Chrysoula Dosiou

Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and Postpartum

Pregnancy has a profound impact on the thyroid gland and thyroid function. The gland increases 10% in size during pregnancy in iodine-replete countries and by 20%– 40% in areas of iodine deficiency. Production of thyroxine (T4) and triiodothyronine (T3) increases by 50%, along with a 50% increase in the daily iodine requirement. These physiological changes may result in hypothyroidism in the later stages of pregnancy in iodine-deficient women who were euthyroid in the first trimester. The range of thyrotropin (TSH), under the impact of placental human chorionic gonadotropin (hCG), is decreased throughout pregnancy with the lower normal TSH level in the first trimester being poorly defined and an upper limit of 2.5 mIU/L. Ten percent to 20% of all pregnant women in the first trimester of pregnancy are thyroid peroxidase (TPO) or thyroglobulin (Tg) antibody positive and euthyroid. Sixteen percent of the women who are euthyroid and positive for TPO or Tg antibody in the first trimester will develop a TSH that exceeds 4.0 mIU/L by the third trimester, and 33%–50% of women who are positive for TPO or Tg antibody in the first trimester will develop postpartum thyroiditis. In essence, pregnancy is a stress test for the thyroid, resulting in hypothyroidism in women with limited thyroidal reserve or iodine deficiency, and postpartum thyroiditis in women with underlying Hashimoto’s disease who were euthyroid prior to conception. Knowledge regarding the interaction between the thyroid and pregnancy/the postpartum period is advancing at a rapid pace. Only recently has a TSH of 2.5 mIU/L been accepted as the upper limit of normal for TSH in the first trimester. This has important implications in regards to interpretation of the literature as well as a critical impact for the clinical diagnosis of hypothyroidism. Although it is well accepted that overt hypothyroidism and overt hyperthyroidism have a deleterious impact on pregnancy, studies are now focusing on the potential impact of subclinical hypothyroidism and subclinical hyperthyroidism on maternal and

Decidual Stromal Cell Response to Paracrine Signals from the Trophoblast: Amplification of Immune and Angiogenic Modulators

Abstract During the invasive phase of implantation, trophoblasts and maternal decidual stromal cells secrete products that regulate trophoblast differentiation and migration into the maternal endometrium. Paracrine interactions between the extravillous trophoblast and the maternal decidua are important for successful embryonic implantation, including establishing the placental vasculature, anchoring the placenta to the uterine wall, and promoting the immunoacceptance of the fetal allograph. To our knowledge, global crosstalk between the trophoblast and the decidua has not been elucidated to date, and the present study used a functional genomics approach to investigate these paracrine interactions. Human endometrial stromal cells were decidualized with progesterone and further treated with conditioned media from human trophoblasts (TCM) or, as a control, with control conditioned media (CCM) from nondecidualized stromal cells for 0, 3, and 12 h. Total RNA was isolated and processed for analysis on whole-genome, high-density oligonucleotide arrays containing 54 600 genes. We found that 1374 genes were significantly upregulated and that 3443 genes were significantly downregulated after 12 h of coincubation of stromal cells with TCM, compared to CCM. Among the most upregulated genes were the chemokines CXCL1 (GRO1) and IL8,CXCR4, and other genes involved in the immune response (CCL8 [SCYA8], pentraxin 3 (PTX3), IL6, and interferon-regulated and -related genes) as well as TNFAIP6 (tumor necrosis factor alpha-induced protein 6) and metalloproteinases (MMP1, MMP10, and MMP14). Among the downregulated genes were growth factors, e.g., IGF1, FGF1, TGFB1, and angiopoietin-1, and genes involved in Wnt signaling (WNT4 and FZD). Real-time RT-PCR and ELISAs, as well as immunohistochemical analysis of human placental bed specimens, confirmed these data for representative genes of both up- and downregulated groups. The data demonstrate a significant induction of proinflammatory cytokines and chemokines, as well as angiogenic/static factors in decidualized endometrial stromal cells in response to trophoblast-secreted products. The data suggest that the trophoblast acts to alter the local immune environment of the decidua to facilitate the process of implantation and ensure an enriched cytokine/chemokine environment while limiting the mitotic activity of the stromal cells during the invasive phase of implantation.

Cost-Effectiveness of Universal and Risk-Based Screening for Autoimmune Thyroid Disease in Pregnant Women

CONTEXT Hypothyroidism in pregnancy can lead to adverse maternal and fetal outcomes. Although screening of high-risk women is advocated, universal screening remains controversial. OBJECTIVE The objective of the study was to compare the cost-effectiveness of universal screening of pregnant women for autoimmune thyroid disease (AITD) with screening only high-risk women and with no screening. DESIGN, SETTING, AND PARTICIPANTS A decision-analytic model compared the incremental cost per quality-adjusted life-year (QALY) gained among the following: 1) universal screening, 2) high-risk screening, and 3) no screening. Screening consisted of a first-trimester thyroid-stimulating hormone level and antithyroid peroxidase antibodies. Women with abnormal results underwent further testing and, when indicated, levothyroxine therapy. Randomized controlled trials provided probabilities for adverse obstetrical outcomes. The model accounted for the development of postpartum thyroiditis and overt hypothyroidism. Additional scenarios in which therapy prevented cases of decreased child intelligence quotient were explored. MAIN OUTCOME MEASURES Medical consequences of AITD in pregnancy, QALY, and costs were measured. RESULTS Risk-based screening and universal screening were both cost-effective relative to no screening, with incremental cost-effectiveness ratios (ICERs) of

Screening pregnant women for autoimmune thyroid disease: a cost-effectiveness analysis.

