Sex differences in neuromuscular and biological determinants of isometric maximal force.

AIM: Force expression is characterized by an interplay of biological and molecular determinants that are expected to differentiate males and females in terms of maximal performance. These include muscle characteristics (muscle size, fiber type, contractility), neuromuscular regulation (central and peripheral factors of force expression), and individual genetic factors (miRNAs and gene/protein expression). This research aims to comprehensively assess these physiological variables and their role as determinants of maximal force difference between sexes. METHODS: Experimental evaluations include neuromuscular components of isometric contraction, intrinsic muscle characteristics (proteins and fiber type), and some biomarkers associated with muscle function (circulating miRNAs and gut microbiome) in 12 young and healthy males and 12 females. RESULTS: Male strength superiority appears to stem primarily from muscle size while muscle fiber-type distribution plays a crucial role in contractile properties. Moderate-to-strong pooled correlations between these muscle parameters were established with specific circulating miRNAs, as well as muscle and plasma proteins. CONCLUSION: Muscle size is crucial in explaining the differences in maximal voluntary isometric force generation between males and females with similar fiber type distribution. Potential physiological mechanisms are seen from associations between maximal force, skeletal muscle contractile properties, and biological markers.

Association analysis of 10 candidate genes causing Mendelian calcium nephrolithiasis in the INCIPE study: a South European general population cohort.

Background: Idiopathic calcium nephrolithiasis (ICN) is a common condition with a complex phenotype influenced by both environmental and genetic factors. In our study we investigated the association of allelic variants with the history of nephrolithiasis. Methods: We genotyped and selected 10 candidate genes potentially related to ICN from 3046 subjects participating in the INCIPE survey cohort (Initiative on Nephropathy, of relevance to public health, which is Chronic, possibly in its Initial stages, and carries a Potential risk of major clinical End-points), a study enrolling subjects from the general population in the Veneto region in Italy. Results: Overall, 66 224 variants mapping on the 10 candidate genes were studied. A total of 69 and 18 variants in INCIPE-1 and INCIPE-2, respectively, were significantly associated with stone history (SH). Only two variants, rs36106327 (chr20:54 171 755, intron variant) and rs35792925 (chr20:54 173 157, intron variant) of the CYP24A1 gene were observed to be consistently associated with ICN. Neither variant has been previously reported in association with renal stones or other conditions. Carriers of CYP24A1 variants showed a significant increase in the ratio of 1,25 (OH)2 vitamin D to 25 (OH) vitamin D compared with controls (P = .043). Although not associated with ICN in this study, the rs4811494 CYP24A1 variant that was reported to be causative of nephrolithiasis was very prevalent in heterozygosity (20%). Conclusion: Our data suggest a possible role for CYP24A1 variants in the risk of nephrolithiasis. Genetic validation studies in larger sample sets will be necessary to confirm our findings.

Increased Prevalence of Unstable HLA-C Variants in HIV-1 Rapid-Progressor Patients.

HIV-1 infection in the absence of treatment results in progression toward AIDS. Host genetic factors play a role in HIV-1 pathogenesis, but complete knowledge is not yet available. Since less-expressed HLA-C variants are associated with poor HIV-1 control and unstable HLA-C variants are associated with higher HIV-1 infectivity, we investigated whether there was a correlation between the different stages of HIV-1 progression and the presence of specific HLA-C allotypes. HLA-C genotyping was performed using allele-specific PCR by analyzing a treatment-naïve cohort of 96 HIV-1-infected patients from multicentric cohorts in the USA, Canada, and Brazil. HIV-1-positive subjects were classified according to their different disease progression status as progressors (Ps, n = 48), long-term non-progressors (LTNPs, n = 37), and elite controllers (ECs, n = 11). HLA-C variants were classified as stable or unstable according to their binding stability to ß2-microglobulin/peptide complex. Our results showed a significant correlation between rapid progression to AIDS and the presence of two or one unstable HLA-C variants (p-value: 0.0078, p-value: 0.0143, respectively). These findings strongly suggest a link between unstable HLA-C variants both at genotype and at allele levels and rapid progression to AIDS. This work provides further insights into the impact of host genetic factors on AIDS progression.

Rehabilitation and Biomarkers of Stroke Recovery: Study Protocol for a Randomized Controlled Trial.

