Risk Factors for Thyroid Dysfunction in Pregnancy: An Individual Participant Data Meta-Analysis.

Background: International guidelines recommend targeted screening to identify gestational thyroid dysfunction. However, currently used risk factors have questionable discriminative ability. We quantified the risk for thyroid function test abnormalities for a subset of risk factors currently used in international guidelines. Methods: We included prospective cohort studies with data on gestational maternal thyroid function and potential risk factors (maternal age, body mass index [BMI], parity, smoking status, pregnancy through in vitro fertilization, twin pregnancy, gestational age, maternal education, and thyroid peroxidase antibody [TPOAb] or thyroglobulin antibody [TgAb] positivity). Exclusion criteria were pre-existing thyroid disease and use of thyroid interfering medication. We analyzed individual participant data using mixed-effects regression models. Primary outcomes were overt and subclinical hypothyroidism and a treatment indication (defined as overt hypothyroidism, subclinical hypothyroidism with thyrotropin >10 mU/L, or subclinical hypothyroidism with TPOAb positivity). Results: The study population comprised 65,559 participants in 25 cohorts. The screening rate in cohorts using risk factors currently recommended (age >30 years, parity ≥2, BMI ≥40) was 58%, with a detection rate for overt and subclinical hypothyroidism of 59%. The absolute risk for overt or subclinical hypothyroidism varied <2% over the full range of age and BMI and for any parity. Receiver operating characteristic curves, fitted using maternal age, BMI, smoking status, parity, and gestational age at blood sampling as explanatory variables, yielded areas under the curve ranging from 0.58 to 0.63 for the primary outcomes. TPOAbs/TgAbs positivity was associated with overt hypothyroidism (approximate risk for antibody negativity 0.1%, isolated TgAb positivity 2.4%, isolated TPOAb positivity 3.8%, combined antibody positivity 7.0%; p < 0.001), subclinical hypothyroidism (risk for antibody negativity 2.2%, isolated TgAb positivity 8.1%, isolated TPOAb positivity 14.2%, combined antibody positivity 20.0%; p < 0.001) and a treatment indication (risk for antibody negativity 0.2%, isolated TgAb positivity 2.2%, isolated TPOAb positivity 3.0%, and combined antibody positivity 5.1%; p < 0.001). Twin pregnancy was associated with a higher risk of overt hyperthyroidism (5.6% vs. 0.7%; p < 0.001). Conclusions: The risk factors assessed in this study had poor predictive ability for detecting thyroid function test abnormalities, questioning their clinical usability for targeted screening. As expected, TPOAb positivity (used as a benchmark) was a relevant risk factor for (subclinical) hypothyroidism. These results provide insights into different risk factors for gestational thyroid dysfunction.

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.

Association of Gestational Free and Total Triiodothyronine With Gestational Hypertension, Preeclampsia, Preterm Birth, and Birth Weight: An Individual Participant Data Meta-analysis.

CONTEXT: Triiodothyronine (T3) is the bioactive form of thyroid hormone. In contrast to thyroid-stimulating hormone and free thyroxine, we lack knowledge on the association of gestational T3 with adverse obstetric outcomes. OBJECTIVE: To investigate the associaiton of gestational free or total T3 (FT3 or TT3) with adverse obstetric outcomes. METHODS: We collected individual participant data from prospective cohort studies on gestational FT3 or TT3, adverse obstetric outcomes (preeclampsia, gestational hypertension, preterm birth and very preterm birth, small for gestational age [SGA], and large for gestational age [LGA]), and potential confounders. We used mixed-effects regression models adjusting for potential confounders. RESULTS: The final study population comprised 33 118 mother-child pairs of which 27 331 had data on FT3 and 16 164 on TT3. There was a U-shaped association of FT3 with preeclampsia (P = .0069) and a J-shaped association with the risk of gestational hypertension (P = .029). Higher TT3 was associated with a higher risk of gestational hypertension (OR per SD of TT3 1.20, 95% CI 1.08 to 1.33; P = .0007). A lower TT3 but not FT3 was associated with a higher risk of very preterm birth (OR 0.72, 95% CI 0.55 to 0.94; P = .018). TT3 but not FT3 was positively associated with birth weight (mean difference per 1 SD increase in TT3 12.8, 95% CI 6.5 to 19.1 g, P < .0001) but there was no association with SGA or LGA. CONCLUSION: This study provides new insights on the association of gestational FT3 and TT3 with major adverse pregnancy outcomes that form the basis for future studies required to elucidate the effects of thyroid function on pregnancy outcomes. Based on the current study, routine FT3 or TT3 measurements for the assessment of thyroid function during pregnancy do not seem to be of added value in the risk assessment for adverse outcomes.

