Laura Trespidi

Endometriosis and pelvic pain: relation to disease stage and localization *

OBJECTIVES To determine whether prevalence and severity of pain symptoms are related to endometriosis stage and site, with particular reference to deep infiltrating vaginal lesions. DESIGN Systematic assessment of chronic pelvic pain symptoms. SETTING University hospital endometriosis center. PATIENTS A total of 244 consecutive symptomatic patients with endometriosis diagnosed at laparoscopy or laparotomy. INTERVENTIONS Assessment of dysmenorrhea and nonmenstrual pain by means of a 10-point linear analog scale, a 7-point multidimensional rating scale, and a 3-point verbal scale; evaluation of deep dyspareunia with the first and third systems only. MAIN OUTCOME MEASURES Prevalence and severity of pain symptoms in relation to endometriosis stage and site of lesions. Correlation between revised American Fertility Society score and symptoms severity, as well as between two pain scales to assess dysmenorrhea and nonmenstrual pain. RESULTS Eighty-eight women had stage I and II disease and 156 had stage III and IV disease. Only ovarian endometriosis was present in 108 patients, only peritoneal implants were present in 37, combined ovarian and peritoneal lesions were present in 57, and histologically confirmed vaginal endometriosis was present in 42. The frequency and severity of deep dyspareunia and the frequency of dysmenorrhea were less in patients with only ovarian endometriosis than in those with lesions at other sites. Patients with vaginal endometriosis had a significantly increased risk of deep dyspareunia compared with those whose lesions were at other sites (odds ratio, 2.55; 95% confidence interval, 1.21 to 5.39). Stage per se, independent of lesion site, was not correlated with frequency and severity of dysmenorrhea and nonmenstrual pain. The severity of deep dyspareunia was related inversely to the endometriosis score (Spearman correlation coefficients for linear analog and verbal rating scales, respectively, -0.22 and -0.20). Kendall test by ranks revealed a correlation between linear analog and multidimensional pain scales in the rating of both dysmenorrhea and nonmenstrual pain (respectively, tau-b, 0.59 and tau-b, 0.68). CONCLUSIONS Endometriosis stage in the current classification was not related consistently to pain symptoms. The presence of vaginal lesions was associated frequently with severe deep dyspareunia. Dysmenorrhea and nonmenstrual pelvic pain were assessed with equal accuracy by a linear analog and a multidimensional scale.

Adenomyosis: A Déjà Vu?

Adenomyosis is a relatively frequent finding in series of hysterectomies performed for menorrhagia and dysmenorrhea. Evident selection biases of the available studies on adenomyosis have always limited the possibilities of defining the real clinical importance of the condition. Until now the only certain diagnoses have been made by histopathologists on uteri removed at surgery, but recently various sufficiently accurate techniques have been suggested which allow diagnosis on the uterus in situ. With the these methods it might be possible to obtain correct information on the epidemiologic characteristics of adenomyosis and to clarify whether it has a pathogenic role in unexplained ovulatory menorrhagia and juvenile dysmenorrhea. Furthermore, resectoscopic treatment has been proposed in some mild forms of adenomyosis to avoid hysterectomy, whereas it seems improbable that medical treatment can offer a definitive solution. The adoption of standard histologic criteria for adenomyosis seems important. Until this is done, it will be difficult to establish whether adenomyosis is really a disease or merely a paraphysiologic condition.

Obstetric and vascular APS: Same autoantibodies but different diseases?

Beta2 glycoprotein I (β2GPI)-dependent antiphospholipid antibodies (aPLs) are the main pathogenic autoantibody population and at the same time the laboratory diagnostic tool for the antiphospholipid syndrome (APS). These antibodies are responsible for both the vascular and the obstetric manifestations of the syndrome but the pathogenic mechanisms behind these manifestations are not the same. For example, thrombotic events do not appear to play a major role in APS miscarriages and a direct reactivity of β2GPI-dependent aPLs on decidual and trophoblast cells was reported. A local expression of β2GPI on these tissues was reported both in physiological conditions and in APS women, thus explaining the local tropism of the autoantibodies. The two hit hypothesis was suggested to explain why the vascular manifestations of APS may occur only occasionally in spite of the persistent presence of aPLs. This is not apparently the case for the obstetric variant of the syndrome, making the difference even more striking. A different pathogenesis may also provide the rationale for the well-known fact that the vascular and the obstetric manifestations may occur independently although in a minority of cases.

