Increased Pregnancy Loss Rate in Thyroid Antibody Negative Women with TSH Levels between 2.5 and 5.0 in the First Trimester of Pregnancy
ABSTRACT The definition of what constitutes a normal TSH during pregnancy is in flux. Recent studies suggested that the first trimester upper limit of normal for TSH should be 2.5 mIU/liter.
The objective of the study was to evaluate the pregnancy loss and preterm delivery rate in first-trimester thyroid peroxidase antibody-negative women with TSH values between 2.5 and 5.0 mIU/liter.
The present study is a component of a recently published large-scale prospective trial that evaluated the impact of levothyroxine treatment on maternal and neonatal complications in thyroid peroxidase-positive women with TSH levels above 2.5 mIU/liter. The present study evaluated 4123 thyroid peroxidase antibody-negative women with TSH levels at or below 5.0 mIU/liter. Women were divided into two groups based on their initial TSH: group A, TSH level below 2.5 mIU/liter, excluding hyperthyroid women defined as an undetectable TSH with an elevated free T(4), and group B, TSH level between 2.5 and 5.0 mIU/liter.
The study was conducted at two ambulatory clinics of community hospitals in southern Italy.
A total of 4123 women were evaluated.
There was no intervention.
The incidence of pregnancy loss and preterm delivery in group A as compared with group B was measured.
The rate of pregnancy loss was significantly higher in group B as compared with group A (6.1 vs. 3.6% respectively, P = 0.006). There was no difference in the rate of preterm delivery between the two groups.
The increased incidence of pregnancy loss in pregnant women with TSH levels between 2.5 and 5.0 mIU/liter provides strong physiological evidence to support redefining the TSH upper limit of normal in the first trimester to 2.5 mIU/liter.
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- "Both maternal hypothyroidism and hyperthyroidism have been associated with a range of malplacentation disorders such as miscarriage, stillbirth , prematurity, pre-eclampsia and fetal growth restriction (Krassas et al., 2010), leading to increased perinatal morbidity and mortality. Even minor perturbations in maternal thyroid activity have been linked to miscarriage (Negro et al., 2010), preterm delivery and placental abruption (Casey et al., 2005). Increasing delay in achieving euthyroidism in pregnancies complicated by maternal thyroid dysfunction has been correlated with greater obstetric risks (Abalovich et al., 2002; LaFranchi et al., 2005), suggesting that key thyroid-responsive events during fetoplacental development are gestational age-dependent and may not be corrected at a later stage of pregnancy. "
ABSTRACT: Does triiodothyronine (T3) regulate the secretion of angiogenic growth factors and cytokines by human decidual cells isolated from early pregnancy? T3 modulates the secretion of specific angiogenic growth factors and cytokines, with different regulatory patterns observed amongst various isolated subpopulations of human decidual cells and with a distinct change between the first and second trimesters of pregnancy. Maternal thyroid dysfunction during early pregnancy is associated with complications of malplacentation including miscarriage and pre-eclampsia. T3 regulates the proliferation and apoptosis of fetal-derived trophoblasts, as well as promotes the invasive capability of extravillous trophoblasts (EVT). We hypothesize that T3 may also have a direct impact on human maternal-derived decidual cells, which are known to exert paracrine regulation upon trophoblast behaviour and vascular development at the uteroplacental interface. This laboratory-based study used human decidua from first (8-11 weeks; n = 18) and second (12-16 weeks; n = 12) trimester surgical terminations of apparently uncomplicated pregnancies. Primary cultures of total decidual cells, and immunomagnetic bead-isolated populations of stromal-enriched (CD10+) and stromal-depleted (CD10-) cells, uterine natural killer cells (uNK cells; CD56+) and macrophages (CD14+) were assessed for thyroid hormone receptors and transporters by immunocytochemistry. Each cell population was treated with T3 (0, 1, 10, 100 nM) and assessments were made of cell viability (MTT assay) and angiogenic growth factor and cytokine secretion (immunomediated assay). The effect of decidual cell-conditioned media on EVT invasion through Matrigel(®) was evaluated. Immunocytochemistry showed the expression of thyroid hormone transporters (MCT8, MCT10) and receptors (TRα1, TRβ1) required for thyroid hormone-responsiveness in uNK cells and macrophages from the first trimester. The viability of total decidual cells and the different cell isolates were unaffected by T3 so changes in cell numbers could not account for any observed effects. In the first trimester, T3 decreased VEGF-A secretion by total decidual cells (P < 0.05) and increased angiopoietin-2 secretion by stromal-depleted cells (P < 0.05) but in the second trimester total decidual cells showed only increased angiogenin secretion (P < 0.05). In the first trimester, T3 reduced IL-10 secretion by total decidual cells (P < 0.05), and reduced granulocyte macrophage colony stimulating factor (P < 0.01), IL-8 (P < 0.05), IL-10 (P < 0.01), IL-1β (P < 0.05) and monocyte chemotactic protein -1 (P < 0.001) secretion by macrophages, but increased tumour necrosis factor-α secretion by stromal-depleted cells (P < 0.05) and increased IL-6 by uNK cells (P < 0.05). In