Background: Stroke is a leading cause of disability. Nonetheless, the care pathway for stroke rehabilitation takes partially into account the needs of chronic patients. This is due in part to the lack of evidence about the mechanisms of recovery after stroke, together with the poor knowledge of related and influencing factors. Here we report on the study protocol "Rehabilitation and Biomarkers of Stroke Recovery," which consists of 7 work-packages and mainly aim to investigate the effects of long-term neurorehabilitation on stroke patients and to define a related profile of (clinical-biological, imaging, neurophysiological, and genetic-molecular) biomarkers of long-term recovery after stroke. The work-package 1 will represent the main part of this protocol and aims to compare the long-term effects of intensive self-rehabilitation vs. usual (rehabilitation) care for stroke. Methods: We planned to include a total of 134 adult subacute stroke patients (no more than 3 months since onset) suffering from multidomain disability as a consequence of first-ever unilateral ischemic stroke. Eligible participants will be randomly assigned to one of the following groups: intensive self-rehabilitation (based on the principles of "Guided Self-Rehabilitation Contract") vs. usual care (routine practice). Treatment will last 1 year, and patients will be evaluated every 3 months according to their clinical presentation. The following outcomes will be considered in the main work-package: Fugl-Meyer assessment, Cognitive Oxford Screen Barthel Index, structural and functional neuroimaging, cortical excitability, and motor and somatosensory evoked potentials. Discussion: This trial will deal with the effects of an intensive self-management rehabilitation protocol and a related set of biomarkers. It will also investigate the role of training intensity on long-term recovery after stroke. In addition, it will define a set of biomarkers related to post-stroke recovery and neurorehabilitation outcome in order to detect patients with greater potential and define long-term individualized rehabilitation programs. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT04323501.

Maternal and fetal Leptin and interleukin 33 concentrations in pregnancy complicated by obesity and preeclampsia.

Objectives: To evaluate maternal and fetal Leptin and IL33 concentrations in pregnancy complicated by obesity and preeclampsia.Study design: A case-control study including 35 subjects with obesity (18 normotensive and 17 preeclamptic) and 47 normal weight controls (42 normotensive and 5 preeclamptic).Main outcome measures: Leptin and IL33 concentrations in maternal serum during pregnancy and in cord blood; uterine artery and umbilical artery Doppler velocimetry.Results: Subjects with obesity who developed preeclampsia had higher first trimester maternal (41.5, interquartile range (IQR) = 15.7-65.1 ng/ml) Leptin concentrations compared to either normal weight with (25, IQR = 20.4-25.8 ng/ml) and without hypertension (14.26, IQR = 8.2-22.8) (p < .05) or normotensive subjects with obesity (30.3, IQR = 10.4-38.4) (p < .05). Subjects with obesity who developed preeclampsia (2.4, IQR = 1.7-3.2 pg/ml) or not (1.4, IQR = 0.8-2 pg/ml) had lower first trimester maternal IL33 levels when compared to controls without hypertension (4.8, IQR = 2.9-5.9 pg/ml) (p < .001). Cord blood Leptin and IL33 concentrations were significantly correlated to third trimester maternal concentrations (Spearman rho = 0.51, p < .001 and Spearman rho = 0.68, p < .001, respectively). Uterine artery pulsatility index (PI) were significantly and directly correlated with maternal Leptin levels (p < .002) and inversely and statistically correlated with maternal IL33 concentrations (p < .001).Conclusions: Compared to lean controls, pregnant subjects with obesity had higher serum Leptin and lower IL33 concentrations at first trimester and during pregnancy. This difference persisted also for those who later developed preeclampsia. The relationship between maternal serum levels of Leptin and IL33 with uterine artery Doppler pulsatility index strongly suggests a role of these two markers in early placentation.

Vaginal development and sexual functioning in young women after stem cell transplantation, chemotherapy, and/or radiotherapy for childhood hematological diseases.