Relation of antepartum stillbirth to birthweight and gestational age: Prospective cohort study.

OBJECTIVES: To investigate the incidence of antepartum stillbirth in relation to the distribution of neonatal/fetal weight for different gestational ages. DESIGN: Prospective observational cohort study. SETTING: Obstetric ultrasound departments in two UK maternity hospitals. POPULATION: 168 966 women with singleton pregnancies attending for routine antenatal care. METHODS: We examined the incidence of antepartum stillbirths, within different birthweight and fetal weight percentile subgroups, conditioning for gestational age. MAIN OUTCOME MEASURES: Incidence of antepartum stillbirth. RESULTS: The risk of stillbirth progressively increased for lower birthweight. Considering the 25-75th percentile as the reference category, the relative risks for stillbirth at <37 weeks' gestation were 7.6 (95% confidence interval [CI] 5.7-10.2) <1st percentile, 2.6 (95% CI 1.8-3.7) 1 to 10th percentile, 1.4 (95% CI 0.9-2.1) 10 to 25th percentile, 0.8 (95% CI 0.4-1.5) 75 to 90th percentile, 0.8 (95% CI 0.4-1.7) 90 to 99th percentile, 0.9 (95% CI 0.3-2.5) >99th percentile. The respective values for births at ≥37 weeks' gestation were 5.0 (95% CI 2.9-8.9), 2.1 (95% CI 1.4-3.3), 1.4 (95% CI 0.9-2.1), 1.2 (95% CI 0.7-1.8), 1.0 (95% CI 0.6-1.8) and 4.0 (95% CI 1.8-9.3). The incidence of stillbirth in ongoing low-risk singleton pregnancies gradually increases for smaller fetuses at any gestational point. The higher incidence (5.56%) was evident for fetal weight <1st percentile between 24 and 28 weeks' gestation. CONCLUSION: Fetal weight and the weight of the stillborn have a continuous association with the incidence of antepartum stillbirth which is affected by gestational age.

TSH and FT4 Reference Intervals in Pregnancy: A Systematic Review and Individual Participant Data Meta-Analysis.

CONTEXT: Interpretation of thyroid function tests during pregnancy is limited by the generalizability of reference intervals between cohorts due to inconsistent methodology. OBJECTIVE: (1) To provide an overview of published reference intervals for thyrotropin (TSH) and free thyroxine (FT4) in pregnancy, (2) to assess the consequences of common methodological between-study differences by combining raw data from different cohorts. METHODS: (1) Ovid MEDLINE, EMBASE, and Web of Science were searched until December 12, 2021. Studies were assessed in duplicate. (2) The individual participant data (IPD) meta-analysis was performed in participating cohorts in the Consortium on Thyroid and Pregnancy. RESULTS: (1) Large between-study methodological differences were identified, 11 of 102 included studies were in accordance with current guidelines; (2) 22 cohorts involving 63 198 participants were included in the meta-analysis. Not excluding thyroid peroxidase antibody-positive participants led to a rise in the upper limits of TSH in all cohorts, especially in the first (mean +17.4%; range +1.6 to +30.3%) and second trimester (mean +9.8%; range +0.6 to +32.3%). The use of the 95th percentile led to considerable changes in upper limits, varying from -10.8% to -21.8% for TSH and -1.2% to -13.2% for FT4. All other additional exclusion criteria changed reference interval cut-offs by a maximum of 3.5%. Applying these findings to the 102 studies included in the systematic review, 48 studies could be used in a clinical setting. CONCLUSION: We provide an overview of clinically relevant reference intervals for TSH and FT4 in pregnancy. The results of the meta-analysis indicate that future studies can adopt a simplified study setup without additional exclusion criteria.