Immune function in children born to mothers with autoimmune diseases and exposed in utero to immunosuppressants.

The administration of immunosuppressive drugs during pregnancy is often necessary in women with autoimmune diseases. Teratogenicity of immunosuppressives during pregnancy has been evaluated, only few data exist about the effects on immune systems. We therefore performed a pilot study on the influence of foetal exposure to immunosuppressives on immune function of babies born to mothers with autoimmune disorders. We investigated serological and cellular parameters as indicators of immune system status. We included in the study 14 babies (mean age 11 months, range 1—24) born to mothers with autoimmune diseases and exposed in utero to different immunosuppressants and, as controls, 14 babies whose mothers had autoimmune manifestations but did not receive immunosuppressive therapy. We evaluated: (i) complete blood count, (ii) immunoglobulin levels and IgG subclasses, (iii) antibody response to hepatitis B vaccine, (iv) leukocyte subpopulations and (v) interleukin-2 and interferon γ in vitro production by resting or activated peripheral blood mononuclear cells. We did not find statistically significant differences between exposed and not exposed babies or among treatments for the tested parameters. Immunosuppressive regimens currently in use for controlling maternal autoimmune disorders do not significantly affect the immune status of the offspring. Lupus (2007) 16, 651—656.

Systemic vasculitis and pregnancy: A multicenter study on maternal and neonatal outcome of 65 prospectively followed pregnancies

OBJECTIVE Systemic vasculitis (SV) are uncommon diseases that rarely affect women during their reproductive age; little data, mainly retrospective, is available on this topic. The aim of our study was to evaluate maternal/neonatal outcome and disease course before, during and after pregnancy. METHODS Sixty-five pregnancies in 50 women with SV were followed by a multispecialistic team in 8 institutions between 1995 and 2014. Clinical data on pregnancy, 1year before and 1year after delivery was retrospectively collected. The rate of pregnancy complications was compared to that of a General Obstetric Population (GOP) of 3939 women. RESULTS In 2 patients the diagnosis of SV was done during pregnancy; 59 out of the remaining 63 started when maternal disease was quiescent. We recorded 56 deliveries with 59 live births, 8 miscarriages and 1 fetal death. In SV, preterm, particularly early preterm (<34weeks) deliveries and cesarean sections appeared significantly more frequent than in GOP (11.3% vs 5.0%, p=0.049 and 48.2% vs 31.0%, p=0.009). Vasculitis-related complications occurred in 23 pregnancies (35.4%), with 5 severe events (7.7%) including 3 cases of transient ischemic attack (TIA). Data about the post-partum period were available for 56 pregnancies: 12 flares (21.4%) occurred, with 1 severe event (1.8%). CONCLUSION SV patients can have successful pregnancies (especially during a disease remission phase) despite an increased rate of preterm delivery. Severe flares were limited, but the occurrence of 3 TIA suggests that particular attention should be given to possible thrombotic complications in SV patients during pregnancy and puerperium.

Veralipride for Hot Flushes during Gonadotropin-Releasing Hormone Agonist Treatment

Hot flushes are the commonest symptom induced by gonadotropin-releasing hormone agonists (GnRHa). We performed an open observational trial to evaluate the efficacy of veralipride, an antidopaminergic drug, in reducing hot flushes in 25 premenopausal women treated with a GnRHa for endometriosis (8 subjects) or menorrhagia (17 subjects). The patients received goserelin depot for 6 months and veralipride was added for the third month. Hot flushes, severe in all women at 2 months, improved in both frequency and intensity in 92% of the subjects during veralipride administration. The benefit obtained persisted until the end of the GnRHa treatment.