To study vaginal development and sexual functioning in young women after childhood hemopoietic stem cell transplantation (HSCT) and radio/chemotherapy. Observational case-control study on 30 young sexually active women survived after HSCT and/or radio/chemotherapy for childhood malignancies or hematologic diseases and 48 controls matched for age. Female Sexual Function Index was lower (median 24.05, IQR = 17.30-28.30 vs. 29.00, IQR = 25.30-31.40, p = 0.001), Female Sexual Distress Scale higher (median 16.00, IQR = 8.00-23.00 vs. 2.00, IQR = 0.00-4.00, p < 0.001), vaginal length shorter (mean difference = 21.1 mm; 95% CI = 19.3-23, p < .001) and vaginal maturation index worst in cases than in controls. Subjects treated by irradiation before HSCT had lower FSFI (median 21.85, IQR = 9.60-31.10 vs. 24.90, IQR = 17.30-28.30) and shorter vaginal length (median 45.55, IQR = 42.60-45.80 vs. 50.10, IQR = 45.30-52.90) compared to those who had not received conditioning treatment (p-values = 0.004 and p = 0.05, respectively). Compared to untreated subjects, women receiving hormonal replacement therapy had higher overall FSFI (p = 0.02), lower FSDS (0.04), and better VMI. Gonadotoxic therapies have adverse effects on vaginal development, sexual functioning, and distress in young females. Hormonal replacement therapy should be shortly considered after main gonodatoxic treatments to improve vaginal and sex health.

Mild-to-moderate foeto-maternal haemorrhage in the third trimester and at term of pregnancy: quantitative determination and clinical-diagnostic evaluation.

BACKGROUND: Foeto-maternal haemorrhage (FMH), a gestational event that occurs before or during delivery, consists of a loss of foetal blood into the maternal circulation. FMH occurs more frequently during the third trimester or labour both in normal and complicated pregnancies. In the case of alloimmunisation, the maternal immunological response and the severity of the resulting foetal or neonatal disease depend on the amount of foetal blood that passes into the maternal circulation. The aim of this study was to determine FMH in the third trimester and at term of pregnancy and to evaluate the role of clinical and ultrasound markers in the prediction of FMH. MATERIALS AND METHODS: FMH was quantified by cytofluorimetric testing at 28 to 35 weeks of gestation in 223 women and at term in 465 women, all with risk factors. Foetal evaluation included foetal movement profile, middle cerebral artery peak velocity of systolic blood flow (MCA-PSV) and cardiotocographic monitoring. RESULTS: All women tested negative for FMH in the third trimester. Four patients (0.9%) tested positive at term, with estimated volumes of bleeding of 2.2, 8.1, 12.3 and 39.8 mL. Three FMH cases (75%) had a non-reassuring cardiotocography compared to 8.9% (42/461) of women without FMH (p=0.003) and two FMH cases reported a reduction in foetal movements reduction compared to four of those without FMH (p=0.001). Mean MCA-PSV was normal in both the groups with and without FMH (p=0.22). DISCUSSION: FMH is rare in pregnancy and at term. Cytofluorimetric testing is a specific method to detect mild-to-moderate FMH even when the MCA-PSV is not informative. Mild-to-moderate FMH is significantly associated with reduced foetal movements and non-reassuring cardiotocographic monitoring.

The Immunosignature of Mother/Fetus Couples in Gestational Diabetes Mellitus: Role of HLA-G 14 bp ins/del and PAPP-A A/C Polymorphisms in the Uterine Inflammatory Milieu.

We enrolled 151 healthy mother/newborn couples and 26 with gestational diabetes mellitus (GDM). HLA-G and PAPP-A plasma levels were measured by ELISA at first and second trimesters, at delivery, and in cord blood. HLA-G 14 bp ins/del and PAPP-A A/C polymorphisms were genotyped. HLA-G del/del and PAPP-A C/C genotypes were more frequent among GDM mothers than controls. We observed a genetic epistasis between the two polymorphisms: the HLA-G del/del and PAPP-A C/C combination was carried by 8% of GDM mothers and 1.3% of controls (OR = 9.5, 95% CI = 0.8-109, p = 0.07). GDM mothers showed increased sHLA-G levels compared to controls (p = 0.004), and those carrying the HLA-G del/del genotype produced more sHLA-G at the second trimester and at delivery (p = 0.014). A genetic pressure by fetal genotype on maternal sHLA-G production was observed in GDM mothers with heterozygous HLA-G del/ins newborns (p = 0.02). Babies born to GDM mothers showed higher sHLA-G concentrations compared to those born to healthy mothers, and those carrying HLA-G del/del showed the highest sHLA-G levels (p = 0.013). PAPP-A amounts significantly increased along pregnancy (p < 0.001), but the median levels at the first and second trimesters were significantly lower in GDM (p = 0.03). Our findings first suggest an involvement of HLA-G and PAPP-A gene-protein interaction in GDM and highlight a possible contribution of the fetus in balancing maternal inflammation.