Association of Thyroid Peroxidase Antibodies and Thyroglobulin Antibodies with Thyroid Function in Pregnancy: An Individual Participant Data Meta-Analysis.

Objectives: Thyroid autoimmunity is common in pregnant women and associated with thyroid dysfunction and adverse obstetric outcomes. Most studies focus on thyroid peroxidase antibodies (TPOAbs) assessed by a negative-positive dichotomy and rarely take into account thyroglobulin antibodies (TgAbs). This study aimed at determining the association of TPOAbs and TgAbs, respectively, and interdependently, with maternal thyroid function. Methods: This was a meta-analysis of individual participant cross-sectional data from 20 cohorts in the Consortium on Thyroid and Pregnancy. Women with multiple pregnancy, pregnancy by assisted reproductive technology, history of thyroid disease, or use of thyroid interfering medication were excluded. Associations of (log2) TPOAbs and TgAbs (with/without mutual adjustment) with cohort-specific z-scores of (log2) thyrotropin (TSH), free triiodothyronine (fT3), total triiodothyronine (TT3), free thyroxine (fT4), total thyroxine (TT4), or triiodothyronine:thyroxine (T3:T4) ratio were evaluated in a linear mixed model. Results: In total, 51,138 women participated (51,094 had TPOAb-data and 27,874 had TgAb-data). Isolated TPOAb positivity was present in 4.1% [95% confidence interval, CI: 3.0 to 5.2], isolated TgAb positivity in 4.8% [CI: 2.9 to 6.6], and positivity for both antibodies in 4.7% [CI: 3.1 to 6.3]. Compared with antibody-negative women, TSH was higher in women with isolated TPOAb positivity (z-score increment 0.40, CI: 0.16 to 0.64) and TgAb positivity (0.21, CI: 0.10 to 0.32), but highest in those positive for both antibodies (0.54, CI: 0.36 to 0.71). There was a dose-response effect of higher TPOAb and TgAb concentrations with higher TSH (TSH z-score increment for TPOAbs 0.12, CI: 0.09 to 0.15, TgAbs 0.08, CI: 0.02 to 0.15). When adjusting analyses for the other antibody, only the association of TPOAbs remained statistically significant. A higher TPOAb concentration was associated with lower fT4 (p < 0.001) and higher T3:T4 ratio (0.09, CI: 0.03 to 0.14), however, the association with fT4 was not significant when adjusting for TgAbs (p = 0.16). Conclusions: This individual participant data meta-analysis demonstrated an increase in TSH with isolated TPOAb positivity and TgAb positivity, respectively, which was amplified for individuals positive for both antibodies. There was a dose-dependent association of TPOAbs, but not TgAbs, with TSH when adjusting for the other antibody. This supports current practice of using TPOAbs in initial laboratory testing of pregnant women suspected of autoimmune thyroid disease. However, studies on the differences between TPOAb- and TgAb-positive women are needed to fully understand the spectrum of phenotypes.

Development of the utero-placental circulation in cesarean scar pregnancies: a case-control study.

