A practical approach to the management of thyroid dysfunction during pregnancy.

Pregnancy has an important impact on the thyroid gland and its function. Thyroid activity changes as a consequence of the novel physiological state of pregnancy and requires a complex hormonal and metabolic adaptation, which is possible only in the presence of a perfectly functioning thyroid gland. In fact, thyroid function is crucial for the success of the implantation and the progression of pregnancy. Abnormal thyroid function is very common among childbearing age women, explaining the high incidence of thyroid diseases that occur during pregnancy. Aim of this work is to analyze the adaptive events that characterize the thyroid function during pregnancy, exploring their hormonal, metabolic and molecular mechanisms. Moreover, the interpretation of the laboratory data necessary to monitor the thyroid functioning during normal pregnancy or in the presence of thyroid abnormalities will be discussed.

Type and Location of Adenomyosis in Women with Recurrent Pregnancy Loss: A Transvaginal Ultrasonographic Assessment.

The current knowledge on adenomyosis as a risk factor for RPL is very scant. Overall 120 women were included in this retrospective observational study. They were divided in three groups each of which consisted of 40 subjects: Group 1: women with RPL who were diagnosed to have adenomyosis on transvaginal ultrasound (TVS); Group 2: patients with RPL without ultrasonographic findings of adenomyosis; Group 3: patients with ultrasound diagnosis of adenomyosis without RPL and at least one live birth pregnancy. The copresence of endometriosis was also investigated. Among women with RPL, patients with adenomyosis (Group 1) had higher number of pregnancy losses (p = 0.03) and lower age at first pregnancy loss (p = 0.03) than women without adenomyosis (Group 2). Moreover, they had more frequently primary RPL (p = 0.008). Adenomyosis of the inner myometrium was found more frequently (p = 0.04) in patients of Group 1 than in patients of Group 3 in which adenomyosis was mainly in the outer myometrium (p= 0.02). No differences were found in the severity of adenomyosis between these two groups of women. TVS findings for endometriosis were observed more frequently in women with adenomyosis without RPL (Group 3) than in the other two groups of patients. Adenomyosis can be a factor involved in RPL. Differences in adenomyosis localization are associated with different risks for RPL. Patients with RPL should be investigated for the presence of adenomyosis and also for the type and localization of the disease in the different myometrial layers.

Pretreatment with myo-inositol in non polycystic ovary syndrome patients undergoing multiple follicular stimulation for IVF: a pilot study.

BACKGROUND: Aim of this pilot study is to examine the effects of myo-inositol administration on ovarian response and oocytes and embryos quality in non PolyCystic Ovary Syndrome (PCOS) patients undergoing multiple follicular stimulation and in vitro insemination by conventional in vitro fertilization or by intracytoplasmic sperm injection. METHODS: One hundred non-PCOS women aged <40 years and with basal FSH <10 mUI/ml were down-regulated with triptorelin acetate from the mid-luteal phase for 2 weeks, before starting the stimulation protocol for oocytes recovery. All patients received rFSH, at a starting dose of 150 IU for 6 days. The dose was subsequently adjusted according to individual response. Group B (n=50) received myo-inositol and folic acid for 3 months before the stimulation period and then during the stimulation itself. Group A (n-50) received only folic acid as additional treatment in the 3 months before and through treatment. RESULTS: Total length of the stimulation was similar between the two groups. Nevertheless, total amount of gonadotropins used to reach follicular maturation was found significantly lower in group B. In addition, the number of oocytes retrieved was significantly reduced in the group pretreated with myo-inositol. Clinical pregnancy and implantation rate were not significantly different in the two groups. CONCLUSIONS: Our findings suggest that the addition of myo-inositol to folic acid in non PCOS-patients undergoing multiple follicular stimulation for in-vitro fertilization may reduce the numbers of mature oocytes and the dosage of rFSH whilst maintaining clinical pregnancy rate. Further, a trend in favor of increased incidence of implantation in the group pretreated with myo-inositol was apparent in this study. Further investigations are warranted to clarify this pharmacological approach, and the benefit it may hold for patients.