Soluble HLA-G concentrations in obese women during pregnancy and in cord blood.

CONTEXT: Little is known about soluble HLA-G (sHLA-G) concentrations in obese pregnant women with uncomplicated pregnancies. OBJECTIVE: To investigate the role of sHLA-G in obese pregnancies. DESIGN: Case-control study, from 2013 to 2015. SETTING: A tertiary care centre. PATIENTS: 168 healthy normal weight women and 59 overweight/obese women; to avoid the effect of preeclampsia on sHLA-G concentrations, cases were further divided in two groups: 42 with normotensive pregnancy and 17 who developed preeclampsia. INTERVENTIONS: all the women enrolled received standard antenatal care and plasma sample collections were performed. MAIN OUTCOME MEASURES: sHLA-G concentrations during pregnancy, before delivery and in cord blood. RESULTS: Maternal sHLA-G concentrations in overweight/obese with normotensive pregnancies increased by 14.7% (IQR=-26.4 to +89.6) in the 2nd trimester and by 19.6% (IQR=-33 to +104) before delivery and were significantly higher than in controls (p=0.024). Median cord blood sHLA-G concentrations were 53.5ng/ml (IQR=36-62.7) in the overweight/obese women with uncomplicated pregnancies (p<0.001 compared to controls) and 19.7ng/ml (IQR=7.5-36.3) in controls. Maternal concentrations of sHLA-G in the two trimesters and before delivery were significantly lower among subjects who developed preeclampsia than in controls (p<0.001) or in obese subjects with normotensive pregnancies (p<0.001). CONCLUSIONS: sHLA-G concentratons are higher in normotensive overweight/obese women and their babies while lower in preeclamptic overweight/obese women and their cords. Obesity influences maternal and fetal sHLA-G concentrations during pregnancy, to optimize the reproductive success, while preeclampsia impairs the mother-offspring antinflammatory response.

The impact of unrecognized autoimmune rheumatic diseases on the incidence of preeclampsia and fetal growth restriction: a longitudinal cohort study.

BACKGROUND: The burden of pregnancy complications associated with well defined, already established systemic rheumatic diseases preexisting pregnancy such as rheumatoid arthritis, systemic lupus erythematosus or scleroderma is well known. Systemic rheumatic diseases are characterized by a long natural history with few symptoms, an undifferentiated picture or a remitting course making difficult a timely diagnosis. It has been suggested that screening measures for these diseases could be useful but the impact of unrecognized systemic rheumatic disorders on pregnancy outcome is unknown. The objective of the study was to evaluate the impact of previously unrecognized systemic autoimmune rheumatic on the incidence of preeclampsia and fetal growth restriction (FGR). METHODS: A longitudinal cohort-study with enrolment during the first trimester of pregnancy of women attending routine antenatal care using a two-step approach with a self-reported questionnaire, autoantibody detection and clinical evaluation of antibody-positive subjects. The incidence of FGR and preeclampsia in subjects with newly diagnosed rheumatic diseases was compared to that of selected negative controls adjusting for potential confounders by logistic regression analysis. RESULTS: The prevalence of previously unrecognized systemic rheumatic diseases was 0.4 % for rheumatoid arthritis (19/5232), 0.25 % (13/5232) for systemic lupus erythematosus, 0.31 % (16/5232) for Sjögren's syndrome, 0.3 % for primary antiphospholipid syndrome (14/5232) and 0.11 % (6/5232) for other miscellaneous diseases. Undifferentiated connective tissue disease was diagnosed in an additional 131 subjects (2.5 %). The incidence of either FGR or preeclampsia was 6.1 % (36/594) among controls and 25.3 % (50/198) in subjects with unrecognized rheumatic diseases (excess incidence = 3.9 % (95 % CI = 2.6-9.6) or 34 % (95 % CI = 22-44) of all cases of FGR/preeclampsia). The incidence of small for gestational age infant (SGA) was higher among subjects with unrecognized rheumatic diseases (41/198 as compared to 46/594; adjOdds Ratio = 3.1, 95 % CI =1.96-4.95) than in controls. The excess incidence associated with unrecognized rheumatic diseases was 2.7 % (95 % CI = 1.5-4) or 25 % (95 % CI = 12.8-34.8) of all SGA cases. CONCLUSIONS: Unrecognized autoimmune systemic rheumatic disorders are associated with a significant proportion of preeclampsia and fetal growth failure, suggesting that their role in the etiology of adverse pregnancy outcome is probably undervalued.