BACKGROUND: Cesarean scar pregnancies carry a high risk of pregnancy complications including placenta previa with antepartum hemorrhage, placenta accreta spectrum, and uterine rupture. OBJECTIVE: To evaluate the development of utero-placental circulation in the first half of pregnancy in ongoing cesarean scar pregnancies and compare it with pregnancies implanted in the lower uterine segment above a previous cesarean delivery scar with no evidence of placenta accreta spectrum at delivery STUDY DESIGN: This was a retrospective case-control study conducted in 2 tertiary referral centers. The study group included 27 women who were diagnosed with a live cesarean scar pregnancy in the first trimester of pregnancy and who elected to conservative management. The control group included 27 women diagnosed with an anterior low-lying placenta or placenta previa at 19 to 22 weeks of gestation who had first and early second trimester ultrasound examinations. In both groups, the first ultrasound examination was carried out at 6 to 10 weeks to establish the pregnancy location, viability, and to confirm the gestational age. The utero-placental and intraplacental vasculatures were examined using color Doppler imaging and were described semiquantitatively using a score of 1 to 4. The remaining myometrial thickness was recorded in the study group, whereas the ultrasound features of a previous cesarean delivery scar including the presence of a niche were noted in the controls. Both the cesarean scar pregnancies and the controls had ultrasound examinations at 11 to 14 and 19 to 22 weeks of gestation. RESULTS: The mean color Doppler imaging vascularity score in the ultrasound examination at 6 to 10 weeks was significantly (P<.001) higher in the cesarean scar pregnancy group than in the controls. High vascularity scores of 3 and 4 were recorded in 20 of 27 (74%) cases of the cesarean scar pregnancy group. There was no vascularity score of 4, and only 3 of 27 (11%) controls had a vascularity score of 3. In 15 of the 27 (55.6%) cesarean scar pregnancies, the residual myometrial thickness was <2 mm. In the ultrasound examination at 11 to 14 weeks, there was no significant difference between the groups in the number of cases with an increased subplacental vascularity. However, 12 cesarean scar pregnancies (44%) presented with 1 or more placental lacunae whereas there was no case with lacunae in the controls. Of the 18 cesarean scar pregnancies that progressed into the third trimester, 10 of them were diagnosed with placenta previa accreta at birth, including 4 creta and 6 increta. In the 19 to 22 weeks ultrasound examination, 8 of the 10 placenta accreta spectrum patients presented with subplacental hypervascularity, out of which 6 showed placental lacunae. CONCLUSION: The vascular changes in the utero-placental and intervillous circulations in cesarean scar pregnancies are due to the loss of the normal uterine structure in the scar area and the development of placental tissue in proximity of large diameter arteries of the outer uterine wall. The intensity of these vascular changes, the development of placenta accreta spectrum, and the risk of uterine rupture are probably related to the residual myometrial thickness of the scar defect at the start of pregnancy. A better understanding of the pathophysiology of the utero-placental vascular changes associated with cesarean scar pregnancies should help in identifying those cases that may develop major complications. It will contribute to providing counseling for women about the risks associated with different management strategies.

Predictive performance for placental dysfunction related stillbirth of the competing risks model for small-for-gestational-age fetuses.

OBJECTIVES: To examine the predictive performance for placental dysfunction related stillbirths of the competing risks model for small-for-gestational-age (SGA) fetuses based on a combination of maternal risk factors, estimated fetal weight (EFW) and uterine artery pulsatility index (UtA-PI); and second, to compare the performance of this model with that of a stillbirth-specific model using the same biomarkers and with the Royal College of Obstetricians and Gynecologists (RCOG) guideline for the investigation and management of the SGA fetus. DESIGN: Prospective observational study. SETTING: Two UK maternity hospitals. POPULATION: A total of 131 514 women with singleton pregnancies attending for routine ultrasound examination at 19-24 weeks of gestation. METHODS: The predictive performance for stillbirth achieved by three models was compared. MAIN OUTCOME MEASURE: Placental dysfunction related stillbirth. RESULTS: At 10% false-positive rate, the competing risks model predicted 59%, 66% and 71% of placental dysfunction related stillbirths, at any gestation, at <37 weeks and at <32 weeks, respectively, which were similar to the respective figures of 62%, 70% and 73% for the stillbirth-specific model. At a screen positive rate of 21.8%, as defined by the RCOG guideline, the competing risks model predicted 71%, 76% and 79% of placental dysfunction related stillbirths at any gestation, at <37 weeks and at <32 weeks, respectively, and the respective figures for the RCOG guideline were 40%, 44% and 42%. CONCLUSION: The predictive performance for placental dysfunction related stillbirths by the competing risks model for SGA was similar to that of the stillbirth-specific model and superior to that of the RCOG guideline. TWEETABLE ABSTRACT: The competing risks approach for SGA is superior to the RCOG guideline in the prediction of placental dysfunction related stillbirths.

Maternal thyroid function at gestational weeks 11-13 in twin pregnancies.

