. MEASUREMENTS AND MAIN RESULTS: Surgical cases were identified. The preoperative ultrasound report and surgical operative notes were each used to retrospectively assign an ASRM score and stage. The breakdown of surgical findings was as follows: ASRM 0 (i.e., no endometriosis), 24/204 (11.8%); ASRM 1, 110/204 (53.9%); ASRM 2, 22/204 (10.8%); ASRM 3, 16/204 (7.8%); ASRM 4, 32 204 (15.7%). The overall accuracy of ultrasound in predicting the surgical ASRM stage was as follows: ASRM 1, 53.4%; ASRM 2, 93.8%; ASRM 3, 89.7%; ASRM 4, 93.1%; grouped ASRM 0, 1, and 2, 94.6%; and grouped ASRM 3 and 4 of 94.6%. Ultrasound had better test performance in higher disease stages. When the ASRM stages were dichotomized, ultrasound had sensitivity and specificity of 94.9% and 93.8%, respectively, for ASRM 0, 1, and 2 and of 93.8% and 94.9%, respectively, for ASRM 3 and 4. CONCLUSION: Ultrasound has high accuracy in predicting the mild, moderate, and severe ASRM stages of endometriosis and can accurately differentiate between stages when ASRM stages are dichotomized (nil/minimal/mild vs moderate/severe). This can have major positive implications on patient triaging at centers of excellence in minimally invasive gynecology for advanced-stage endometriosis.

The Use of Ultrasound in Detecting Endometriosis: Endometriotic Nodule Detected on Ultrasound but not Visualized on Laparoscopy.

The gold standard for diagnosis of endometriosis remains direct visualization at laparoscopy and histological confirmation. However, ultrasound is emerging as a key modality in detecting endometriosis. This case demonstrates how ultrasound has the ability to detect lesions that may not be visible on laparoscopy. A left uterosacral ligament (LUSL) deep endometriosis (DE) nodule was detected on preoperative ultrasound. During laparoscopy, no abnormalities were visualized at that site. Given ultrasound's high specificity for DE, the LUSL was resected; histopathology confirmed DE. This case demonstrates the utility of ultrasound and its ability to detect lesions that may not be visible to a surgeon's eye at laparoscopy. Laparoscopy may fail to identify not only sites of endometriosis but also the extent of infiltration of the disease. The utility of ultrasound for pre-operative mapping can guide surgeons in targeted excision of all lesions at the time of surgery, potentially leading to lower rates of suboptimal resection and residual disease. Interestingly, this case may support the theory of müllerianosis, whereby, during fetal organogenesis, misplaced endometrial tissue develops into endometriosis, allowing it to potentially later manifest as DE.

Similarities and differences of dietary and other determinants of iodine status in pregnant women from three European birth cohorts.

PURPOSE: As a component of thyroid hormones, adequate iodine intake is essential during pregnancy for fetal neurodevelopment. Across Europe, iodine deficiency is common in pregnancy, but data are lacking on the predictors of iodine status at this life stage. We, therefore, aimed to explore determinants of iodine status during pregnancy in three European populations of differing iodine status. METHODS: Data were from 6566 pregnant women from three prospective population-based birth cohorts from the United Kingdom (ALSPAC, n = 2852), Spain (INMA, n = 1460), and The Netherlands (Generation R, n = 2254). Urinary iodine-to-creatinine ratio (UI/Creat, µg/g) was measured in spot-urine samples in pregnancy (≤ 18-weeks gestation). Maternal dietary intake, categorised by food groups (g/day), was estimated from food-frequency questionnaires (FFQs). Multivariable regression models used dietary variables (energy-adjusted) and maternal characteristics as predictors of iodine status. RESULTS: Median UI/Creat in pregnant women of ALSPAC, INMA, and Generation R was 121, 151, and 210 µg/g, respectively. Maternal age was positively associated with UI/Creat in all cohorts (P < 0.001), while UI/Creat varied by ethnicity only in Generation R (P < 0.05). Of the dietary predictors, intake of milk and dairy products (per 100 g/day) was positively associated with UI/Creat in all cohorts [ALSPAC (B = 3.73, P < 0.0001); INMA (B = 6.92, P = 0.002); Generation R (B = 2.34, P = 0.001)]. Cohort-specific dietary determinants positively associated with UI/Creat included fish and shellfish in ALSPAC and INMA, and eggs and cereal/cereal products in Generation R. CONCLUSIONS: The cohort-specific dietary determinants probably reflect not only dietary habits but iodine-fortification policies; hence, public-health interventions to improve iodine intake in pregnancy need to be country-specific.

Iodine nutrition status in Spain Needs for the future. / La nutrición de yodo en España. Necesidades para el futuro.