Early, Incomplete, or Preclinical Autoimmune Systemic Rheumatic Diseases and Pregnancy Outcome.

OBJECTIVE: To evaluate the impact of preclinical systemic autoimmune rheumatic disorders on pregnancy outcome. METHODS: In this longitudinal cohort study, patients were enrolled during the first trimester of pregnancy if they reported having had connective tissue disorder symptoms, were found to be positive for circulating autoantibodies, and on clinical evaluation were judged to have a preclinical or incomplete rheumatic disorder. The incidence of fetal growth restriction (FGR), preeclampsia, and adverse pregnancy outcomes in patients with preclinical rheumatic disorders was compared with that in selected controls, after adjustment for confounders by penalized logistic regression. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. RESULTS: Of 5,232 women screened, 150 (2.9%) were initially diagnosed as having a suspected rheumatic disorder. After a mean ± SD postpartum follow-up of 16.7 ± 5.5 months, 64 of these women (42.7%) had no clinically apparent rheumatic disease and 86 (57.3%) had persistent symptoms and positive autoantibody results, including 10 (6.7%) who developed a definitive rheumatic disease. The incidences of preeclampsia/FGR and of small for gestational age (SGA) infants were 5.1% (23 of 450) and 9.3% (42 of 450), respectively, among controls, 12.5% (8 of 640) (OR 2.7 [95% CI 1.1-6.4]) and 18.8% (12 of 64) (OR 2.2 [95% CI 1.1-4.5]), respectively, among women with no clinically apparent disease, and 16.3% (14 of 86) (OR 3.8 [95% CI 1.9-7.7]) and 18.6% (16 of 86) (OR 2.3 [95% CI 1.2-4.3]), respectively, among those with persisting symptoms at follow-up. Mean ± SD umbilical artery Doppler pulsatility indices were higher among women with no clinically apparent disease (0.95 ± 0.2) and those with persisting symptoms (0.96 ± 0.21) than in controls (0.89 ± 0.12) (P = 0.01 and P < 0.001, respectively). CONCLUSION: In our study population, preclinical rheumatic disorders were associated with an increased risk of FGR/preeclampsia and SGA. The impact of these findings and their utility in screening for FGR/preeclampsia need to be confirmed in population studies.

Soluble HLA-G concentrations in maternal blood and cervical vaginal fluid of pregnant women with preterm premature rupture of membranes.

OBJECTIVE: To evaluate soluble HLA-G (sHLA-G) concentrations in maternal blood serum and cervical vaginal fluid in pregnancies complicated by preterm premature rupture of membranes (PPROM) compared to controls. STUDY DESIGN: Case-control study of 24 women with PPROM and 40 controls. MAIN OUTCOME MEASURES: Vaginal and serum sHLA-G and IL-6 concentrations. FINDINGS: Women with PPROM had significantly higher serum and vaginal sHLA-G concentrations compared to controls (respectively median 31.48U\ml versus 13.9U\ml p<0.001 and 1.7U\ml versus 0.1U\ml p<0.001). Vaginal expression of IL-6 was higher in PPROM cases compared to controls (respectively, median 31.19pg\ml versus 6.67pg\ml; p<0.001). Higher serum and vaginal sHLA-G were associated with both a shorter length of pregnancy and histological chorioamnionitis in the PPROM group. CONCLUSIONS: Higher vaginal and serum sHLA-G in PPROM cases may be a sign of local and systemic inflammation.

Connective tissue diseases and autoimmune thyroid disorders in the first trimester of pregnancy.