Veralipride for hot flushes induced by a gonadotropin-releasing hormone agonist: a controlled study*†

OBJECTIVES To evaluate the efficacy of veralipride, a benzamide derivative, in the treatment of hot flushes induced by GnRH agonists (GnRH-a) and to study peripheral blood mononuclear cell beta-endorphin concentrations during drug administration. DESIGN Randomized, placebo-controlled, double-blind trial. SETTING Academic department of obstetrics and gynecology. PATIENTS Forty women of mean age 43 +/- 5 years who experienced disturbing hot flushes during a 4-month course of tryptorelin depot for myoma-associated menorrhagia. INTERVENTIONS Treatment with oral veralipride 100 mg/d (20 subjects) or matching placebo (20 subjects) during the third month of GnRH-a administration. MAIN OUTCOME MEASURES Modifications of frequency and severity of hot flushes as shown by a 0 to 6-point vasomotor scoring system and variations of beta-endorphin levels in peripheral blood mononuclear cells. RESULTS Two subjects in each group dropped out of the study. The median (range) vasomotor score at the end of the second month of treatment was 4 (3 to 6) in both the veralipride and placebo group. At the end of the third and fourth months the median (range) scores were, respectively, 2 (0 to 6) versus 4 (1 to 6) and 2 (0 to 5) versus 4 (1 to 6). No significant variations in mononuclear cell beta-endorphin concentrations were recorded. Serum PRL levels rose from 11.7 +/- 5.7 to 132.3 +/- 65.0 ng/mL (conversion factor to SI unit, 1.0) during veralipride administration and returned to 10.6 +/- 3.7 ng/mL after drug withdrawal. CONCLUSION Veralipride reduced vasomotor symptoms induced by a GnRH-a. Transient hyperprolactinemia was the main side effect observed. The mode of action of the drug in GnRH-a-treated patients and possible interactions with endogenous opioid peptides need further elucidation.

Update on the current recommendations and outcomes in pregnant women with antiphospholipid syndrome

Pregnancy morbidity is part of the clinical spectrum of the antiphospholipid syndrome (APS), a chronic autoimmune condition serologically characterized by the persistent positivity of antiphospholipid antibodies (aPL). Antiplatelet and anticoagulant agents are the mainstay of the treatment of obstetric APS. However, there is an ongoing debate about the optimal management of women with most severe aPL-mediated obstetric complications, women not fulfilling APS criteria and those with refractory disease. Unfortunately, the literature cannot provide definite answers to these controversial issues, being flawed by many limitations. The evidence supporting the recommended therapeutic management of different aPL-related obstetrical clinical manifestations is presented, with a critical appraisal of each approach.

Neurofibromatosis type 1 and pregnancy: Maternal complications and attitudes about prenatal diagnosis