Although iodine nutrition in Spain has improved in recent years, the problem is not completely resolved. It is necessary that health institutions establish measures to ensure an adequate iodine nutrition of the population, especially among the highest risk groups (children and adolescents, women of childbearing age, pregnant women and nursing mothers). A low salt intake should be advised, but it should be iodized. It is also imperative that food control agencies establish effective control over adequate iodization of salt. Indicators on iodine nutrition should be included in future health surveys. The EUthyroid study and the Krakow Declaration on iodine nutrition provide an opportunity to set up a pan-European plan for the prevention of iodine deficiency that should be considered and used by health authorities.

Iodine contents in conventional ultra-high temperature (UHT) processed cow milk: Changes over the year and regional differences. Implications for epidemiological studies on iodine nutritional status. / Contenido de yodo de la leche convencional ultrapasteurizada (UHT) de vaca: Variaciones a lo largo del año y diferencias regionales. Implicaciones para los estudios epidemiológicos sobre el estado de nutrición de yodo.

BACKGROUND AND OBJECTIVES: Ultra-high temperature (UHT) processed cow milk is the milk most commonly consumed in Southwest Europe. The study objectives were: 1) to describe the pattern followed by iodine concentration (IC) in conventional UHT milk over the year, and 2) to find out any differences in IC in this type of milk depending on its geographical origin. MATERIAL AND METHODS: Bricks of conventional UHT cow milk of commercial brands available in food stores in Vitoria-Gasteiz (Araba/Álava), Basque Country (Spain) were bought for 12 consecutive months, and their ICs were measured using high performance liquid chromatography. RESULTS: Median (P25-P75) IC in UHT milk (n=489) was 190 (159-235)µg/L. IC in milk showed great changes over the year, reaching peak values between January and May (241 [201-272]µg/L), and minimal levels between July and November (162 [134-185]µg/L) (P<.0001). The IC of milk packed in Germany was significantly lower than that of milks packed in Spain and France, 119 (106-156)µg/L versus 189 (159-229)µg/L and 205 (176-243)µg/L respectively (P<.0001). CONCLUSIONS: Conventional UHT cow milk is a very important nutritional source of iodine, but its IC is highly variable. Knowledge of the pattern followed by IC in milk over the year is of great interest for planning epidemiological studies on iodine nutritional status in schoolchildren and for interpretation of their results.

A Novel Ultrasound Technique Called Saline Infusion SonoPODography to Visualize and Understand the Pouch of Douglas and Posterior Compartment Contents: A Feasibility Study.

Women with infertility are often investigated with saline-infusion sonohysterography and hysterosalpingo-contrast-sonography. The high prevalence of endometriosis in this population also warrants an evaluation with transvaginal ultrasound for deep endometriosis. To minimize investigations, we prospectively evaluated the feasibility of a novel combined ultrasound technique called saline-infusion sonoPODography. In most patients, the fluid infused to assess the cavity and tubal patency spilled through patent tubes and filled the pouch of Douglas, yielding a "standoff" view of posterior compartment structures, including uterosacral ligaments, rectovaginal septum, and the pouch of Douglas. We believe this improved our ability to evaluate this space.

Association of Maternal Iodine Status With Child IQ: A Meta-Analysis of Individual Participant Data.

CONTEXT: Although the consequences of severe iodine deficiency are beyond doubt, the effects of mild to moderate iodine deficiency in pregnancy on child neurodevelopment are less well established. OBJECTIVE: To study the association between maternal iodine status during pregnancy and child IQ and identify vulnerable time windows of exposure to suboptimal iodine availability. DESIGN: Meta-analysis of individual participant data from three prospective population-based birth cohorts: Generation R (Netherlands), INMA (Spain), and ALSPAC (United Kingdom); pregnant women were enrolled between 2002 and 2006, 2003 and 2008, and 1990 and 1992, respectively. SETTING: General community. PARTICIPANTS: 6180 mother-child pairs with measures of urinary iodine and creatinine concentrations in pregnancy and child IQ. Exclusion criteria were multiple pregnancies, fertility treatment, medication affecting the thyroid, and preexisting thyroid disease. MAIN OUTCOME MEASURE: Child nonverbal and verbal IQ assessed at 1.5 to 8 years of age. RESULTS: There was a positive curvilinear association of urinary iodine/creatinine ratio (UI/Creat) with mean verbal IQ only. UI/Creat <150 µg/g was not associated with lower nonverbal IQ (-0.6 point; 95% CI: -1.7 to 0.4 points; P = 0.246) or lower verbal IQ (-0.6 point; 95% CI: -1.3 to 0.1 points; P = 0.082). Stratified analyses showed that the association of UI/Creat with verbal IQ was only present up to 14 weeks of gestation. CONCLUSIONS: Fetal brain development is vulnerable to mild to moderate iodine deficiency, particularly in the first trimester. Our results show that potential randomized controlled trials investigating the effect of iodine supplementation in women with mild to moderate iodine deficiency on child neurodevelopment should begin supplementation not later than the first trimester.