OBJECTIVE: To investigate the rates and coexistence of autoimmune thyroid and connective tissue diseases (CTD) during the first trimester of pregnancy and their influence on pregnancy outcome. STUDY DESIGN: A cohort study of 150 women with CTD diagnosed during first trimester of pregnancy and 150 negative controls. MAIN OUTCOME MEASURES: Screening of CTD by a self-reported questionnaire, rheumatic and thyroid autoantibody detection, clinical rheumatological evaluation and obstetric outcomes. RESULTS: Out of 3852 women screened, 61 (1.6%) were diagnosed with undefined connective tissue disease (UCTD), 28 (0.7%) with major CTD (six rheumatoid arthritis, five systemic lupus erythematosus, eight Sjogren syndrome, five anti-phospholipid syndrome, two systemic sclerosis, one mixed CTD and one monoarticular arthritis) and 61 (1.6%) had insufficient criteria for a diagnosis of a rheumatic disease. The overall prevalence of either thyroid peroxidase (TPO-a) or thyroglobulin (TG-a) autoantibodies detection was 8% (12/150) among controls, 62.3% (38/61) among UCTD and 60.7% (17/28) in women with a major CTD (p<.001 compared to controls for both comparisons). After adjustment for confounders, overall CTDs (major or undefined) (OR=3.54, 95% CI; 1.61-7.78) and TPO-a plus TG-a positivity (OR=2.78, 95% CI;1.29-5.98) were independently associated with increased risks of moderate-severe complications of pregnancy (miscarriage, fetal growth restriction, preeclampsia, delivery before 34 weeks). CONCLUSIONS: Rheumatic and thyroid autoantibodies during pregnancy are closely associated. Thyroid antibodies could add to the risk of adverse pregnancy outcome associated with connective tissue diseases.

Maternal and neonatal outcomes in pregnant women with autoimmune diseases in Pavia, Italy.

BACKGROUND: The increased number of childbearing women with autoimmune diseases leads to a growing interest in studying relationship among maternal disease, therapy, pregnancy and off-spring. The aim of this study was to determine the impact of autoimmune disease on pregnancy and on neonatal outcome, taking into account the maternal treatment and the transplacental autoantibodies passage. METHODS: We studied 70 infants born to 70 pregnant women with autoimmune disease attended in Fondazione IRCCS Policlinico San Matteo, Pavia, Italy from June 2005 to June 2012. Maternal and neonatal characteristics were collected and relevant clinical, laboratory, therapeutics, sonographic and electrocardiographic investigations were recorded and analyzed. RESULTS: We observed a high rate of spontaneous abortions in medical history, 29 %, and 18.6 % of preterm births and 22.9 % of low birth weight (< 2500 g). Transplacental autoantibodies passage wasn't related to maternal or obstetrical complication, but anti-Ro/SSA positive pregnancies correlated with abnormal fetal heart rate (P = 0.01). Pregnant women on therapy showed an higher incidence of maternal (p = 0.002), obstetric (p = 0.007) complications and an increased rate of intrauterine growth restriction (p = 0.01) than the untreated ones. CONCLUSIONS: Autoimmune diseases in pregnancy require to be carefully monitored to ensure the best possible management of mothers, fetuses and newborns due to the high rate of morbidity specially in case of maternal polytherapy and/or anti-Ro/SSA positivity.

Association between previously unknown connective tissue disease and subclinical hypothyroidism diagnosed during first trimester of pregnancy.

OBJECTIVE: To investigate the presence of autoimmune rheumatic disorders among women with autoimmune thyroid disorders diagnosed during the first trimester of pregnancy and subsequent pregnancy outcomes. DESIGN: Case-control study. SETTING: Tertiary obstetric and gynecologic center. PATIENT(S): Pregnant women in the first trimester of pregnancy. INTERVENTION(S): Clinical, laboratory, ultrasonographic evaluations. MAIN OUTCOME MEASURE(S): Thyroid-stimulating hormone (TSH) level; antibodies against thyroperoxidase, thyroid globulin and TSH receptor detection; screening for rheumatic symptoms and antinuclear antibodies (ANA); uterine artery pulsatility index evaluation; pregnancy complication onset. RESULT(S): Out of 3,450 women enrolled, 106 (3%) were diagnosed with autoimmune thyroid disorders. ANA were present in 18 (16.9%) of 106 cases and 26 (12.6%) of 206 controls. Of the cases, 28 (26.4%) of 106 reported rheumatic symptoms, 5 of these were diagnosed with Sjögren syndrome or with undefined connective tissue disease. Autoimmune thyroid diseases are statistically significantly associated with a higher risk of preeclampsia, fetal growth restriction, and overall pregnancy complications compared with controls, with a higher uterine artery pulsatility index, suggesting a defective placentation in thyroid disorders. The effect of ANA-positivity on moderate/severe adverse pregnancy outcomes was statistically significant among the patients with thyroid disorders (9 of 18 as compared to 8 of 88, odds ratio 9.65; 95% confidence interval, 2.613-7.81). CONCLUSION(S): Connective tissue diseases are frequently associated with autoimmune thyroid disorders diagnosed during the first trimester of pregnancy. Thyroid autoimmunity and ANA positivity independently increased the risk of adverse pregnancy outcomes.

