'Non-criteria antiphospholipid antibodies': bridging the gap between seropositive and seronegative antiphospholipid syndrome.

OBJECTIVE: We aimed to analyse the prevalence of non-criteria anti-phospholipid (aPL) antibodies and their role in the diagnosis, treatment and prognosis in a cohort of patients with clinical features consistent with a diagnosis of antiphospholipid syndrome (APS), but persistently negative for criteria aPL - anti-cardiolipin antibodies (aCL), anti-ß2-glycoprotein I antibodies (aß2-GPI) and lupus anticoagulant (LA) - named seronegative APS (SN-APS). METHODS: Sera from SN-APS patients were tested for aCL by TLC-immunostaining, anti-vimentin/cardiolipin (aVim/CL) and anti-phosphatidylserine/prothrombin (anti-PS/PT) by ELISA. Control groups of our study were APS patients and healthy controls. RESULTS: We enrolled 114 consecutive SN-APS patients, 69 (60.5%) resulted positive for at least one non-criteria test in two occasions 12 weeks apart. Among the persistently positive patients to these tests, 97% resulted positive for aCL by TLC-immunostaining, 52.3% for aVim/CL and 17.4% for aPS/PT. SN-APS patients with double positivity (aCL by TLC-immunostaining and aVim/CL) showed a likelihood positive ratio of 8 to present mixed thrombotic and obstetrical features. Among SN-APS patients tested positive, after the therapeutic changes, three cases of recurrent thrombosis were observed [median follow-up 41 months (IQR 39.5)]. Twenty pregnancies were recorded in 17 SN-APS patients after the detection of unconventional aPL and 12 of them (60%) experienced a good outcome under conventional treatment for APS. CONCLUSIONS: This is the largest monocentric study demonstrating that aCL tested by TLC-immunostaining and aVim/CL can detect aPL positivity in SN-APS. It may encourage clinicians to monitor and provide adequate targeted therapy, which improve SN-APS prognosis.

Human Leukocyte Antigen (HLA) Typing Study Identifies Maternal DQ2 Susceptibility Alleles among Infertile Women: Potential Associations with Autoimmunity and Micronutrients.

BACKGROUND: The interplay between female fertility and autoimmune diseases (AIDs) can involve HLA haplotypes and micronutrients. We analyzed the distribution of HLA-DQ2/-DQ8 in women with infertility or recurrent spontaneous abortion (RSA) and possible associations with AIDs and micronutrient status. METHODS: Consecutive women (n = 187) with infertility and RSA, and controls (n = 350) were included. All women were genotyped for HLA-DQ2 (DQA1*0201, A1*05, and B1*02) and -DQ8 (DQA1*03 and DQB1*0302) alleles. Serum 25(OH)D, VB12, folate, and ferritin were evaluated. RESULTS: DQA1*05/B1*02 and the occurrence of at least one DQ2 allele were more prevalent among RSA and infertile women than controls. Infertile women showed lower 25(OH)D and higher prevalence of AIDs than RSA women. In the multivariate analysis, DQA1*05/B1*02 was associated with a significantly higher risk of AIDs in infertile women, and DQA1*05 was independently associated with both 25(OH)D deficiency and AIDs. In RSA women, the presence of AIDs was associated with a significantly higher risk of 25(OH)D deficiency. CONCLUSION: Our findings showed, for the first time, a higher proportion of DQ2 alleles in infertile and RSA women as compared to controls. Predisposing DQ2 alleles are independent risk factors for AIDs and 25(OH)D deficiency in infertile women and could represent biomarkers for performing early detection of women requiring individually tailored management.

Low Preconception Complement Levels Are Associated with Adverse Pregnancy Outcomes in a Multicenter Study of 260 Pregnancies in 197 Women with Antiphospholipid Syndrome or Carriers of Antiphospholipid Antibodies.