BACKGROUND: Thyroid disease during pregnancy may be associated with increased risk of various pregnancy complications. It is known that serum thyrotropin (TSH) is suppressed because of the increased hormone production induced by human chorionic gonadotrophin (hCG) in early pregnancy, and that higher hCG levels in twin pregnancies may cause a more pronounced physiologic suppression. The recognition of this phenomenon is important in order to avoid unnecessary concerns and to correctly establish the diagnosis of overt thyroid disease in twin pregnancies. The aim of this study was to establish reference ranges of maternal serum TSH and free thyroxine (FT4) at gestational weeks 11-13 in twin pregnancies. METHODS: This is a case series of 177 dichorionic and 58 monochorionic twin pregnancies with normal outcomes, and 19 monochorionic pregnancies complicated by severe twin-twin transfusion syndrome. Maternal serum concentrations of TSH, FT4, antithyroperoxidase, and antithyroglobulin antibodies were measured at gestational weeks 11-13. The measured TSH and FT4 were converted to multiple of median (MoM) of normal singleton pregnancies and MoM values in the different groups were compared. RESULTS: In the antibody-negative twin pregnancies with normal outcomes, compared to singletons, serum TSH MoM was lower (median 0.62 [interquartile range [IQR 0.16-1.18] vs. 1.01 [IQR 0.61-1.51]; p < 0.0001), FT4 MoM was not significantly different (median 0.98 [IQR 0.91-1.08] vs. 0.99 [IQR 0.91-1.09]; p = 0.975), and free ß-hCG MoM was higher (median 1.91 [IQR 1.33-2.59] vs. 0.98 [IQR 0.66-1.50]; p < 0.0001). In the antibody-positive group (n = 37), compared to the negative group (n = 198), the median TSH was higher, but FT4 and free ß-hCG were not significantly different. In the twin-twin transfusion syndrome group, compared to normal twin pregnancies, TSH, FT4, and free ß-hCG were not significantly different. CONCLUSION: In twins, compared to singleton pregnancies, TSH is lower but FT4 is not significantly different. These reference ranges of thyroid hormones in twins can form the basis for the study of early thyroid function in pathological pregnancies and the investigation of the consequences of overt and subclinical hypothyroidism on twin pregnancy outcome.

Noninvasive prenatal testing for fetal trisomies in a routinely screened first-trimester population.

OBJECTIVE: We sought to assess performance of noninvasive prenatal testing for fetal trisomy in a routinely screened first-trimester pregnancy population. STUDY DESIGN: This was a cohort study of 2049 pregnant women undergoing routine screening for aneuploidies at 11-13 weeks' gestation. Plasma cell-free DNA analysis using chromosome-selective sequencing was used. Laboratory testing on a single plasma sample of 2 mL was carried out blindly and results were provided as risk score (%) for trisomies 21 and 18. RESULTS: Trisomy risk scores were given for 95.1% (1949 of 2049) of cases including all 8 with trisomy 21 and 2 of the 3 with trisomy 18. The trisomy risk score was >99% in the 8 cases of trisomy 21 and 2 of trisomy 18 and <1% in 99.9% (1937 of 1939) of euploid cases. CONCLUSION: Noninvasive prenatal testing using chromosome-selective sequencing in a routinely screened population identified trisomies 21 and 18 with a false-positive rate of 0.1%.

Fetal fraction in maternal plasma cell-free DNA at 11-13 weeks' gestation: effect of maternal and fetal factors.

OBJECTIVE: It was the aim of this study to examine the possible effects of maternal and fetal characteristics on the fetal fraction in maternal plasma cell-free DNA (cfDNA) at 11-13 weeks' gestation. METHODS: In a nested case-control study, cfDNA was extracted from maternal plasma obtained before chorionic villous sampling from 300 euploid, 50 trisomy 21 and 50 trisomy 18 pregnancies at 11-13 weeks' gestation. Chromosome-selective sequencing of maternal cfDNA non-polymorphic and polymorphic loci, where fetal alleles differ from maternal alleles, was used to determine the proportion of DNA which is of fetal origin. Multivariate regression analysis was used to determine which of the factors amongst maternal weight, racial origin, smoking status, plasma storage time, serum pregnancy-associated plasma protein (PAPP)-A and free ß-subunit of human chorionic gonadotropin (ß-hCG), fetal crown-rump length, nuchal translucency thickness, gender and karyotype were significant predictors of the fetal fraction. RESULTS: Significant independent prediction of fetal fraction was provided by maternal weight, serum PAPP-A and serum free ß-hCG multiples of the median, but not by other maternal characteristics, fetal karyotype, crown-rump length or nuchal translucency thickness. Fetal fraction increased with serum metabolite levels and decreased with maternal weight. CONCLUSIONS: The fetal fraction in maternal plasma cfDNA increases with serum PAPP-A and free ß-hCG and decreases with maternal weight.