Neurofibromatosis type 1 (NF1) is one of the most commoninherited genetic disorders with an incidence of 1/2,500 to 1/3,300 live births. The disease is caused by a mutation in NF1,atumorsuppressorgeneon17q11.2codingforneurofibromin,orbyamicrodeletioninvolvingtheNF1anditssurroundingregion.NF1is an autosomal dominant condition with complete penetranceafter childhood. Almost half the cases result from a de novomutation,whiletheothersinheritthealteredgenefromanaffectedparent.Thediseaseismarkedbypoorgenotype–phenotypecorre-lation and high inter- and intra-familial variability. Thereforegenetic counseling for affected individuals is hampered by thedifficulty in forecasting the clinical outcome for future offspring.Prenatal testing can be carried out if the parental mutation isknown, or if there are multiple affected family members, andlinkagehasbeenestablishedwithinthefamily;suchtestingisusefulfor establishing the presence of the parental mutation in the fetalDNA, but, as noted, cannot make any prediction about diseaseseverity [Origone et al., 2000; Terzi et al., 2009].Pregnancyhasalwaysbeenconsideredacriticaltimeforwomenwith NF1 because of reports of increased complications duringgestationarisingfrompre-eclampsia,pretermlabor,IUGR,hyper-tension, oligohydramnios, and spontaneous abortion and/or still-birth [Blickstein and Lancet, 1987; Sharma et al.,1991;Segalet al.,1999].Furthermore,casereportsdescribedtheassociationbetweenpregnancy and HELLP syndrome [Hagymasy et al., 1998; Agarwaletal.,2003],diagnosisofmalignantperipheralnervesheathtumor(MPNST)[Posmaaetal.,2003;KelloggandWatson,2010;Nelsonet al., 2010] and the occurrence of pheochromocytoma [Liu et al.,1996]. Although Dugoff and Sujansky [1996] presented a largestudy of pregnancy in 105 women, including data from 247gestations and noted a greater cesarean rate than in thegeneral population, they did not find an increased incidence ofany of these complications. However they did describe thegrowth of new neurofibromas and the enlargement ofexistingneurofibromasinmorethanthehalf.Althoughthemajor-ity of NF1 pregnant women did not report complications, someinvestigators proposed special monitoring in specific situations[Chetty et al., 2011].Here we describe our experience in the management of preg-nancies in women with NF1, and their attitude towards prenataldiagnosis. We included 43 women with a total of 79 pregnancies.Eightofthewomen(18.6%)werereferredforcareduringtheentiregestationalperiod,whiletheother35womenhadtheirpregnanciesdetected before joining our program; for them we obtained datafrom a review of their medical records and through personalinterviews. Among these 79 pregnancies, 65 were carried to termwhile the other 14 resulted in five first trimester spontaneousabortions, seven elective terminations (not related to concernsaboutNF1),andtwotherapeuticabortionsafterprenataldiagnosisthrough chorionic villus sampling (CVS). Two of the 65 full termpregnancies were twins, for a total of 67 live births.Forwomenvisitingourcenterbeforeandduringtheirpregnan-cies, we set up a model based on a set of preconceptional multi-specializedevaluationsthatwefeltwereaprerequisiteforaproperpersonalized management of pregnancy in women with NF1. The

Beyond thrombosis: Anti-β2GPI domain 1 antibodies identify late pregnancy morbidity in anti-phospholipid syndrome

Antibodies against β2 glycoprotein I (anti-β2GPI) have been identified as the main pathogenic autoantibody subset in anti-phospholipid syndrome (APS); the most relevant epitope is a cryptic and conformation-dependent structure on β2GPI domain (D) 1. Anti-β2GPI domain profiling has been investigated in thrombotic APS, leading to the identification of antibodies targeting D1 as the main subpopulation. In contrast, scarce attention has been paid to obstetric APS, hence this study aimed at characterizing the domain reactivity with regards to pregnancy morbidity (PM). To this end, 135 women with persistently positive, medium/high titre anti-β2GPI IgG, without any associated systemic autoimmune diseases and at least one previous pregnancy were included: 27 asymptomatic carriers; 53 women with obstetric APS; 20 women with thrombotic APS; and 35 women with both thrombotic and obstetric complications. Anti-D1 and anti-D4/5 antibodies were tested using a chemiluminescent immunoassay and a research ELISA assay, respectively (QUANTA Flash® β2GPI Domain 1 IgG and QUANTA Lite® β2GPI D4/5 IgG, Inova Diagnostics). Positivity for anti-D1 antibodies, but not anti-D4/5 antibodies, was differently distributed across the 4 subgroups of patients (p < 0.0001) and significantly correlated with thrombosis (χ2 = 17.28, p < 0.0001) and PM (χ2 = 4.28, p = 0.039). Patients with triple positivity for anti-phospholipid antibodies displayed higher anti-D1 titres and lower anti-D4/5 titres compared to women with one or two positive tests (p < 0.0001 and p = 0.005, respectively). Reactivity against D1 was identified as a predictor for PM (OR 2.4, 95% confidence interval [CI] 1.2-5.0, p = 0.017); in particular, anti-D1 antibodies were predictive of late PM, conveying an odds ratio of 7.3 (95% CI 2.1-25.5, p = 0.022). Positivity for anti-D1 antibodies was not associated with early pregnancy loss. Anti-D4/5 antibodies were not associated with clinical APS manifestations. As a whole, our data suggest that anti-D1 antibodies are significantly associated not only with thrombosis, but also with late PM, while positive anti-D4/5 antibodies are not predictive of thrombosis or PM.