contrast, in the second trimester T3 increased IL-10 secretion by total decidual cells (P < 0.01) but did not affect cytokine secretion by uNK cells and macrophages. Conditioned media from first trimester T3-treated total decidual cells and macrophages did not alter EVT invasion compared with untreated controls. Thus, treatment of decidual cells with T3 resulted in changes in both angiogenic growth factor and cytokine secretion in a cell type-specific and gestational age-dependent manner, with first trimester decidual macrophages being the most responsive to T3 treatment, but these changes in decidual cell secretome did not affect EVT invasion in vitro. Our results are based on in vitro findings and we cannot be certain if a similar response occurs in human pregnancy in vivo. Optimal maternal thyroid hormone concentrations could play a critical role in maintaining a balanced inflammatory response in early pregnancy to prevent fetal immune rejection and promote normal placental development through the regulation of the secretion of critical cytokines and angiogenic growth factors by human decidual cells. Our data suggest that there is an ontogenically determined regulatory 'switch' in T3 responsiveness between the first and second trimesters, and support the notion that the timely and early correction of maternal thyroid dysfunction is critical in influencing pregnancy outcomes. This study is funded by Wellbeing of Women (RG/1082/09 to S.Y.C., M.D.K., J.A.F., L.S.L., G.E.L.) and Action Medical Research - Henry Smith Charity (SP4335 to M.D.K., S.Y.C., L.S.L., J.A.F.). The authors have no conflicts of interest to disclose.Human Reproduction 03/2014; 29(6). DOI:10.1093/humrep/deu046 · 4.59 Impact Factor
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- "Th ere are many studies with confl icting results in the literature about the possible association of hypothyroidism and positive thyroid autoantibodies as a risk factor for infertility and 1st trimester miscarriage (Abalovich et al. 2002; Negro et al. 2010; "
ABSTRACT: Prevalence of abnormalities in thyroid hormones and thyroid autoantibodies in patients with a history of early pregnancy loss (EPL) (n = 17) and unexplained infertility (UI) (n = 25), were compared with that of 45 control patients. TSH, antithyroid peroxidase (anti-TPO) and antithyroglobulin (anti-TG) antibody levels in UI and EPL groups were similar to that of the control group. TSH was normal in 39, 22 and 13 of control, UI and EPL patients, respectively. Among patients with a normal TSH, fT4 was higher (p < 0.001) and fT3 was lower (p < 0.001) in infertile patients when compared with the control group. Thyroid function tests seem to be associated with infertility but their association with EPL is weaker. Infertility seems to be associated with a high fT4 and low fT3 status. Thyroid autoantibodies do not seem to be associated with either infertility or EPL.Journal of Obstetrics and Gynaecology 11/2013; 33(8):862-4. DOI:10.3109/01443615.2013.817983 · 0.60 Impact Factor
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- "Thyroid peroxidase is an enzyme made in the thyroid gland that is important in the production of thyroid hormone. Subclinical hypothyroid antithyroid peroxidase antibody positive (TPOAb+) women were at higher risk of pregnancy complications and there was a higher miscarriage rate in TPOAb-patients when TSH was above 2.5 mIU/L (Negro et al., 2010a). In contrast, analysis of several cohorts reported no adverse outcomes from subclinical maternal hypothyroidism (Cleary–Goldman et al., 2008; Männistö et al., 2009). "
ABSTRACT: Iodine deficiency is an important nutritional deficiency, with more than 2 billion people worldwide estimated to be at risk. The developing fetus and young children are particularly at risk. During pregnancy and lactation, iodine requirements increase, whether in iodine-poor or iodine-sufficient countries, making the mother and the developing fetus vulnerable. The American Thyroid Association (ATA) recommends 250 micrograms per day of iodine intake for pregnant and lactating women. The thyroid gland is able to adapt to the changes associated with pregnancy as long as sufficient iodine is present. Dietary intake is the sole source of iodine, which is essential to the synthesis of thyroid hormones. Iodine is found in multiple dietary sources including iodized salt, dairy products, seaweed, and fish. Prenatal vitamins containing iodine are a good source of iodine, but iodine content in multivitamin supplements is highly variable. Congenital hypothyroidism is associated with cretinism. Clinical hypothyroidism has been associated with increased risk of poor perinatal outcome including prematurity, low birth weight, miscarriage, preeclampsia, fetal death, and impaired fetal neurocognitive development. Subclinical hypothyroidism is also associated with poor pregnancy outcomes and potential fetal neurocognitive deficits, but the data are more variable than those for clinical hypothyroidism. We concur with the ATA recommendation that all pregnant and lactating women should ingest (through diet and supplements) 250 micrograms of iodine daily. To achieve this goal, we recommend that all pregnant and lactating women take daily iodine supplementation of 150 micrograms. Birth Defects Research (Part A) 94:677-682, 2012. © 2012 Wiley Periodicals, Inc.Birth Defects Research Part A Clinical and Molecular Teratology 09/2012; 94(9):677-82. DOI:10.1002/bdra.23051 · 2.21 Impact Factor