Prediction of early pregnancy maternal thyroid impairment in women affected with unexplained recurrent miscarriage.

BACKGROUND: Proper maternal thyroid function is necessary for a successful pregnancy. In order to identify women who may experience miscarriage due to transient impairment of the pituitary-thyroid axis in early pregnancy, we aimed to investigate the ratio between basal and peak thyroid stimulating hormone (TSH) [following stimulus with thyrotrophin-releasing hormone (TRH)] in euthyroid women with unexplained recurrent miscarriage (RM). METHODS: We have established a 'iTSHa index' (TSH increase after TRH adjusted for the levels of basal TSH), determining TSH serum levels at time 0 and 20 min after TRH stimulus in 463 consecutive women attending two antenatal care units for two or more miscarriages occurring within the first 10 weeks of pregnancy. RESULTS: The mean basal TSH serum levels were higher (P < 0.001) in RM women [2.1 µIU/ml; 95% confidence interval (CI): 2.0-2.2] compared with the controls (1.3 µIU/ml; 95% CI: 1.2-1.4). Establishing serum TSH at an individual level, a large overlap was observed and the receiver operating characteristic curves did not allow us to find an optimal cut-off point with an adequate sensitivity/specificity ratio. Therefore, we suggest a novel statistical model, the 'iTSHa index' (available on www.afar.it/tsh-trh-miscarriage), that is capable of identifying women with RM due to transient thyroid function impairment of the early pregnancy, in particular when baseline serum TSH is less than 1.5 µIU/ml, i.e. well below the conventional upper cut-off indicated as 'safe' in those who want to conceive. CONCLUSIONS: A transient impairment of thyroid function in early pregnancy may cause an inadequate adaptation to the increased thyroid requirement and may be implicated in RM. The evaluation of the proposed iTSHa index, if validated in a larger cohort of patients, may provide information useful to identifying a subset of healthy women, without evidence of thyroid dysfunction or autoimmunity and a TSH in the low-normal reference range, who may be at risk of RM.

IVF pregnancies: neonatal outcomes after the new Italian law on assisted reproduction technology (law 40/2004).

OBJECTIVE: To compare maternal and neonatal outcome of pregnancies achieved by assisted reproduction technique (ART) according to the guidelines of the newly established Italian ART law 40/2004, with that of naturally conceived. DESIGN: Three hundred and sixty-four ART pregnancies and 304 naturally conceived pregnancies were analyzed in terms of the incidence of obstetric complications and perinatal outcome. Control group was enrolled prospectively after being matched for an extensive number of maternal characteristics. RESULTS: Among singletons, ART pregnancies when compared to naturally conceived pregnancies showed a higher incidence of pregnancy loss (23.4% versus 10.5%) and a lower mean birth weight. A higher but not significant incidence of small for gestational age fetuses was observed in ART pregnancies, compared to those from normally conceived pregnancies (7.2% versus 2.7%). Moreover, the ART pregnancies showed a slightly, but nonetheless significantly shorter mean gestational age (38.6 versus 39.3 weeks) and more frequent preterm deliveries (11%) than the control group (2.7%). No difference was found in terms of other obstetric complications such as pregnancy-induced hypertension, gestational diabetes and placental abruption. Neonatal outcome was similar in both groups. CONCLUSION: Although the obstetric outcome among singleton ART pregnancies was good, these patients should be considered obstetric risk cases. The different frequency of complications is not related to maternal age or parity and could be the consequence of infertility or the procedures by which these women conceived. The reasons are, however, unclear and further studies are necessary.

Diagnostic evaluation of women experiencing repeated in vitro fertilization failure.