Chromosome-selective sequencing of maternal plasma cell-free DNA for first-trimester detection of trisomy 21 and trisomy 18.

OBJECTIVE: The purpose of this study was to assess the prenatal detection rate of trisomy 21 and 18 and the false-positive rate by chromosome-selective sequencing of maternal plasma cell-free DNA. STUDY DESIGN: Nested case-control study of cell-free DNA was examined in plasma that was obtained at 11-13 weeks before chorionic villous sampling from 300 euploid pregnancies, 50 pregnancies with trisomy 21, and 50 pregnancies with trisomy 18. Laboratory personnel were blinded to fetal karyotype. RESULTS: Risk scores for trisomy 21 and 18 were given for 397 of the 400 samples that were analyzed. In all 50 cases of trisomy 21, the risk score for trisomy 21 was ≥ 99%, and the risk score for trisomy 18 was ≤ 0.01%. In all 50 cases of trisomy 18, the risk score for trisomy 21 was ≤ 0.01%, and the risk score for trisomy 18 was ≥ 99% in 47 cases, 98.8% in 1 case, 88.5% in 1 case, and 0.11% in 1 case. In 3 of the 300 euploid pregnancies (1%), no risk score was provided, because there was failed amplification and sequencing. In the remaining 297 cases, the risk score for trisomy 21 was ≤ 0.01%, and the risk score for trisomy 18 was ≤ 0.01% in 295 cases, 0.04% in 1 case, and 0.23% in 1 case. Therefore, the sensitivity for detecting trisomy 21 was 100% (50/50 cases); the sensitivity for trisomy 18 was 98% (49/50 cases), and the specificity was 100% (297/297 cases). CONCLUSION: In this study, chromosome-selective sequencing of cell-free DNA separated all cases of trisomy 21 and 98% of trisomy 18 from euploid pregnancies.

Maternal thyroid function at eleven to thirteen weeks of gestation and subsequent delivery of small for gestational age neonates.

BACKGROUND: Studies have shown that altered thyroid function in early pregnancy may affect normal placental development and hence fetal growth. Our hypothesis is that maternal thyroid function in the first trimester is altered in pregnancies that subsequently deliver small for gestational age (SGA) neonates. METHODS: Maternal serum thyroid-stimulating hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3) were measured at 11(+0) to 13(+6) weeks' gestation in 212 singleton pregnancies with no history of thyroid disease that subsequently delivered SGA neonates and the values were compared with the results of 3598 normal pregnancies delivering neonates with birth weight above the 5th percentile for gestation. RESULTS: There were no significant differences between the normal and SGA groups in median multiple of the median (MoM) TSH (1.07 vs. 1.061 MoM), FT4 (0.992 vs. 1.010 MoM), and FT3 (0.991 vs. 0.990 MoM). CONCLUSION: In women with no history of thyroid disease delivering SGA neonates, thyroid function during the first trimester of pregnancy is not significantly different from women delivering non-SGA neonates.

Maternal thyroid function at 11-13 weeks of gestation and spontaneous preterm delivery.

OBJECTIVE: To estimate the possible association between spontaneous early preterm delivery and maternal thyroid dysfunction in early pregnancy. METHODS: Maternal serum concentrations of thyroid-stimulating hormone (TSH), free thyroxine, antithyroperoxidase, and antithyroglobulin antibodies at 11-13 weeks of gestation were compared in 102 singleton pregnancies, resulting in spontaneous delivery before 34 weeks and 4,318 normal pregnancies delivering after this gestation. RESULTS: In the preterm delivery group, compared with the normal outcome group, there was no significant difference in antithyroid antibody positivity (16.7% compared with 16.8%). In the antithyroid antibody-negative pregnancies in the preterm delivery group, compared with the normal outcome group, the median free thyroxine multiple of the median was reduced (0.94 compared with 0.99 multiple of the median, P<.001), but the median TSH multiple of the median was not significantly different (0.99 compared with 1.01 multiple of the median, P=.331). CONCLUSION: In pregnancies resulting in spontaneous early preterm delivery, there is no evidence of increased prevalence of antithyroid antibody positivity or maternal thyroid dysfunction at 11-13 weeks. LEVEL OF EVIDENCE: II.

