Impact of pregnancy on progression of preclinical autoimmune disorders: a prospective cohort study.

OBJECTIVES: The objective of this study was to evaluate the role of pregnancies in the progression from the preclinical phase of autoimmune disorder to a definite rheumatic disease. METHODS: A cohort study of women with symptoms and laboratory findings suggestive for autoimmune disorder were enrolled during the first trimester of pregnancy and followed-up for 5 years with clinical and laboratory assessment. Multinomial logistic regression was used to compute the risk of progression to definite autoimmune disease correcting for confounders. RESULTS: At the end of follow-up, out of 208 subjects, 81 (38.9%) were considered negative, 53 (25.5%) had symptoms and abnormalities of autoantibody profile compatible with a non-criteria rheumatic status and 74 (35.6%) had a definite rheumatic disease (43 undifferentiated connective tissue disease, 5 systemic lupus erythematosus, 3 SS, 10 antiphospholipid syndrome, and 12 miscellaneous autoimmune disorders). The median time from enrolment to definite diagnosis was 28 months (interquartile range = 18-42). The rate of progression towards a definite autoimmune disease was 47.1% (48/102) among subjects with one or more subsequent viable pregnancies compared with 24.5% (26/106) of those with no subsequent pregnancies (adjusted odds ratio = 4.9, 95% CI: 2.4, 10). The occurrence of preeclampsia during the index pregnancy or subsequent pregnancy was an additional and independent risk factor for progression to a definite autoimmune disease (adjusted odds ratio = 4.3, 95% CI: 1.2, 14.8). CONCLUSIONS: Among women with suspected autoimmune disease during pregnancy, additional viable pregnancies and diagnosis of preeclampsia were independently associated with an increased rate of progression to definite rheumatic disorder. Hormonal modifications associated with pregnancy could worsen preclinical rheumatic disorders favouring their progression to a defined autoimmune disease.

Maternal and foetal placental vascular malperfusion in pregnancies with anti-phospholipid antibodies.

OBJECTIVE: The objective of the study was to evaluate the rates of pathological placental lesions among pregnant subjects positive for aPL antibodies. METHODS: We performed a longitudinal case-control study including 27 subjects with primary APS, 51 with non-criteria APS, 24 with aPL antibodies associated with other well-known CTDs enrolled at the end of the first trimester of pregnancy and 107 healthy controls. RESULTS: Compared with controls and after correction for multiple comparisons, primary, non-criteria APS and aPL associated to CTD, subjects had lower placental weight, volume and area. After penalized logistic regression analysis to correct for potential confounders, placental lesions suggesting severe maternal vascular malperfusion (MVM) were more common among primary [odds ratio (OR) 11.7 (95% CI 1.3, 108)] and non-criteria APS [OR 8.5 (95% CI 1.6, 45.9)] compared with controls. The risk of foetal vascular malperfusion (FVM) was higher in primary APS [OR 4.5 (95% CI 1.2, 16.4)], aPL associated with CTDs [OR 3.1 (95% CI 1.5, 6.7)] and non-criteria APS [OR 5.9 (95% CI 1.7, 20.1)] compared with controls. Among clinical and laboratory criteria of APS, first trimester aCL IgG >40 UI/ml [OR 4.4 (95% CI 1.3, 14.4)], LA positivity [OR 6.5 (95% CI 1.3, 33.3)] and a history of pre-eclampsia at <34 weeks [OR 32.4 (95% CI 6.5, 161)] were the best independent first trimester predictors of severe MVM [area under the curve 0.74 (95% CI 0.6, 0.87)]. CONCLUSION: Compared with healthy controls, pregnant subjects with aPL antibodies have an increased risk of placental lesions, suggesting MVM and FVM. First-trimester variables such as aCL IgG >40 UI/ml and a history of pre-eclampsia were significant predictors of both severe MVM and FVM.

Circulating endothelial progenitor cells during pregnancy in multiple sclerosis.