OBJECTIVE: The aim of the study was to propose a set of tests to clarify the diagnosis of repeated implantation failure in patients undergoing in vitro fertilization (IVF). STUDY DESIGN: Fifty-nine patients with at least two unsuccessful IVF attempts were included in the study. Blood samples were evaluated for the presence of underlying thyroid abnormalities, antiphospholipid antibodies (aPL), increased levels of natural killer cells (NK), inherited thrombophilia and mouse embryo assay factor (MEA-f). The same tests were performed on 20 normal fertile control patients. RESULTS: Seventy-six percent of IVF patients showed at least one abnormal result. This incidence was higher with respect to that found among control patients (45%). The prevalence of thyroid abnormalities, aPL and increased NK level was higher in IVF patients whereas no differences were observed in terms of prevalence of inherited thrombophilias and MEA-f. CONCLUSIONS: A better understanding of reproductive failure mechanisms should allow an effective diagnostic flow chart and a focused therapeutic option for patients experiencing repeated IVF failure. With this objective in mind, our data provide two important results: thyroid abnormalities, aPL and increased NK levels are more prevalent in women experiencing IVF failure. No evidence was found for an association between inherited thrombophilia and MEA-f and failure to achieve pregnancy after IVF.

Uterine junctional zone at three-dimensional transvaginal ultrasonography in patients with recurrent miscarriage: a new diagnostic tool?

OBJECTIVE: To evaluate the characteristics of the uterine junctional zone (JZ) by three-dimensional (3D) transvaginal sonography (TVS) in women with recurrent miscarriage (RM) as compared to normal fertile controls. STUDY DESIGN: The thickness and the morphology of the JZ were evaluated in 75 women with a history of RM due to different causes and in 20 fertile women without a history of miscarriages or pelvic disease. All patients included in the study were selected among those who attended the outpatient clinic of "Tor Vergata" University. The JZ characteristics were evaluated in the midluteal phase of the cycle on the uterine coronal section obtained by 3D TVS. RESULTS: Patients with RM showed a JZ maximum thickness significantly increased when compared to that observed in control group (5.8±0.7 vs. 5.0±1.1mm). When grouped according to the different causes of RM, all groups of patients with RM showed an increased JZ thickness when compared to fertile women, with the exception of those with anti-phospholipid antibody syndrome, probably due to the small number of cases with this pathology. CONCLUSIONS: A thickened JZ could be an independent indicator of the risk of miscarriage and may represent an important contributing factor to some causes of RM. These observations may offer new perspectives for the screening and treatment of patients with RM. Although further studies are needed to ascertain if the reduction of the JZ thickness can determine a better pregnancy outcome, 3D TVS evaluation of the JZ could provide the opportunity to identify women in which appropriate therapeutic protocols can improve the possibility of successful pregnancy.

GSTO1 uncommon genetic variants are associated with recurrent miscarriage risk.

OBJECTIVE: To explore the role of the GSTO1 gene in the pathogenesis of recurrent miscarriage (RM). DESIGN: Genetic association study. SETTING: Rome, Italy. PATIENT(S): 123 women with RM and 130 women without pregnancy complications. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Genotyping of two single nucleotide polymorphisms (A140D and E208K) and a 3-bp deletion (E155del) of the GSTO1 gene. RESULT(S): We found a statistically significant association between GSTO1*E208K variants and RM risk. Specifically, we identified this uncommon genetic variant only in women with RM. None of the women with physiologic pregnancies were carriers of K208 allele. CONCLUSION(S): GSTO1 has a role in detoxification metabolism, and we hypothesize that a functional variation of GSTO1 is a RM risk factor that interacts with environmental conditions.

Further evidence on the role of thyroid autoimmunity in women with recurrent miscarriage.