Maternal thyroid function at 11-13 weeks of gestation in fetal trisomies 21 and 18.

OBJECTIVE: To examine the association between maternal serum levels of thyroid stimulating hormone (TSH) and free ß-human chorionic gonadotrophin (free ß-hCG) in trisomy 21, trisomy 18 and euploid pregnancies at 11-13 weeks and investigate the potential value of TSH in first-trimester screening for aneuploidies. METHODS: Maternal serum TSH and free ß-hCG levels at 11-13 weeks in 25 trisomy 21 and 25 trisomy 18 pregnancies were compared with levels in 3592 unaffected pregnancies. Only women with no history of thyroid disease and negative for antithyroid antibodies were included. RESULTS: Serum TSH in the trisomy 21 pregnancies was lower [0.76 multiples of the normal median (MoM), interquartile range (IQR) 0.46-1.09 MoM] and in trisomy 18 it was higher (1.25 MoM, IQR 0.88-1.98 MoM) than in unaffected pregnancies (1.01 MoM, IQR 0.61-1.51 MoM). There were significant associations between TSH and free ß-hCG in the unaffected pregnancies (r = - 0.214, p < 0.0001), but not in those with trisomy 21 (r = - 0.157, p = 0.452) or trisomy 18 (r = - 0.176, p = 0.401). CONCLUSIONS: hCG, rather than TSH, may be the primary thyrotropic factor in early pregnancy. Measurement of TSH does not improve the performance of screening for trisomies 21 and 18 provided by nuchal translucency, free ß-hCG and pregnancy-associated plasma protein-A.

Maternal thyroid function at 11 to 13 weeks of gestation and subsequent development of preeclampsia.

OBJECTIVE: To determine if maternal thyroid function in the first trimester is altered in pregnancies that subsequently develop preeclampsia (PE). METHODS: Mean arterial pressure (MAP), uterine artery pulsatility index (PI) maternal serum thyroid stimulating hormone (TSH), free thyroxine (FT4) and free triiodothyronine (FT3) at 11 to 13 weeks of gestation were measured in 102 singleton pregnancies that subsequently developed PE, and the values were compared to the results of 4318 normal pregnancies. RESULTS: In both the PE groups that required delivery before 34 weeks (early-PE) and the late-PE group, compared with the unaffected group, the median MAP multiple of the normal median (MoM) and uterine artery PI MoM were significantly increased. In late-PE but not in early-PE, compared with the unaffected group, the median TSH MoM was significantly increased and the median FT4 MoM was decreased. Logistic regression analysis demonstrated that TSH MoM provided a significant contribution in the prediction of late-PE. CONCLUSION: Impaired thyroid function may predispose to the development of late-PE, and measurement of maternal serum TSH can improve the prediction of late-PE provided by a combination of factors in the maternal history and the measurements of MAP and uterine artery PI.

Maternal thyroid function at 11-13 weeks of gestation in women with hypothyroidism treated by thyroxine.

OBJECTIVE: The aim of this study in pregnant women with hypothyroidism treated by levothyroxine is to examine the interrelations between thyroid-stimulating hormone (TSH), free thyroxine (FT(4)) and free tri-iodothyronine (FT(3)), and examine whether in such patients the treatment is adequate. METHODS: This was a retrospective cross-sectional study. Maternal serum concentrations of FT(3), FT(4) and TSH were measured at 11-13 weeks in 164 singleton pregnancies from women with hypothyroidism before pregnancy receiving treatment with thyroxine. The values were compared to the results in 4,318 normal singleton pregnancies. RESULTS: In the hypothyroid group, compared to the normal group, there was an increase in median TSH (1.990 vs. 1.007 MoM) and FT(4) (1.052 vs. 0.992 MoM) and decrease in FT(3) (0.901 vs. 0.991 MoM). Serum FT(4) was at or above the 2.5th centile in 158 (96.3%) cases but TSH was above the 97.5th centile in 48 (29.3%) and FT(3) was below the 2.5th centile in 49 (29.9%) cases. In both the hypothyroid and unaffected groups there were significant associations between TSH and FT(4), TSH and FT(3) and between FT(3) and FT(4). CONCLUSIONS: In a high proportion of pregnant women with hypothyroidism treated with levothyroxine there is evidence of persistent hypothyroidism because the treatment is inadequate in correcting the levels of FT(3).