BACKGROUND: Endothelial progenitor cells (EPCs) have been shown to increase during physiological pregnancy and are believed to play a fundamental role in the process of placentation. Reduced levels of EPCs during pregnancy have been associated with preeclampsia and miscarriage. Women with multiple sclerosis (MS) are not at increased risk of preeclampsia nor of general adverse obstetric outcome, in contrast with some other autoimmune diseases. OBJECTIVE: The aim of this study was to evaluate circulating EPCs levels in pregnant patients with MS. METHODS: CD34+ and CD133+ were longitudinally detected by flow cytometry in the maternal plasma of 29 healthy controls and 9 MS patients and in the cord blood of their newborns. RESULTS: EPCs were affected by pregnancy with the same trend in both groups (CD34+ p = 0.0342; CD133+ p = 0.0347). EPCs during pregnancy were increased in MS (mean ± SD: CD34+ cells 0.038 ± 0.010; CD133+ 0.024 ± 0.009) with respect to healthy controls (mean ± SD: CD34+ cells 0.022 ± 0.006; CD133+ 0.016 ± 0.004), CD34+ p = 0.0004; CD133+ p = 0.0109. EPCs levels of the cord blood of MS patients' newborns mild correlated with maternal EPC levels at delivery (CD34+: spearman's Rho 0.658, p = 0.054; CD133+: spearman's Rho 0.758, p = 0.018). CONCLUSIONS: This work identified increased circulating EPC levels during pregnancy, following the same trend both in MS patients and healthy controls. Despite the similar trend, the levels of circulating EPCs were significantly higher in MS patients with respect to the control population. A correlation was also found in MS patients between cord blood EPCs and circulating EPCs at delivery.

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.

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.

Placental pathologic features in obesity.

INTRODUCTION: Obesity in pregnancy is associated with adverse long-term consequences both in the mother and in offspring. Maternal obesity induces a metabolic-inflammatory state that could impact on placental function and could mediate the adverse outcomes. The purpose of this study was to compare the major placental histological characteristics of non-diabetic obese women to lean controls, focusing on uncomplicated pregnancies. METHODS: Prospective case-control study comparing placental histopathological features between 122 non-diabetic obese women and 185 non-obese controls. The analysis was performed on overall subjects, then uncomplicated pregnancies from both groups were analyzed. Placenta pathologic findings were recorded according to standard classification. RESULTS: Both in overall analysis and among the subset of subjects with an uncomplicated pregnancy, obese subjects had higher risks of maternal vascular malperfusion (MVM) (respectively OR=2.2, 95%CI =1.3-3.7 and OR=4.2, 95%CI=2.1-8.5), fetal vascular malperfusion (FVM) (respectively OR=6.3, 95%CI=3.1-12.5 and OR=7.2, 95%CI=3-17.2), maternal and fetal inflammatory response placental lesions and villitis (VUE) (respectively OR=2.5, 95%CI=1.1-5.6 and OR=10.8, 95%CI=3.3-35.3) compared to controls. Among uncomplicated pregnancies and after adjustment for confounders, first trimester BMI was significantly associated with overall MVM, overall FVM, maternal inflammatory, fetal inflammatory response and VUE. DISCUSSION: Placentas from obese women showed a significantly higher risk of maternal and fetal vascular and inflammatory placental lesions, both in overall population and in the subgroup with uncomplicated pregnancies. The metabolic and inflammatory dysfunctions typical of obesity could have an impact on placental development and function, which could be a mediator of the detrimental effects of obesity on pregnancy outcome and on future health of the offspring.

Prevalence and significance of previously undiagnosed rheumatic diseases in pregnancy.

OBJECTIVES: The objective of this study was to evaluate the rates of previously undiagnosed rheumatic diseases during the first trimester of pregnancy and their impact on the pregnancy outcome. METHODS: Pregnant women in their first trimester were screened using a two-step approach using a self-administered 10-item questionnaire and subsequent testing for rheumatic autoantibodies (antinuclear antibody, anti-double-stranded DNA, anti-extractable nuclear antigen, anticardiolipin antibodies, anti-ß2-glycoprotein I antibodies and lupus anticoagulant) and evaluation by a rheumatologist. Overall, the complications of pregnancy evaluated included fetal loss, pre-eclampsia, gestational diabetes, fetal growth restriction, delivery at less than 34 weeks, neonatal resuscitation and admission to the neonatal intensive care unit. RESULTS: Out of the 2458 women screened, the authors identified 62 (2.5%) women with previously undiagnosed undifferentiated connective tissue disease (UCTD) and 24 (0.98%) women with previously undiagnosed definite systemic rheumatic disease. The prevalences were seven (0.28%) for systemic lupus erythematosus and Sjogren's syndrome, six (0.24%) for rheumatoid arthritis, three (0.12%) for antiphospholipid syndrome and one (0.04%) for systemic sclerosis. In multiple exact logistic regression, after adjustment for potential confounders, the OR of overall complications of pregnancy were 2.81 (95% CI 1.29 to 6.18) in women with UCTD and 4.57 (95% CI 1.57 to 13.57) in those with definite diseases, respectively, compared with asymptomatic controls. CONCLUSIONS: In our population approximately 2.5% and 1% of first trimester pregnant women had a previously undiagnosed UCTD and definite systemic rheumatic disease, respectively. These conditions were associated with significant negative effects on the outcome of pregnancy.