It has been twenty years since the first paper reporting the association between thyroid antibodies (TAIs) and spontaneous miscarriage was published. Following this observation, several studies have clearly demonstrated an increased prevalence of TAI in patients with recurrent miscarriage (RM). However, the exact mechanism underlying this association remains a matter of debate. The aim of the present study was to evaluate the thyroid function, throughout a specific test, in patient with RM and TAI focusing on the hypothesis that TAI should be an indirect sign of a mild thyroid dysfunction. 46 patients with RM and TAI were included in the study. All patients underwent short TRH stimulation test showing an abnormal response in the vast majority of cases (65%). Normal FT4 and FT3 mean values were found whereas TSH values were in the upper normal range (2.64 ± 1.3 mUI/L). Our data support the hypothesis that in patients with RM the presence of TAI is an indirect sign of a subtle thyroid dysfunction detectable by a specific test. This test give the possibility to identify women with RM in which specific therapeutic approaches could effectively improve the possibility for a successful pregnancy.

[Effect of cinacalcet on parathyroid hormone level in hypercalcemic hyperparathyroidism of patients with renal transplantation]. / Efecto de cinacalcet sobre la hormona paratiroidea en el hiperparatiroidismo hipercalcémico del trasplantado renal.

BACKGROUND AND OBJECTIVES: Cinacalcet reduces parathyroid hormone (PTH) levels in uremic hyperparathyroidism (HPT), and in renal transplantation it is useful in the management of HPT with hypercalcemia. Our main aim is to evaluate if cinacalcet administered once daily, reduces and maintains reduced PTH levels for 24 hours in renal transplant recipients with HPT and hypercalcemia. PATIENTS AND METHOD: We studied PTH levels and other bone biomarkers in two groups of renal transplant recipients: one with HPT and hypercalcemia (Group 1), another without alteration of mineral metabolism (Group 2), and a third group of healthy volunteers (Group 3): 35 subjets. Group 1 received a single dose of 60 mg of cinacalcet at 9 am. In all the groups we withdrew blood samples at 8, 10, 11, 12, 13, 19 hours (day 1) and 9 am the following day (day 2), determining levels of PTH and bone biomarkers. RESULTS: In Group 1, basal PTH levels decreased shortly after dispensing cinacalcet (basal PTH level 237 [86.7] versus 10 hour level 113 [54.7] p<0.05), objectifying a progressive increase to a similar level to baseline after 24 hours of the administration (day 2 9h PTH level 241 [117.4] ns). In Group 2, comparisons among PTH mean levels were not different at any time. In Group 3, the mean baseline PTH level was higher than that observed at 10h (47 [22.7] versus 28 [11.2] p<0.05) and other comparisons were not significant. Beta-ctx was higher at baseline in the three groups in comparison with levels at 11, 12, 13 and 19 hour, and similar to that at 10 am on day 1 and 9 am on day 2. With respect to other bone biomarkers, no differences were observed. CONCLUSION: Cinacalcet administered once daily reduces PTH in renal transplant recipients with HPT and hypercalcemia, without holding it for 24 hours.

Glutathione S-transferase genes and the risk of recurrent miscarriage in Italian women.

OBJECTIVE: To investigate the role of glutathione S-transferases (GSTs) in the pathogenesis of recurrent miscarriage (RM). DESIGN: Genetic association study. SETTING: University of Rome, Tor Vergata and San Giovanni Calibita, Fatebenefratelli Hospital. PATIENT(S): One hundred twenty-one women with RM and 113 women without pregnancy complications. INTERVENTION(S): Genomic DNA extracted from buccal cells and screening of positive/null genotypes of GSTM1 and GSTT1 genes and single nucleotide polymorphisms of GSTA1, GSTO2, and GSTP1 genes. MAIN OUTCOME MEASURE(S): Occurrence of GST polymorphisms. RESULT(S): Women with at least one GSTA1*-69T allele are more frequent in the RM group than in the control group: 67% vs. 48%, respectively. Significant outcomes were obtained considering different genetic models: codominant, dominant, and log-additive. In addition, the combined analysis suggests that GSTA1 and GSTM1 variants have a significant interaction in RM risk. CONCLUSION(S): Our study highlighted a significant association between the GSTA1 gene and an increased risk of RM. In particular, the -69T allele in the GSTA1 gene may be considered as a predisposing factor of RM.

Low-dose aspirin and omega-3 fatty acids improve uterine artery blood flow velocity in women with recurrent miscarriage due to impaired uterine perfusion.