Antiphospholipid antibodies (aPL) can induce fetal loss in experimental animal models. Human studies did find hypocomplementemia associated with pregnancy complications in patients with antiphospholipid syndrome (APS), but these results are not unanimously confirmed. To investigate if the detection of low C3/C4 could be considered a risk factor for adverse pregnancy outcomes (APO) in APS and aPL carriers' pregnancies we performed a multicenter study including 503 pregnancies from 11 Italian and 1 Russian centers. Data in women with APS and asymptomatic carriers with persistently positive aPL and preconception complement levels were available for 260 pregnancies. In pregnancies with low preconception C3/C4, a significantly higher prevalence of pregnancy losses was observed (p = 0.008). A subgroup analysis focusing on triple aPL-positive patients found that preconception low C3 and/or C4 levels were associated with an increased rate of pregnancy loss (p = 0.05). Our findings confirm that decreased complement levels before pregnancy are associated with increased risk of APO. This has been seen only in women with triple aPL positivity, indeed single or double positivity does not show this trend. Complement levels are cheap and easy to be measured therefore they could represent a useful aid to identify patients at increased risk of pregnancy loss.

The link between immunity, autoimmunity and endometriosis: a literature update.

Endometriosis (EMS), an estrogen-dependent inflammatory disorder affects approximately 5-10% of the general female population of reproductive age and 20-90% of women with pelvic pain and infertility. Many immunological factors are known to contribute significantly to the pathogenesis and pathophysiology of EMS, and both chronic local inflammation and autoantibodies in EMS shares many similarities with autoimmune diseases (AD). However, the autoimmune etiology in EMS remains controversial, and its evidence on autoimmune basis may be limited. Here we aim to review the current understanding between autoimmunity and EMS to provide important knowledge to develop future potential immunomodulatory therapy for the treatment of EMS.

A Monocentric Cohort of Obstetric Seronegative Anti-Phospholipid Syndrome.

The present study was conducted to diagnose obstetric anti-phospholipid syndrome (OAPS) in patients with clinical signs suggestive of anti-phospholipid syndrome (APS), but persistently negative for conventional anti-phospholipid antibodies (aPL). Sera from 61 obstetrical seronegative APS (SN-APS) patients were analyzed for anti-cardiolipin antibodies (aCL) using thin-layer chromatography (TLC)-immunostaining, for anti-cardiolipin/vimentin antibodies (aCL/Vim), anti-phosphatidylserine/prothrombin antibodies, IgA anti-ß2glycoprotein I antibodies (aß2GPI), and IgA aCL antibodies by enzyme-linked immunosorbent assay. Taken together, our findings show that in 50 out of 61 SN-APS (81.9%) at least one aPL/cofactor antibody was detected using the assays under test. Results revealed that 76% of SN-APS patients resulted positive for aCL by TLC-immunostaining, 54% for aCL/Vim, 12% for aPS/PT, 4% for IgA aß2GPI, and 2% for IgA aCL. Thirty-five out of 61 patients were followed up and the tests were repeated on two occasions, at least 12 weeks apart. Twenty-six out of 35 SN-APS (74.3%) were positive at least one non-conventional test; only 2 patients (5.7%) did not confirm the positivity to the second test. These findings suggest that non-conventional tests, mainly aCL/Vim and aCL detected by TLC-immunostaining, seem to be the most sensitive approaches for finding out aPL in patients with obstetric SN-APS. The use of these tests can be useful for accurate and timely diagnosis of patients with obstetrical APS who are negative for conventional laboratory criteria markers.

Vitamin D deficiency in an Italian cohort of infertile women.

PROBLEM: The purpose of this study was to explore whether vitamin D might be a marker of female primary infertility in association with the presence of autoimmune diseases (ADs). METHODS: The study was a cross-sectional descriptive study in consecutive outpatients of the Polymedical Center for Prevention of Recurrent Spontaneous Abortion (RSA), in Rome, Italy. Women were eligible if they received a diagnosis of primary infertility or RSA. Serum vitamin D, calcium, and PTH were analyzed. RESULTS: Women with primary infertility (n=70) or RSA/non-infertile (n=105) were enrolled; controls (n=250) were included. Infertile women presented lower vitamin D (P=0.03) and higher prevalence of AD (P=0.007) than non-infertile women. In the multivariate analysis, the presence of ADs is associated with higher odds of infertility (OR=2.2), while normal vitamin D was a protective factor (OR=0.9). CONCLUSION: We described that having vitamin D deficiency and suffering from an AD are independent risk factors for women primary infertility. Supplementation of vitamin D might be useful for pregnancy outcome.