Newborn screening for homocystinurias: Recent recommendations versus current practice.

PURPOSE: To assess how the current practice of newborn screening (NBS) for homocystinurias compares with published recommendations. METHODS: Twenty-two of 32 NBS programmes from 18 countries screened for at least one form of homocystinuria. Centres provided pseudonymised NBS data from patients with cystathionine beta-synthase deficiency (CBSD, n = 19), methionine adenosyltransferase I/III deficiency (MATI/IIID, n = 28), combined remethylation disorder (cRMD, n = 56) and isolated remethylation disorder (iRMD), including methylenetetrahydrofolate reductase deficiency (MTHFRD) (n = 8). Markers and decision limits were converted to multiples of the median (MoM) to allow comparison between centres. RESULTS: NBS programmes, algorithms and decision limits varied considerably. Only nine centres used the recommended second-tier marker total homocysteine (tHcy). The median decision limits of all centres were ≥ 2.35 for high and ≤ 0.44 MoM for low methionine, ≥ 1.95 for high and ≤ 0.47 MoM for low methionine/phenylalanine, ≥ 2.54 for high propionylcarnitine and ≥ 2.78 MoM for propionylcarnitine/acetylcarnitine. These decision limits alone had a 100%, 100%, 86% and 84% sensitivity for the detection of CBSD, MATI/IIID, iRMD and cRMD, respectively, but failed to detect six individuals with cRMD. To enhance sensitivity and decrease second-tier testing costs, we further adapted these decision limits using the data of 15 000 healthy newborns. CONCLUSIONS: Due to the favorable outcome of early treated patients, NBS for homocystinurias is recommended. To improve NBS, decision limits should be revised considering the population median. Relevant markers should be combined; use of the postanalytical tools offered by the CLIR project (Collaborative Laboratory Integrated Reports, which considers, for example, birth weight and gestational age) is recommended. tHcy and methylmalonic acid should be implemented as second-tier markers.

Thyroid Function Reference Values in Healthy Iodine-Sufficient Pregnant Women and Influence of Thyroid Nodules on Thyrotropin and Free Thyroxine Values.

BACKGROUND: Thyroid function assessment in pregnancy requires specific reference intervals stratified by gestational age and according to each laboratory method. Thyroid nodules may influence thyroid function in pregnant women. The aims of this study were to define the reference values of thyrotropin (TSH) and free thyroxine (fT4) in the three pregnancy trimesters in iodine-sufficient pregnant women, and to analyze the influence of thyroid nodules on thyroid function during pregnancy. METHODS: This was a prospective, longitudinal study comprising 400 pregnant women with no history of thyroid disease and no medication influencing thyroid function. TSH, fT4, antithyroglobulin, and antithyroid peroxidase antibodies were measured each trimester by chemiluminescent immunoassays. Urinary iodine concentration was measured in the first trimester when a thyroid echography was also performed. Women with multiple gestation pregnancies, positive thyroid autoimmunity, TSH values >5 or <0.1 mIU/L with a simultaneous fT4 level above the general population reference value in the first trimester, or clinically significant thyroid nodules (nodules ≥1 cm and/or multiple nodules) were excluded to establish TSH and fT4 reference values. RESULTS: Reference intervals in the first, second, and third trimesters were 0.13-4.16, 0.31-3.73, and 0.58-4.36 mIU/L, respectively, for TSH, and 0.85-1.24, 0.82-1.20, and 0.67-1.06 ng/dL, respectively, for fT4. The total prevalence of thyroid nodules was 28.8% [95% confidence interval (CI) 24.4-33.5%], and 6.0% of the participants showed clinically significant nodules. Pregnant women with thyroid nodules (n = 115) showed consistently lower TSH values during all pregnancy stages (first trimester: median 1.14 mIU/L [interquartile range (IQR) 0.53-1.75 mIU/L] vs. 1.48 mIU/L [IQR 0.94-2.19 mIU/L], p < 0.001; second trimester: 1.22 mIU/L [IQR 0.66-1.77 mIU/L] vs. 1.45 mIU/L [1.04-2.05 mIU/L], p = 0.001; third trimester: 1.74 mIU/L [IQR 1.08-2.36 mIU/L] vs. 1.93 mIU/L [IQR 1.37-2.58 mIU/L], p = 0.041) and higher fT4 values in the first trimester (M ± SD = 1.08 ± 0.14 ng/dL vs. 1.03 ± 0.12, p < 0.001) compared to those without nodules (n = 285). Both pregnant women with clinically significant thyroid nodules and those with nonsignificant ones had lower TSH values than women without nodules. CONCLUSIONS: TSH/fT4 reference intervals in pregnant women from the authors' geographical area will thyroid dysfunction in pregnancy to be appropriately diagnosed. The prevalence of thyroid nodules is high in iodine-sufficient pregnant women, and is associated with low TSH values across pregnancy.