OBJECTIVE: To determine the effect of different therapeutic approaches on uterine artery blood flow in women with recurrent miscarriage (RM) and impaired uterine perfusion. DESIGN: Prospective, randomized study. SETTING: Department of Obstetrics and Gynecology, University of Rome "Tor Vergata," Italy. PATIENT(S): Sixty women with unexplained RM and impaired uterine perfusion. INTERVENTION(S): Patients were randomly assigned to three different therapeutic regimens: 20 patients received a daily dose of 100 mg of aspirin (LDA); 20 patients were treated with omega-3 fatty acids (Omega(3)), 4 g daily; and 20 patients received LDA plus Omega(3). MAIN OUTCOME MEASURE(S): Doppler measurement of uterine artery pulsatility index (PI) was performed, in the midluteal phase of the cycle, before and after 2 months of therapy. RESULT(S): All therapeutic regimens induced an improvement in uterine perfusion with a significant reduction of uterine artery PI values. LDA alone or in combination with Omega(3) was found to achieve the highest improvement of uterine blood flow. Omega-3 supplementation was less effective, as reflected by the lower PI values. CONCLUSION(S): LDA and Omega(3) are effective in improving uterine artery blood flow velocity in women with RM due to abnormal uterine perfusion. Further studies are needed to determine whether the improvement of uterine perfusion may lead to a better pregnancy outcome.

Midluteal phase Doppler assessment of uterine artery blood flow in nonpregnant women having a history of recurrent spontaneous abortions: correlation to different etiologies.

OBJECTIVE: To compare the impedance to uterine artery blood flow, during the midluteal phase, in women with recurrent spontaneous abortion (RSA) as compared to normal fertile controls. DESIGN: A prospective study involving women with a history of RSA and fertile controls. SETTING: University of Rome "Tor Vergata." PATIENT(S): Two hundred thirty women with RSA and 50 fertile controls referred for routine examination. INTERVENTION(S): Transvaginal Doppler examination of uterine arteries during the midluteal phase of untreated cycles. MAIN OUTCOME MEASURE(S): The mean pulsatility index (PI) of uterine arteries. RESULT(S): Uterine arteries PI values in RSA patients (2.42 +/- 0.79) were significantly higher with respect to those found in the control group (2.08 +/- 0.47). When patients were grouped according to the different RSA causes, the highest PI values were found among patients with uterine abnormalities (2.82 +/- 1.0), antiphospholipid antibodies syndrome (2.70 +/- 1.1), and unexplained RSA (2.60 +/- 0.7). These values were significantly higher with respect to that found in the control group. No differences were observed in PI values between fertile patients and those with RSA due to thyroid abnormalities (2.10 +/- 0.55), inherited thrombophilia (2.03 +/- 0.45), autoimmune pathology (2.34 +/- 1.18), and genetic anomalies (2.47 +/- 0.54). Similar results were observed when patients were grouped according to primary and secondary RSA. CONCLUSION(S): Increased resistance to uterine blood flow may be an important contributing factor to some causes of RSA and may represent an independent indication of the risk of pregnancy loss.

Hysteroscopic metroplasty improves gestational outcome in women with recurrent spontaneous abortion.

STUDY OBJECTIVE: To compare the reproductive outcome in women with recurrent spontaneous abortion (RSA) associated with septate uterus after hysteroscopic metroplasty compared with patients who did not undergo surgery. DESIGN: Longitudinal evaluation (Canadian Task Force classification II-2). SETTING: University of Rome, Tor Vergata-affiliated endoscopic unit. PATIENTS: Forty-eight consecutive women with septate uterus and RSA were enrolled in the study. INTERVENTIONS: Hysteroscopic metroplasty. MEASUREMENTS AND MAIN RESULTS: Reproductive outcome in terms of term pregnancy was significantly improved after hysteroscopic metroplasty compared with controls (76% vs. 20%). No differences were found in the prevalence of preterm delivery between groups (4% vs. 5%). CONCLUSION: Our data suggest that hysteroscopic septum incision can improve pregnancy outcome in patients with RSA associated with septate uterus.