6,753/QALY and

The Immune Environment in Human Endometrium during the Window of Implantation

7,138/QALY, respectively. Universal screening was cost-effective compared with risk-based screening, with an ICER of

Continued Rapid Increase in Thyroid Cancer Incidence in California: Trends by Patient, Tumor, and Neighborhood Characteristics

7,258/QALY. Screening remained cost-effective in various clinical scenarios, including when only overt hypothyroidism was assumed to have adverse obstetrical outcomes. Universal screening was cost-saving in the scenario of untreated maternal hypothyroidism resulting in decreased child intelligence, with levothyroxine therapy being preventive. CONCLUSIONS Universal screening of pregnant women in the first trimester for AITD is cost-effective, not only compared with no screening but also compared with screening of high-risk women.

MANAGEMENT OF ENDOCRINE DISEASE: Isolated maternal hypothyroxinemia during pregnancy: Knowns and unknowns

OBJECTIVE Untreated maternal hypothyroidism during pregnancy can have adverse consequences on maternal health and child intelligence quotient (IQ). Our objective was to examine the cost-effectiveness of screening pregnant women for autoimmune thyroid disease. DESIGN We developed a state-transition Markov model and performed a cost-effectiveness analysis of screening pregnant US women, aged 15-45 years, with no known history of thyroid disease, in the first trimester. METHODS Three strategies were compared: 1) no screening, 2) one-time screening using anti-thyroid peroxidase (anti-TPO) antibodies, and 3) one-time screening using TSH. Screening tests were added to the laboratory tests of the first prenatal visit. Abnormal screening tests were followed by further testing and subsequent thyroxine treatment of hypothyroid women. RESULTS Screening pregnant women in the first trimester using TSH was cost-saving compared with no screening. Screening using anti-TPO antibodies was cost-effective compared with TSH screening with an incremental cost-effectiveness ratio of

Craniosynostosis and risk factors related to thyroid dysfunction.

15,182 per quality-adjusted life year. Screening using TSH remained cost-saving across a wide range of ages at screening, costs of treatment, and probabilities of adverse outcomes. The cost-effectiveness of anti-TPO screening compared with TSH screening was mostly influenced by the probability of diagnosing hypothyroidism in unscreened subjects or subjects with a normal screening test. Screening remained highly cost-effective in scenarios where we assumed no improvement of child IQ outcomes by levothyroxine treatment. CONCLUSION Screening all pregnant women for autoimmune thyroid disease in the first trimester is cost-effective compared with not screening.

Development of prognostic signatures for intermediate-risk papillary thyroid cancer.

Problem:  Changes in the immune environment in the endometrium are believed to be important for successful implantation and maintenance of pregnancy. We have previously investigated global gene profiling in human endometrium during the window of implantation by oligonucleotide microarray technology, and analysis of these data underscore the regulation of a group of immune‐related genes. The present study was therefore conducted to examine the pattern of expression and regulation of these genes including decay accelerating factor (DAF), indoleamine 2,3 dioxygenase (IDO), interleukin‐15 (IL‐15), IL‐15 receptor alpha subunit (IL‐15Rα), interferon regulatory factor‐1 (IRF‐1), lymphotactin (Lpn), natural killer‐associated transcript 2 (NKAT2) and NKG5 in secretory and proliferative human endometrium.

Molecular phenotyping of human endometrium distinguishes menstrual cycle phases and underlying biological processes in normo-ovulatory women.

Background: Thyroid cancer incidence is increasing worldwide. Incorporating 22 years of incidence data through 2009, we extend examination of these trends among a wide array of subgroups defined by patient (age, sex, race/ethnicity, and nativity), tumor (tumor size and stage), and neighborhood (socioeconomic status and residence in ethnic enclaves) characteristics, to identify possible reasons for this increase. Methods: Thyroid cancer incidence data on 10,940 men and 35,147 women were obtained from the California Cancer Registry for 1988–2009. Population data were obtained from the 1990 and 2000 U.S. Census. Incidence rates and 95% confidence intervals (CI) were calculated and incidence trends were evaluated using Joinpoint regression to evaluate the timing and magnitude of change [annual percentage change (APC) and rate ratios]. Results: The incidence of papillary thyroid cancer continues to increase in both men (APC, 5.4; 95% CI, 4.5–6.3 for 1998–2009) and women (APC, 3.8; 95% CI, 3.4–4.2 for 1998–2001 and APC, 6.3; 95% CI, 5.7–6.9 for 2001–2009). Increasing incidence was observed in all subgroups examined. Conclusions: Although some variation in the magnitude or temporality of the increase in thyroid cancer incidence exists across subgroups, the patterns (i) suggest that changes in diagnostic technology alone do not account for the observed trends and (ii) point to the importance of modifiable behavioral, lifestyle, or environmental factors in understanding this epidemic. Impact: Given the dramatic and continued increase in thyroid cancer incidence rates, studies addressing the causes of these trends are critical. Cancer Epidemiol Biomarkers Prev; 23(6); 1067–79. ©2014 AACR.