Maternal thyroid function at 11 to 13 weeks of gestation and subsequent fetal death.

BACKGROUND: Studies have shown that overt hypothyroidism is associated with a substantial risk of miscarriage. There is controversy as to whether subclinical hypothyroidism has the same effect and whether such effect is mediated by the presence of antithyroid antibodies. Our hypothesis is that maternal thyroid function in the first trimester is altered in pregnancies ending in miscarriage or fetal death. METHODS: Thyroid-stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine, anti-thyroperoxidase antibody, and anti-thyroglobulin antibody at 11-13 weeks of gestation were measured in 202 singleton pregnancies that subsequently resulted in miscarriage or fetal death, and the values were compared with the results of 4318 normal pregnancies. RESULTS: In the fetal loss group, compared to the unaffected group, there was an increase in median TSH multiple of the normal median (1.133 vs. 1.007 MoM), decrease in median FT4 MoM (0.958 vs. 0.992 MoM), and increase in the incidence of TSH above the 97.5th centile (5.9% vs. 2.5%) and FT4 below the 2.5th centile (5.0% vs. 2.5%). Logistic regression analysis demonstrated that in the prediction of fetal loss there were significant contributions from FT4 MoM, maternal black ethnic origin, history of chronic hypertension, and use of ovulation drugs. The prevalence of antithyroid antibody positivity was not significantly different in the fetal loss group compared to that of normal pregnancies (15.3% vs. 16.8%). CONCLUSIONS: Impaired thyroid function may predispose to miscarriage and fetal death.

Maternal thyroid function at 11-13 weeks of gestation.

OBJECTIVE: To establish normal ranges of maternal serum thyroid-stimulating hormone (TSH), free thyroxine (FT4) and free triiodothyronine (FT3) at 11-13 weeks of gestation. METHODS: Maternal serum concentrations of FT3, FT4, TSH, anti-thyroperoxidase (anti-TPO) and anti-thyroglobulin (anti-Tg) antibodies were measured at 11-13 weeks. Normal ranges were constructed from the data of singleton pregnancies with no anti-thyroid antibodies resulting in live births after 34 weeks of phenotypically normal neonates with birth weight above the 5th percentile. Adjustments were made for maternal characteristics found by multiple regression analysis to affect the levels of TSH, FT3 and FT4. RESULTS: 3,592 of the 4,318 pregnancies examined were antibody negative, and in this group serum TSH increased whereas FT3 and FT4 decreased with gestation, and all three were lower in black than in white women. Serum FT3 and FT4 decreased but TSH did not change significantly with maternal age; TSH and FT3 increased whereas FT4 decreased with body mass index; TSH decreased whereas FT3 and FT4 increased with serum free beta-hCG. In the antibody-positive group, compared to the negative group, median TSH was higher and median FT3 and FT4 were lower. CONCLUSION: The study established normal ranges for maternal thyroid function at 11-13 weeks.

Novel compound heterozygous nonsense mutations in the hairless gene causing atrichia with papular lesions.

BACKGROUND: Atrichia with papular lesions (APL) is a rare autosomal recessive condition resulting from mutations in the hairless (HR) gene. OBJECTIVE: In the present study, we investigated the molecular basis of APL in a non-consanguineous Korean family. METHODS: Direct automated DNA sequencing of the HR gene and restriction digestion analysis were used to identify and confirm the mutation in our proband. RESULTS: Sequencing of the HR gene revealed two novel nonsense mutations in exons 2 and 4 which were subsequently confirmed via enzymatic restriction. No mutations have previously been detected in this population. CONCLUSION: The growing number of heterozygous mutations in non-consanguineous pedigrees supports the hypothesis that APL is more common than previously expected.