Efecto de cinacalcet sobre la hormona paratiroidea en el hiperparatiroidismo hipercalcémico del trasplantado renal / Effect of cinacalcet on parathyroid hormone level in hypercalcemic hyperparathyroidism of patients with renal transplantation

Fundamento y objetivo: Cinacalcet reduce la hormona paratiroidea (PTH) en el hiperparatiroidismo (HPT) urémico. En el trasplante renal ayuda al manejo del HPT con hipercalcemia. Pretendemos valorar si cinacalcet, administrado en dosis única diaria, reduce y mantiene descendido el valor de PTH durante 24 horas en el trasplantado renal con HPT e hipercalcemia. Pacientes y método: Estudiamos la PTH y otros biomarcadores óseos en dos grupos de trasplantados renales: uno con HPT e hipercalcemia (Grupo 1), otro sin alteración del metabolismo mineral (Grupo 2), y un tercer grupo de voluntarios sanos (Grupo 3). En total se incluyeron 35 sujetos. El Grupo 1 recibió cinacalcet a dosis de 60mg vía oral en dosis única a las 9 horas. A todos se les extrajeron muestras de sangre a las 8, 10, 11, 12, 13, 19 horas (día 1) y 9 horas del día siguiente (día 2), determinando valores de PTH y biomarcadores óseos. Resultados: En el Grupo 1, el valor basal de PTH descendió de forma significativa en los instantes posteriores, observando un valor similar en el día 2. En el Grupo 2, la PTH basal fue superior respecto al valor 10h (p<0,05). En el Grupo 3, los valores medios de PTH fueron semejantes entre instantes. Beta-ctx fue superior en el nivel basal en los tres grupos respecto a los instantes 11, 12, 13 y 19 horas, y semejante en el instante 10h del día 1 y 9h del día 2. Sobre otros biomarcadores óseos no hubo variaciones.Conclusiones: Cinacalcet reduce la PTH en trasplantados renales con HPT e hipercalcemia, sin matenerlo durante 24 horas, y no modifica otros biomarcadores óseos (AU)

Background and objectives: Cinacalcet reduces parathyroid hormone (PTH) levels in uremic hyperparathyroidism (HPT), and in renal transplantation it is useful in the management of HPT with hypercalcemia. Our main aim is to evaluate if cinacalcet administered once daily, reduces and maintains reduced PTH levels for 24hours in renal transplant recipients with HPT and hypercalcemia. Patients and method: We studied PTH levels and other bone biomarkers in two groups of renal transplant recipients: one with HPT and hypercalcemia (Group 1), another without alteration of mineral metabolism (Group 2), and a third group of healthy volunteers (Group 3): 35 subjets. Group 1 received a single dose of 60mg of cinacalcet at 9 am. In all the groups we withdrew blood samples at 8, 10, 11, 12, 13, 19hours (day 1) and 9 am the following day (day 2), determining levels of PTH and bone biomarkers. Results: In Group 1, basal PTH levels decreased shortly after dispensing cinacalcet (basal PTH level 237 [86.7] versus 10 hour level 113 [54.7] p<0.05), objectifying a progressive increase to a similar level to baseline after 24hours of the administration (day 2 9h PTH level 241 [117.4] ns). In Group 2, comparisons among PTH mean levels were not different at any time. In Group 3, the mean baseline PTH level was higher than that observed at 10h (47 [22.7] versus 28 [11.2] p<0.05) and other comparisons were not significant. Beta-ctx was higher at baseline in the three groups in comparison with levels at 11, 12, 13 and 19 hour, and similar to that at 10 am on day 1 and 9 am on day 2. With respect to other bone biomarkers, no differences were observed. Conclusion: Cinacalcet administered once daily reduces PTH in renal transplant recipients with HPT and hypercalcemia, without holding it for 24hours