Systemic Sclerosis: Exploring the Potential Interplay Between Thyroid Disorders and Pregnancy Outcome in an Italian Cohort.

BACKGROUND: Evidence has shown that pregnancy failure (PF) in women with systemic sclerosis (SSc) consists mainly of preterm delivery (PD) and intrauterine growth restriction (IUGR). Thyroid dysfunction (TD) and Hashimoto's thyroiditis (HT) represent a common feature of SSc. Since TD has been associated with PF, its presence in SSc women may potentially affect pregnancy outcome. OBJECTIVES: To analyze the interplay between TD and PF in a cohort of SSc women. METHODS: SSc women (n=77) and age-matched controls from the general obstetric population (n=50) were included. Clinical/biochemical/instrumental data exploring TD and the visceral involvement were collected in the context of a clinical practice setting. Pregnancy outcome was assessed by registering the history of primary infertility, recurrent spontaneous abortion, PD (≤ 37 gestational week), IUGR, and intrauterine fetal death. RESULTS: A higher prevalence of PD/IUGR was recorded in the SSc cohort than the controls (P = 0.04). SSc women with PF showed a higher prevalence of diffuse SSc than women without PF (P = 0.03). Scl-70 positive SSc women had a higher prevalence of PF than women with anti-centromere positivity (P = 0.01). A higher prevalence of HT was recorded in SSc women with PF than in patients without (P = 0.04). CONCLUSIONS: Our findings support the evidence that women with SSc can have successful pregnancies despite a higher prevalence of PD/IUGR. Diffuse SSc and Scl-70 positivity may predispose SSc women to PF. Routine thyroid workup may be included in the multi-specialist monitoring of SSc women for the early detection of thyroid dysfunctions.

Recurrent Angioedema: Occurrence, Features, and Concomitant Diseases in an Italian Single-Center Study.

BACKGROUND: Angioedema (AE) is a potentially life-threatening condition with hereditary (HAE), acquired (AAE), or iatrogenic causes. A careful workup allows for the identification of the etiology of attacks and the appropriate management. In this cohort study, based on a clinical practice setting, we aimed at investigating clinical and laboratory findings concerning different features of patients with recurrent AE who were referred to a single, tertiary-level center for HAE. METHODS: Clinical and laboratory data of patients fulfilling the criteria for C1-inhibitor-deficient HAE (C1-INH-HAE), C1-INH-AAE, angiotensin-converting enzyme inhibitor-related AE (ACEI-RA), and idiopathic AAE (I-AAE) were evaluated. Descriptive statistics were analyzed by means of the Mann-Whitney U test. The Fisher exact test was used for group comparisons. RESULTS: Patients were diagnosed with type 1 HAE (n = 14), type 2 HAE (n = 1), C1-INH-AAE (n = 8), ACEI-RA (n = 16), or I-AAE (n = 26). We included only patients with concomitant autoimmune diseases from the I-AAE group (n = 8, aut-I-AAE). Age at disease onset and at diagnosis was younger in type 1 HAE than in all the other groups. The diagnostic delay was longer in type 1 HAE than in ACEI-RA. C4 and C1q levels were lower in C1-INH-AAE than in type 1 HAE, ACEI-RA, and aut-I-AAE. Both HAE and C1-INH-AAE showed lower C1-INH antigen and function compared to the other groups. Peripheral attacks were more frequent in type 1 HAE, while airway, abdominal, and oral attacks were prevalent in C1-INH-AAE. CONCLUSION: Investigating the clinical and laboratory features of recurrent AE without wheals represents a major topic for facilitating early diagnosis and improving treatment strategies for this heterogeneous and misdiagnosed condition.

