Pregnancies in women receiving renal transplant for lupus nephritis: description of nine pregnancies and review of the literature.

BACKGROUND: Few data are available on pregnancy in renal transplanted women for lupus nephritis (LN). METHODS: Among 38 women with LN who received a renal transplant in our Unit, three had nine pregnancies. During the pregnancies, patients were followed by a multidisciplinary team including gynecologists and nephrologists. RESULTS: Two patients received a living related and one a deceased kidney transplant. The immunosuppressive therapy consisted of steroids calcinurin inhibithors and mycophenolate mofetil. The last drug was substituted with azathioprine in prevision of pregnancy. All patients had normal renal function and urinalysis. In two patients some signs of immunological activity persisted after transplantation. Five pregnancies ended in miscarriage and four in live births. Two pregnancies were uneventful. Pre-eclampsia occurred in a hypertensive patient in two pregnancies that ended in preterm delivery in one case and in a small for gestation age in both cases. And finally, follow-up graft function and urinalysis continued to be normal in all patients. CONCLUSIONS: After renal transplantation our LN women continue to have frequent miscarriages. The other pregnancies ended in live births and, with the exception of pre-eclampsia in a hypertensive patient, no renal or extra-renal complications occurred during or after pregnancy, even in cases with active immunological tests.

Obstetric and vascular APS: same autoantibodies but different diseases?

Beta2 glycoprotein I (ß2GPI)-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 ß2GPI-dependent aPLs on decidual and trophoblast cells was reported. A local expression of ß2GPI 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.

Monitoring and treatment of anti-D in pregnancy.

Prophylactic anti-D is a very safe and effective therapy for the suppression of anti-D immunization and thus prevention of haemolytic disease of the foetus and newborn. However, migration from countries with low health standards and substantial cuts in public health expenses have increased the incidence of anti-D immunization in many "developed" countries. Therefore, this forum focuses on prenatal monitoring standards and treatment strategies in pregnancies with anti-D alloimmunization. The following questions were addressed, and a response was obtained from 12 centres, mainly from Europe.

Providing high-quality care remotely to patients with rare bone diseases during COVID-19 pandemic.

During the COVID-19 outbreak, the European Reference Network on Rare Bone Diseases (ERN BOND) coordination team and Italian rare bone diseases healthcare professionals created the "COVID-19 Helpline for Rare Bone Diseases" in an attempt to provide high-quality information and expertise on rare bone diseases remotely to patients and healthcare professionals. The present position statement describes the key characteristics of the Helpline initiative, along with the main aspects and topics that recurrently emerged as central for rare bone diseases patients and professionals. The main topics highlighted are general recommendations, pulmonary complications, drug treatment, trauma, pregnancy, children and elderly people, and patient associations role. The successful experience of the "COVID-19 Helpline for Rare Bone Diseases" launched in Italy could serve as a primer of gold-standard remote care for rare bone diseases for the other European countries and globally. Furthermore, similar COVID-19 helplines could be considered and applied for other rare diseases in order to implement remote patients' care.

Pregnancy complications of the antiphospholipid syndrome.

Starting from their first description, antiphospholipid antibodies (aPL) were associated with repeated miscarriages and fetal losses. Other complications of pregnancy like preterm birth,with pre-eclampsia or severe placental insufficiency were also frequently reported and are included in the current classification criteria of the antiphospholipid syndrome (APS). The titre, the isotype of the antibodies or their antigen specificity may be important in the risk level determination. Some of the difference in the reported results can be explained by the poor standardization achieved in aPL testing or by the not univocal classification of pregnancy complications. The pathogenesis of pregnancy failures is linked to the thrombophilic effect of aPL but also to different mechanisms including a direct effect of antibodies on the throphoblast differentiation and invasion. The study of experimental animal models provided sound evidence of the pathogenic role of aPL both in lupus prone and naive mice. The definition of APS as a condition linked to high obstetric risk and the application of an effective therapy have completely changed the prognosis of pregnancy in these patients. In fact, despite the high number of complications and preterm delivery, today a successful outcome can be achieved in the large majority of the cases.

A gonadotropin-releasing hormone agonist versus a low-dose oral contraceptive for pelvic pain associated with endometriosis.