Soluble HLA-G in pregnancies complicated by autoimmune rheumatic diseases.

Autoimmune rheumatic diseases in pregnancies are associated with increased adverse obstetric outcomes. We compared maternal soluble human leucocyte antigen-G (sHLA-G) blood levels in subjects with a rheumatic disease preexisting pregnancy and unaffected controls. Third-trimester blood maternal sHLA-G concentrations were significantly higher in subjects with rheumatic diseases than in controls (mean 93.1ng/ml [SD 42.1] vs 58.1ng/ml [SD 96.3], p=0.003). Cord blood sHLA-G concentrations were significantly higher in rheumatic disease than in those born to control mothers (median 41.2ng/ml [IQR: 3.3-44.0] vs 17.9ng/ml [IQR: 17.2-88.1], p=0.007). A strict positive correlation (r=0.88, p<0.001) was found between the maternal and fetal titers of ANA autoantibodies as well as between maternal and fetal sHLAG circulating levels (r=0.58 and r=0.67, respectively, for controls and cases, p<0.001). Maternal s-HLA-G blood concentrations were significantly higher in subjects with rheumatic disease DEL/DEL homozygous for a polymorphism of the 3' untranslated regulatory region of HLA-G (HLA-G 14bp) than in the corresponding healthy controls (mean values 141.5ng/ml [SD: 166] vs 54.2ng/ml [SD: 35], p=0.009). Increasing maternal and cord blood levels of s-HLA-G concentrations among pregnant subjects with rheumatic diseases compared with controls suggest that autoimmune diseases prompt a maternal and fetal immune response that favors pregnancy immune tolerance.

Adolescent and adult uterine volume and uterine artery Doppler blood flow among subjects treated with bone marrow transplantation or chemotherapy in pediatric age: a case-control study.

OBJECTIVE: To compare uterine and ovarian volumes and uterine artery (UA) Doppler blood flow among women who were treated with antineoplastic regimens when pediatric aged versus healthy controls. DESIGN: Case-control study. SETTING: Tertiary obstetric and gynecologic center. PATIENT(S): One hundred twenty-seven women who were treated for childhood cancer with bone marrow transplantation (BMT) and∖or chemotherapy and total body irradiation (TBI) and 64 age-matched healthy controls. INTERVENTION(S): Ultrasonographic and clinical evaluations. MAIN OUTCOME MEASURE(S): Uterine and ovarian volume, detection of follicles, and UA pulsatility index (PI). RESULT(S): Median uterus and ovarian volumes were reduced by 64% (95% CI, 56.6-70.6) and 83.6% (95% CI, 79.6-86.7), respectively, among cases compared with controls. Median UA PI among cases was increased by 30.3% (95% CI, 19.6-40.8) compared with controls. Ovarian follicles were identified in 24 (18.9%) of 127 cases and 25 (39%) of 64 controls. Uterine volume was reduced after TBI (percent reduction 81.9%; 95% CI, 71.8-87.8) or busulfan (percentage reduction 67.4%; 95% CI, 58.5-75.6) compared with those who had not received a conditioning regimen (percentage reduction 24.4%; 95% CI, 7.6-38.2). The only factors independently associated with reduced uterine and ovarian volumes compared with controls were TBI, busulfan, and BMT. The worst effect on UA PI resulted from BMT and a diagnosis of hematologic disease. CONCLUSION(S): Bone marrow transplantation as main treatment and TBI and busulfan as conditioning regimens had the worst effect on uterine and ovarian sizes compared with controls. These data should be considered in counseling families on preserving future fertility in children undergoing BMT.