Elevated Serum Level of HMGB1 in Patients with the Antiphospholipid Syndrome.

Pregnancy problems are common in patients with rheumatic disease; indeed, autoimmune disorders and autoantibodies can affect pregnancy progress and lead to maternal complications. Recent studies have highlighted a close association between HMGB1, chronic inflammation, and autoimmune diseases. Thus, in this investigation, we analyzed serum levels of HMGB1, an alarmin which plays a pivotal role in inducing and enhancing immune cell function. Sera from 30 patients with antiphospholipid syndrome (11 primary and 19 secondary APS), 35 subjects with pregnancy morbidity, and 30 healthy women were analysed for HMGB1 and its putative receptor RAGE (sRAGE) by Western blot and for TNF-α by ELISA. Results revealed that APS patients showed significantly increased serum levels of HMGB1, sRAGE, and the proinflammatory cytokine TNF-α, as compared to healthy women. However, also, the pregnancy morbidity subjects showed significantly increased levels of HMGB1 and sRAGE as well as TNF-α compared to healthy women. Our findings suggest that in subjects with pregnancy morbidity, including obstetric APS, elevated levels of HMGB1/sRAGE may represent an alarm signal, indicating an increase of proinflammatory triggers. Further studies are needed to evaluate the role of HMGB1/sRAGE as a possible tool to evaluate the risk stratification of adverse pregnancy outcomes.

Innate Immune System at the Maternal-Fetal Interface: Mechanisms of Disease and Targets of Therapy in Pregnancy Syndromes.

The maternal-fetal interface is an immunologically unique site that allows the tolerance to the allogenic fetus and maintains host defense against possible pathogens. Balanced immune responses are required for the maintenance of successful pregnancy. It has been demonstrated that innate immune disturbances may be responsible for some adverse pregnancy outcomes such as preeclampsia (PE); hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome; intrauterine growth restriction (IUGR); and recurrent spontaneous abortion (RSA). Observational studies suggest that immunomodulatory treatments in pregnancy-specific complications may improve both the hematological/biochemical features in the mother and the perinatal outcomes. The following review will discuss how recent and relevant findings in the field of the innate immunity have advanced our understanding of the role of inflammation and innate immune system in the pathogenesis of pregnancy failure and will discuss the therapeutic outcomes of the existing studies and clinical trials in light of these new insights.

A nationwide survey of hereditary angioedema due to C1 inhibitor deficiency in Italy.

INTRODUCTION: Hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE type I) or dysfunction (C1-INH-HAE type II) is a rare disease characterized by recurrent episodes of edema with an estimated frequency of 1:50,000 in the global population without racial or gender differences. In this study we present the results of a nationwide survey of C1-INH-HAE patients referring to 17 Italian centers, the Italian network for C1-INH-HAE, ITACA. METHODS: Italian patients diagnosed with C1-INH-HAE from 1973 to 2013 were included in the study. Diagnosis of C1-INH-HAE was based on family and/or personal history of recurrent angioedema without urticaria and on antigenic and/or functional C1-INH deficiency. RESULTS: 983 patients (53% female) from 376 unrelated families were included in this survey. Since 1973, 63 (6%) patients diagnosed with C1-INH-HAE died and data from 3 patients were missing when analysis was performed. Accordingly, the minimum prevalence of HAE in Italy in 2013 is 920:59,394,000 inhabitants, equivalent to 1:64,935. Compared to the general population, patients are less represented in the early and late decades of life: men start reducing after the 5(th) decade and women after the 6(th). Median age of patients is 45 (IQ 28-57), median age at diagnosis is 26 years (IQ 13-41). C1-INH-HAE type 1 are 87%, with median age at diagnosis of 25 (13-40); type 2 are 13% with median age at diagnosis of 31 (IQ 16-49). Functional C1INH is ≤50% in 99% of patients. Antigen C1INH is ≤50% in 99% of type 1. C4 is ≤50% in 96% of patients. The chance of having C1-INH-HAE with C4 plasma levels >50% is < 0.05. CONCLUSION: This nationwide survey of C1-INH-HAE provides for Italy a prevalence of 1:64,935. C1-INH-HAE patients listed in our database have a shorter life expectancy than the general population. An increased awareness of the disease is needed to reduce this discrepancy. Measurement of C4 antigen can exclude diagnosis of C1-INH-HAE with an accuracy > 95%. This parameter should be therefore considered for initial screening in differential diagnosis of angioedema.