OBJECTIVES: To evaluate the efficacy of goserelin versus a low-dose cyclic oral contraceptive (OC) in improving pelvic pain in women with endometriosis and to compare recurrence of symptoms during follow-up. DESIGN: Open-label, randomized trial. SETTING: University hospital endometriosis center. PATIENTS: Fifty-seven women with moderate or severe pelvic pain and laparoscopically diagnosed endometriosis. INTERVENTIONS: Six-month treatment with goserelin depot (n = 29) or a low-dose cyclic OC (n = 28) followed by 6-month follow-up. MAIN OUTCOME MEASURES: Variation in severity of symptoms during treatment and at the end of follow-up as shown by a linear analog scale and a verbal rating scale. RESULTS: At 6 months of treatment, a significant reduction in deep dyspareunia was observed in both groups, with goserelin superior to the OC at linear analog scale assessment. Nonmenstrual pain was diminished on both scales without differences between treatments. Women taking the OC experienced a significant reduction in dysmenorrhea. At the end of follow-up, symptoms reappeared without differences in severity between the groups. CONCLUSIONS: Low-dose cyclic OCs may be a valuable alternative for the treatment of dysmenorrhea and nonmenstrual pain associated with endometriosis. Symptoms recurred in most subjects 6 months after drug withdrawal.

PIP: Physicians at the University of Milan in Italy compared data on 29 endometrial patients who received 3.6 mg goserelin in a 28-day subcutaneous depot formulation for 6 months to treat nonmenstrual pelvic pain, dysmenorrhea, and pain during coitus (dyspareunia) with data on 28 other endometrial patients treated with a low-dose monophasic oral contraceptive (OC) (.02 mg ethinyl estradiol and 0.15 mg desogestrel) for 6 months. They followed the women for 6 months after treatment ended. The physicians wanted to determine the efficacy of goserelin, a gonadotropin-releasing hormone (GnRH) agonist, versus a low dose OC to relieve pelvic pain in patients with endometriosis and to compare pain recurrence after drug withdrawal. (GnRH agonists are current medical treatments for pelvic pain, but they have several side effects and are expensive; and therefore their use is restricted.) At the end of treatment, both goserelin and the low-dose OC significantly reduced dyspareunia (p .01), especially goserelin according to the linear analog scale (pain symptom score, 1.8 points lower). Both treatments improved nonmenstrual pain equally at the end of treatment (p .01). The low-dose OC reduced dysmenorrhea greatly at the end of treatment (p .01). The researchers could not evaluate dysmenorrhea in goserelin cases, since these patients experienced amenorrhea. The only persistent significant reduction at the end of follow-up occurred with dyspareunia in goserelin patients (p .05). In the other patients, pelvic pain returned to baseline levels 6 months after treatment ended. The severity of pelvic pain did not differ between groups 6 months after follow-up. These results suggested that low-dose OCs may be an effective alternative treatment for dysmenorrhea and nonmenstrual pelvic pain linked to endometriosis.

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.

Very low dose danazol for relief of endometriosis-associated pelvic pain: a pilot study.

OBJECTIVES: To evaluate the efficacy and safety of very low dose danazol in improving pelvic pain in women with endometriosis, the benefit of preceding the treatment by a short course of a GnRH agonist, symptoms recurrence after drug withdrawal, and variations in menstrual pattern. DESIGN: Open-label, randomized study. SETTING: University hospital endometriosis center. PATIENTS: Forty-two women with moderate or severe pelvic pain and laparoscopically diagnosed endometriosis. INTERVENTIONS: Treatment with oral danazol, 50 mg/d, for 9 months (group I, n = 21) or leuprolide depot for 3 months followed by oral danazol, 50 mg/d, for 6 months (group II, n = 21), and a 6-month follow-up. MAIN OUTCOME MEASURES: Variations in severity of symptoms during treatment and at the end of follow-up as shown by a linear analog scale and a verbal rating scale; menstrual blood loss as assessed by a pictorial chart. RESULTS: Four patients withdrew from the study, one in each group at the fifth month of treatment (for persistent pain) and one in each group during follow-up (they requested additional therapy); one woman in group I was lost to follow-up. Significant improvements were obtained in dysmenorrhea, deep dyspareunia, and nonmenstrual pain in both treatment schedules without differences between the groups. Also menstrual blood loss was significantly reduced in both groups. A temporary fall in high and rise in low density lipoprotein cholesterol was observed in the study population. At the end of follow-up symptoms recurred without significant differences in median pain scores with respect to baseline. CONCLUSION: Very low dose danazol may be an alternative for temporary relief of endometriosis-associated pain. Ovulation is not always inhibited and barrier contraception is needed. Side effects occur but are rarely severe. Further data are required to evaluate the influence of long-term administration on the lipid profile.

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.

Pregnancy at forty and over: a case-control study.