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.

Placental pathologic features in thyroid autoimmunity.

INTRODUCTION: Data on placental pathologic features associated with thyreoperoxidase antibodies (TPO Ab) and/or hypothyroidism are limited. The objective of the study was to analyze placental pathologic features of women with TPO Ab positivity. METHODS: Prospective case-control observational study of pregnancy outcome among women screened for TPO Ab positivity and/or isolated hypothyroidism (TSH>4mU/L) during the first trimester of pregnancy. Placenta pathologic findings were recorded according to standard classification. RESULTS: The overall rates of TPO Ab positivity and isolated hypothyroidism with negative TPO Ab were 9.6% (86/899) and 2.7% (24/899), respectively. Among TPO Ab positive cases, 77.9% (67/86) and 22.1% (19/86) had TSH ≥2.5mU/L or <2.5mU/L, respectively. Compared to controls, mean first and second trimester uterine artery Doppler pulsatility indices (PI) were higher, placental volume and area were lower among cases with TSH≥2.5mU/L. The rates of fetal growth restriction (FGR)/small for gestational age (SGA) (20/67 versus 8/110, Adjusted Odds Ratio (AdjOR) = 10.8,95%CI = 2.7-44), placental pathological features suggesting decidual vasculopathy (37/67 versus 27/110, AdjOR = 2.7,95%CI = 1.1-6.8) or severe maternal vascular malperfusion (MVM) (22/67 versus 9/110, AdjOR = 5.8,95%CI = 1.6-20.1) were higher among cases with TSH ≥2.5mU/L than in controls. Similar results were obtained comparing overall TPO Ab positive subjects to controls. The increased risk of defective placentation and FGR associated with TPO Ab was independent of simultaneous presence of antinuclear antibodies (ANA) and TSH concentration. DISCUSSION: First trimester TPO Ab positivity was associated with increased rates of abnormal uterine artery Doppler PI and placental features of MVM. This association was independent of TSH concentration and presence of ANA.

Endothelial Progenitor Cell CD34+ and CD133+ Concentrations and Soluble HLA-G Concentrations During Pregnancy and in Cord Blood in Undifferentiated Connective Tissue Diseases Compared to Controls.

The objective of this study is to evaluate endothelial progenitor cells (EPCs) CD34+ CD133- and CD34+ CD133+ and soluble HLA-G (sHLA-G) concentrations among undifferentiated connective tissue disease (UCTD) subjects, compared to controls, during pregnancy and in cord blood. This is a case-control study including 29 controls and 29 UCTDs. CD34+ CD133-, CD34+ CD133+, and sHLA-G concentrations were detected in maternal plasma and in cord blood. This study was approved by the Medical-Ethical Committee of our Institution (Current Research Project N. 901-rcr2017i-23 of IRCCS Foundation Policlinico San Matteo of Pavia). Circulating CD34+ CD133- and CD34+ CD133+ counts and sHLA-G (soluble human leucocyte antigen G) concentrations in maternal peripherical blood were higher in UCTD compared to those in controls in first and third trimester of pregnancy and at delivery (p < 0.001). Maternal CD34+ CD133- and CD34+ CD133+ counts were strongly and significantly correlated in UCTD (Spearman's rho = 0.79, p < 0.0001) but not in controls (Spearman's rho = 0.10, p = 0.35). Cord blood CD34+ CD133- and CD34+ CD133+ median counts and median sHLA-G concentrations were higher among UCTD subjects than in controls (p < 0.001). Cord blood CD34+ and CD133+ counts were inversely and significantly correlated with sHLA-G concentrations among UCTDs, but not in controls. Early UCTD is characterized by increased EPC levels in maternal plasma and in cord blood and higher levels of sHLA-G, compared to controls. Data suggest that fetoplacental unit plays an independent role in the EPC response to a systemic autoimmune disease.

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.

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.

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.

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.

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.

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.

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.

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.