Prolactin and natural killer cells: evaluating the neuroendocrine-immune axis in women with primary infertility and recurrent spontaneous abortion.

PROBLEM: An association between serum prolactin (PRL) and peripheral blood natural killer (NK) cells has been described in healthy women. We explored for the first time the PRL response to the thyrotrophin-releasing hormone (TRH) test and the association between PRL and NK cells in women with reproductive failure. METHODS: A total of 130 women [31 primary infertility, 69 recurrent spontaneous abortion (RSA), and 30 fertile women] were evaluated by a TRH test to analyze the following: basal PRL (bPRL), peak-time PRL, PRL absolute and relative increase, decline-time PRL. Hyperprolactinaemia (HPRL) was defined as bPRL ≥15 ng/mL. NK cells were characterized by immunophenotyping. RESULTS: Significantly higher bPRL levels were found in the infertile women than in controls. Both the infertile and the RSA women showed significantly elevated NK levels. bPRL levels correlated with NK cells in HPRL-infertile women. CONCLUSIONS: In patients with HPRL, an association between NK cell and bPRL results. The dynamic test in the infertile women would help in the management of the pregnancy impairment.

Neglected primary omental pregnancy after laparoscopic and medical treatment: a difficult diagnosis?

The following case report describes a rare case of omental pregnancy in a fertile 34-year-old woman at 5 + 3 weeks of gestation who presented with abdominal pain. Clinical examination, vital signs, and laboratory values were within normal limits, so the woman was hospitalized and monitored. Laparoscopic exploration was performed according to the preoperative diagnosis of tubal pregnancy, but it showed normal pelvic organs. In view of the growth of the ß-HCG value, a medical approach was attempted, without success. Due to hemodynamic instability, an emergency laparotomy was performed, and it showed an omental pregnancy, confirmed at the pathological examination.

Smell and autoimmunity: a comprehensive review.

The sense of smell is an ancient sensory modality vital for sampling and perceiving the chemical composition of surrounding environments. Olfaction involves a pathway of biochemical and electrophysiological processes, which allows the conversion of molecular information into sensations. Disturbances in the olfactory function have been investigated mainly in neurological/neurodegenerative disorders such as Alzheimer's and Parkinson's diseases; impaired sense of smell has been associated with depressed mood. Only recently, smell capability was tested in other diseases, particularly autoimmune diseases. Shoenfeld and colleagues opened this chapter showing that patients affected with systemic lupus erythematosus (SLE) have disturbances in their olfactory functions and revealed its association with neuropsychiatric manifestations of the disease. This evidence was confirmed in experimental models and replicated in other SLE populations. The connection between autoimmunity and the sense of smell was lately emphasized by studies on patients with Sjögren's syndrome and in patients with other autoimmune/immune-mediated diseases, such as polydermatomyositis, recurrent spontaneous abortion, and hereditary angioedema. Genetic susceptibility and hormonal and environmental factors may play a role in these conditions. Olfactory receptor gene clusters are located in proximity to key locus of susceptibility for autoimmune diseases such as the major histocompatibility complex, suggesting not only a physic linkage, but a functional association. Nonetheless, gender- and hormone-mediated effects are fundamental in the development of autoimmune diseases. The different connections between smell and autoimmunity, genes and hormones may suggest that this is another tessera of a mosaic which is waiting the answer of Oedipus.

Pregnancy and autoimmunity: a common problem.