Temporal variation in soluble human leukocyte antigen-G (sHLA-G) and pregnancy-associated plasma protein A (PAPP-A) in pregnancies complicated by gestational diabetes mellitus and in controls.

PROBLEM: To target gestational diabetes mellitus (GDM) by means of temporal variation in pregnancy-associated plasma protein A (PAPP-A) and soluble human leukocyte antigen-G (sHLA-G). METHOD OF STUDY: Retrospective analysis of PAPP-A and sHLA-G blood levels in historical samples of 112 GDM and 112 controls, drawn at first trimester, and prospective study in 18 GDM and 105 controls collected in triplicate along the pregnancy. Six hundred and sixty-five samples were analyzed. RESULTS: Gestational diabetes mellitus had significantly lower first-trimester PAPP-A concentrations than controls (2343±1519 versus 2996±1955 mU/mL, in retrospective brunch and 2490.57±1828.52 versus 3240.84±1930.69 mU/L in prospective one, P<0.001). First-trimester sHLA-G level was significantly lower in GDM than in controls (52.88±59.69 versus 66.81±50.14 ng/mL, P<0.001) and increased during gestation in diabetic women showing an opposite trend with respect to the controls. CONCLUSION: PAPP-A and sHLA-G are independent markers of GDM. Quantitative variations during pregnancy help to early unravel the onset of GDM.

Gestational diabetes mellitus: including serum pregnancy-associated plasma protein-A testing in the clinical management of primiparous women? A case-control study.

AIMS: To assess pregnancy-associated plasma protein A (PAPP-A) correlation with GDM and its usefulness in predicting GDM in primiparous women. METHODS: First trimester data related to 307 pregnant women affected by GDM and 366 control pregnant women were retrieved from a computer data base and integrated with ad hoc data. Clinical data were recorded at delivery. A logistic model was used to analyze the association between first trimester data and subsequent clinical outcomes. We derived a risk score using both classical risk factors for GDM and PAPP-A. RESULTS: Diabetic and control women were significantly different in terms of age (p<0.001), BMI (p<0.001), weight (p<0.001), family history of diabetes (p<0.001), PAPP-A concentration and PAPP-A corrected multiple of the median (MoM) (p<0.001). The ROC-AUC of the clinical risk score was 0.60 (95%CI 0.56-0.64), the adjusted score including PAPP-A MoM was 0.70 (95%CI 0.66-0.74). CONCLUSIONS: Low PAPP-A was strongly associated with GDM and lower values were found in diabetic women needing insulin therapy. Adding PAPP-A to first trimester screening could improve the prediction of women at high risk who will develop GDM. Further studies are needed to validate the applicability of our findings in different populations and settings.

Uterine artery Doppler velocimetry and obstetric outcomes in connective tissue diseases diagnosed during the first trimester of pregnancy.

OBJECTIVE: To evaluate the effect of connective tissue disease (CTD) diagnosed during the first trimester on uterine arteries (UtA) Doppler velocities and on pregnancy outcomes. METHOD: Pregnant women were screened for CTDs during the first trimester, using a questionnaire, testing for autoantibodies, rheumatologic examination and UtA Doppler evaluations. RESULTS: Out of 3932 women screened, 491 (12.5%) were screened positive at the questionnaire; of them, 165(33.6%) tested positive for autoantibodies, including 66 eventually diagnosed with undifferentiated connective tissue disease (UCTD), 28 with a definite CTD and 71 with insufficient criteria for a diagnosis. Controls were 326 women screened negative for autoantibodies. In logistic analysis, women diagnosed with either UCTD (OR = 7.9, 95% CI = 2.3-27.3) or overt CTD (OR = 24.9, 95% CI = 6.7-92.4), had increased rates of first trimester bilateral UtA notches compared with controls. The rates of bilateral UtA notches persisting in the second (15/94 vs 0/326, p < 0.001) and third trimesters (7/94 vs 0/326, p < .001) were higher among women with CTDs than in controls. The risk of complications (preeclampsia, fetal growth restriction, prematurity, diabetes, fetal loss) was higher (OR = 7.8, 95% CI = 3.6-17.0) among women with CTDs than in controls. CONCLUSION: Women with undiagnosed CTDs have higher rates of bilateral UtA Doppler notches throughout pregnancy and increased rates of adverse pregnancy outcomes than controls.