We compared obstetric prognosis in 327 women > or = 40 years old (148 nulliparas, 279 multiparas) with 20-30-year-old matched controls who delivered at our department between 1988 and 1990. Gestational diabetes and chronic hypertension were the only more frequent antepartum complications in cases than controls (2.4% vs. 0.3% and 3.4% vs. 0.3%, respectively). There were more premature deliveries in cases than controls (19% vs. 8%) but no difference in postdate deliveries. Cesarean section was more frequent in cases than controls in both nulliparas (64% vs. 30%) and multiparas (43% vs. 12%). Incidence of abdominal delivery for acute obstetrical indications was not increased in older gravidas. Significant differences were observed in low birthweight (17% vs. 5%) and 5-min Apgar score < 7 (8% vs. 2%). Most of the abnormal Apgar scores were recorded after cesarean section; values for vaginally-delivered infants were comparable in older and younger women. Perinatal mortality was similar in the two groups.

Gonadotropin releasing hormone agonist treatment before hysteroscopic endometrial resection.

OBJECTIVES: To evaluate the effects of treatment with the gonadotropin releasing hormone (GnRH) agonist goserelin before endometrial resection on absorption of distension medium fluid and technical feasibility of the surgical procedure. METHODS: Fifty-five patients reporting menorrhagia underwent endometrial resection after 2 months of goserelin depot therapy (33 cases) or during the proliferative phase of the cycle (22 controls). RESULTS: In the cases, the mean distension medium deficit +/- S.D. was 511 +/- 196 ml versus 647 +/- 245 ml in controls (P = 0.03), and the operating times were, respectively, 14 +/- 4 versus 18 +/- 5 min (P = 0.002). The intrauterine operating conditions were considered excellent or good in 64% of the cases versus 27% of the controls (chi 2 = 5.60, P = 0.02). CONCLUSIONS: GnRH agonists induce endometrial thinning, so that when administered before intrauterine interventions, mucus cellular debris and bleeding should be reduced during surgery and hysteroscopic visibility increased; the operating time may thus be shorter and fluid absorption decreased. However, more data are needed before considering GnRH agonists a proven effective means of facilitating endometrial resection.

Abnormal uterine bleeding associated with iron-deficiency anemia. Etiology and role of hysteroscopy.

We reviewed the clinical and histologic records of 61 consecutive premenopausal women with abnormal uterine bleeding and moderate to severe iron-deficiency anemia investigated in a tertiary care and referral center. Excessive bleeding was caused by benign lesions in 67% of the cases and by anovulation in 25% and was unexplained in 8%. Hysteroscopy revealed an organic intrauterine lesion (submucous myomas in 38%, endometrial polyps in 13%, submucous adenomyomas in 3%) that could be treated endoscopically in more than half the patients. In populations without nutritional deficiencies, a woman of reproductive age with sideropenic anemia and no other evident cause of blood loss or systemic disease should be considered menorrhagic until proven otherwise. Hysteroscopy should be included in evaluations of abnormal uterine bleeding.

Laparoscopic uterine biopsy for diagnosing diffuse adenomyosis.

OBJECTIVE: To investigate the possibility of diagnosing diffuse adenomyosis with the uterus in situ. STUDY DESIGN: Myometrial needle biopsy was performed on a prospectively evaluated series of 72 women undergoing laparoscopy for infertility and/or chronic pelvic pain. Before surgery the patients completed a questionnaire on the presence and severity of dysmenorrhea according to a linear analog and verbal rating scale. A single specimen was taken from along the median line in the upper third of the posterior uterine wall using a 14-gauge Tru-cut needle inserted through the anterior abdominal wall under laparoscopic guidance. RESULTS: No complications occurred. Adenomyosis was diagnosed in 8 of the 42 subjects with menstrual pain and 5 of the 30 asymptomatic ones (19% versus 17%) and pelvic endometriosis in 27 and 10, respectively (64% versus 33%, P = .02). The frequency of moderate or severe dysmenorrhea was greater in women with adenomyosis than in those without adenomyosis or endometriosis, but the difference was not statistically significant. Conversely, menstrual pain was significantly more frequent and severe in patients with endometriosis as compared with women who had neither endometriosis nor adenomyosis. CONCLUSION: Uterine needle biopsy is simple, rapid and safe, but its overall clinical importance, as well as the predictive value of a normal histologic result, requires further investigation.

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 gamma 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.

Electrocardiographic abnormalities in infants born from mothers with autoimmune diseases--a multicentre prospective study.

