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.

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.

First trimester pregnancy-associated plasma protein-A in pregnancies complicated by subsequent gestational diabetes.

OBJECTIVE: To compare routine first trimester biochemical and ultrasound markers in pregnancies complicated by gestational diabetes with those of a control group. METHODS: First trimester data including the screening test for Down syndrome were retrieved from a computer data base. Clinical data were recorded at delivery. A multivariate quantile regression model was used to analyze the association between first trimester data and subsequent clinical outcomes in a case-control study design. RESULTS: In the group of women who developed second trimester gestational diabetes, both first trimester median (1494 vs 2225 mU/L, P < 0.001) and adjusted multiple of median pregnancy-associated plasma protein-A (PAPP-A) concentrations (1.2 vs 0.7, P < 0.001) were significantly lower than in the control group. Differences between observed and expected crown-to-rump length expressed in mm was lower in women destined to develop gestational diabetes than in the control group (0.2 vs 1.4 mm, P < 0.005). In multivariate models, first trimester maternal PAPP-A concentrations correlated independently and inversely to pregestational body mass index (BMI, P = 0.004), subsequent gestational diabetes (P < 0.001) and pregnancy complications (P = 0.036). CONCLUSIONS: First trimester PAPP-A concentrations were lower among pregnant women with subsequent gestational diabetes than in the control group.

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.

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.

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.

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.

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.