Successful pregnancy is considered a Th1-Th2 cooperation phenomenon (Th, T-helper), with a predominantly Th2-type lymphocytes response, together with the emerging role of interleukin (IL)-12, IL-15 and IL-18 and of other unidentified soluble factors dependent on natural killer (NK) cells. In the pathogenesis of recurrent spontaneous abortion (RSA), immunological factors have been involved such as decidual cells, complement system, cytokines and genes of the hystocompatibility complex that can determine the success or the failure of a pregnancy. A deeper insight into apparently unexplained RSA shows increasing evidences supporting both alloimmune and autoimmune mechanisms, with autoantibodies playing a major role. The best-characterised pathogenic autoantibodies are anti-phospholipid antibodies, and also other autoantibodies, such as anti-Ro/SSA and anti-La/SSB, have been found to be associated with an increased rate of abortion, poor pregnancy outcome and several other obstetric manifestations. This intriguing mixture has been unveiled only in the last few years with the discovery of novel pathogenic mechanisms that can be targeted in the prevention and treatment of obstetrical complications occurring in the course of an autoimmune disease.

International consensus and practical guidelines on the gynecologic and obstetric management of female patients with hereditary angioedema caused by C1 inhibitor deficiency.

BACKGROUND: There are a limited number of publications on the management of gynecologic/obstetric events in female patients with hereditary angioedema caused by C1 inhibitor deficiency (HAE-C1-INH). OBJECTIVE: We sought to elaborate guidelines for optimizing the management of gynecologic/obstetric events in female patients with HAE-C1-INH. METHODS: A roundtable discussion took place at the 6th C1 Inhibitor Deficiency Workshop (May 2009, Budapest, Hungary). A review of related literature in English was performed. RESULTS: Contraception: Estrogens should be avoided. Barrier methods, intrauterine devices, and progestins can be used. Pregnancy: Attenuated androgens are contraindicated and should be discontinued before attempting conception. Plasma-derived human C1 inhibitor concentrate (pdhC1INH) is preferred for acute treatment, short-term prophylaxis, or long-term prophylaxis. Tranexamic acid or virally inactivated fresh frozen plasma can be used for long-term prophylaxis if human plasma-derived C1-INH is not available. No safety data are available on icatibant, ecallantide, or recombinant human C1-INH (rhC1INH). Parturition: Complications during vaginal delivery are rare. Prophylaxis before labor and delivery might not be clinically indicated, but pdhC1INH therapeutic doses (20 U/kg) should be available. Nevertheless, each case should be treated based on HAE-C1-INH symptoms during pregnancy and previous labors. pdhC1INH prophylaxis is advised before forceps or vacuum extraction or cesarean section. Regional anesthesia is preferred to endotracheal intubation. Breast cancer: Attenuated androgens should be avoided. Antiestrogens can worsen angioedema symptoms. In these cases anastrozole might be an alternative. Other issues addressed include special features of HAE-C1-INH treatment in female patients, genetic counseling, infertility, abortion, lactation, menopause treatment, and endometrial cancer. CONCLUSIONS: A consensus for the management of female patients with HAE-C1-INH is presented.

Urinary phthalate monoesters concentration in couples with infertility problems.

The widespread use of phthalates results in human exposure: phthalates are rapidly metabolized to their respective monoesters and other oxidative products, which are glucuronidated and excreted through the urine and feces. Several in vivo studies showed that some phthalates, in particular diethyl-hexyl phthalate (DEHP), diethyl phthalate (DEP), di(n-butyl)phthalate (DnBP) and n-butylbenzylphthalate (BBzP), are able to interact with the human endocrine system, interfering with the reproduction ability. In this study, 56 couples were recruited from a centre of assisted reproduction. Spot urine samples were collected and five urinary metabolites of the above phthalates were determined using an HPLC/MS/MS analytical method with isotopic dilution. The results were compared with those of 56 couples of parents of one or more children and the statistical analysis revealed a significant difference between the two groups in terms of urinary concentrations of phthalates metabolites. A further step will be the correlation of these results with information on the life styles and working conditions collected through a specifically designed questionnaire.

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.