OBJECTIVES: To assess the prevalence of congenital heart block (CHB) and electrocardiographic (ECG) abnormalities in infants of anti-Ro/SSA-positive women. METHODS: Sixty anti-Ro-positive and 36 anti-Ro-negative patients were prospectively followed before/during pregnancy and underwent weekly fetal echocardiography from 18th to 26th weeks of gestational age. Infants' ECG and/or ECG-Holter were performed at 1, 3, 6 and 12 months. ECG of 200 consecutive neonates were used as a healthy control group. RESULTS: One of 61 fetuses of anti-Ro-positive mothers developed CHB (20th week); another anti-Ro-positive baby developed second degree atrioventricular (AV) block (30th week). The prevalence of transient first degree AV block detected post-natally was significantly higher in the anti-Ro-positive group, in comparison with healthy controls (P = 0.002). No differences in corrected QT (QTc) interval prolongation prevalence (>/=440 ms) was observed between the anti-Ro-positive and -negative groups, but both were significantly higher than that of the control population (P < 0.001). ECG-Holter showed QTc prolongation in 59% of infants of anti-Ro-positive and in 60% of infants of anti-Ro-negative mothers. Holter QTc was >/=470 ms in four infants of anti-Ro-positive group and two of anti-Ro-negative group. Known acquired causes of QTc prolongation were excluded. CONCLUSIONS: This prospective study confirms the low occurrence of CHB in newborns from anti-Ro-positive mothers. ECG abnormalities (first degree AV block and QTc interval prolongation) are frequent in infants of mothers with autoimmune diseases, independently of maternal disease, autoantibody profile and treatment during pregnancy.

Does contraception modify the risk of endometriosis?

Long episodes of regular, prolonged, abundant menstrual flows are generally agreed to increase the risk of endometriosis. Since oral oestrogen-progestogen combinations reduce and intra-uterine contraceptive devices increase menstrual flow, an effect on the risk of development of endometriosis in women utilizing these forms of contraception could be expected. Analysis of the most recent epidemiological observations shows no consensus on a possible relationship between use of cyclic oral contraceptives and endometriosis, with an increase, a decrease, and no effect on the risk of developing the disease all being reported. A lower relative risk of endometriosis in previous users of the intrauterine contraceptive device was only found in two series, most of the other data suggesting a rise in risk or no effect. Further studies on the relationship between type of contraception and endometriosis are needed to demonstrate whether the risk of development of the disease could be influenced, and whether well tolerated, relatively inexpensive, long-term treatment might be available for symptomatic patients not desiring offspring.

PIP: Epidemiologic studies on endometriosis have indicated that the various risk factors proposed have only led to less than conclusive findings. Menstrual cycle characteristics is one risk factor which seems to be significantly associated with the incidence of endometriosis. This article presents a review of epidemiological data from recently published literature. This review was conducted to clarify whether or not contraception is a risk factor for developing endometriosis. The use of oral estrogen-progestogen was the first form of contraception reviewed. Overall, there seemed to be an unclear picture presented by the seven articles reviewed. The relationship between oral contraceptive use and risk of developing endometriosis is not clearly demonstrated. The use of the IUD as another method of contraception was explored next. Most published studies suggest either no effect or an increase in risk for developing endometriosis with a history of IUD use. Further studies are needed.

A modified technique for correction of the complete septate uterus.

When correcting a complete uterine septum, it is recommended that one should spare the cervical portion to avoid the possible risk of cervical incompetence. However, it may be difficult to create a communication between the uterine cavities above the internal os. In seven patients with complete septate uterus we incised the cervical portion with Metzenbaum scissors and the corporal portion with microscissors under hysteroscopic guidance. The operating times were shorter and the distension fluid deficit smaller compared with nine historical controls in whom the cervical septum was spared. No intraoperative or obstetric complications were associated with cervical septal section. This modified technique is simple, rapid, safe, inexpensive, and may be considered among the alternative treatments to correct a complete septate uterus.

Formulation study and anti-inflammatory efficacy of topical semi-solids containing a nitro ester of flurbiprofen.

A new nitro-oxybutylester of flurbiprofen (NO-FP) is a promising anti-inflammatory drug in the treatment of dermatological disorders, and the feasibility of its cutaneous administration was evaluated. Four different semi-solid formulations were evaluated in order to assess the influence of the composition on the drug amount retained in the stratum corneum and epidermis (SCE). The lipophilic ointment induced the highest NO-FP amount retained in the SCE and, therefore, skin permeation enhancers (Transcutol), Lauroglycol), oleic acid and isopropyl myristate) were added to this formulation. The in vitro NO-FP amounts retained in the SCE were correlated with the solubility parameters, and a good linear correlation was found (r(2) = 0.925). The formulation of the lipophilic ointment was optimized, and the activity of this preparation was verified in methyl-nicotinate-induced contact urticaria and UV-induced erythema obtaining good results in terms of efficacy and safety.