Perinatal outcome in pregnant women with cancer: are there any effects of chemotherapy?

Cancer is the leading cause of death in women of reproductive age. During the last decades and especially in developed countries, the incidence of cancer is increasing dramatically, with an incidence of 1 in 1,000 pregnancies. This is mostly related to delay of pregnancy into the late reproductive years. The aim of this study was to investigate the outcome of pregnancy in women with diagnosis of cancer; in particular, neonatal morbidity and mortality, after in utero exposure to chemotherapy, were evaluated. A total of 59 singletons and one twin pregnancy complicated by cancer were followed at our tertiary centre over the last 15 years. A different treatment, based on surgery and/or chemotherapy in pregnancy or delayed to the postpartum period, was employed. There were 59 live births (97%), one foetal loss and one stillbirth at 28 weeks. The congenital malformation rate was 5% (n = 3). The rate of preterm birth was 83%. The mean birthweight and mean birthweight percentile were 2,098 g (740-3930) and 46 (7-93), respectively; 32% of neonates were small for gestational age (SGA). Dividing the population into treated or untreated with chemotherapy, the rate of SGA was not statistically significant different between the two groups. Our results showed that chemotherapy administered during the second trimester or later did not influence intrauterine foetal growth, but the high prevalence of SGA neonates in the two groups, exposed or not exposed to chemotherapy, suggests an influence of maternal cancer per se on foetal growth.

Epidermal growth factor-like domain 7 promotes migration and invasion of human trophoblast cells through activation of MAPK, PI3K and NOTCH signaling pathways.

Epidermal growth factor-like domain 7 (Egfl7) is a gene that encodes a partially secreted protein and whose expression is largely restricted to the endothelia. We recently reported that EGFL7 is also expressed by trophoblast cells in mouse and human placentas. Here, we investigated the molecular pathways that are regulated by EGFL7 in trophoblast cells. Stable EGFL7 overexpression in a Jeg3 human choriocarcinoma cell line resulted in significantly increased cell migration and invasiveness, while cell proliferation was unaffected. Analysis of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways showed that EGFL7 promotes Jeg3 cell motility by activating both pathways. We show that EGFL7 activates the epidermal growth factor receptor (EGFR) in Jeg3 cells, resulting in downstream activation of extracellular regulated kinases (ERKs). In addition, we provide evidence that EGFL7-triggered migration of Jeg3 cells involves activation of NOTCH signaling. EGFL7 and NOTCH1 are co-expressed in Jeg3 cells, and blocking of NOTCH activation abrogates enhanced migration of Jeg3 cells overexpressing EGFL7. We also demonstrate that signaling through EGFR and NOTCH converged to mediate EGFL7 effects. Reduction of endogenous EGFL7 expression in Jeg3 cells significantly decreased cell migration. We further confirmed that EGFL7 stimulates cell migration by using primary human first trimester trophoblast (PTB) cells overexpressing EGFL7. In conclusion, our data suggest that in trophoblast cells, EGFL7 regulates cell migration and invasion by activating multiple signaling pathways. Our results provide a possible explanation for the correlation between reduced expression of EGFL7 and inadequate trophoblast invasion observed in placentopathies.

The relationship between TORCH complex false positivity and obstetric outcome in patients with antiphospholipid syndrome.

OBJECTIVE: The presence of TORCH IgM positivity is not a specific indicator of primary infection; the assessment of IgG avidity index has been shown to be useful in identifying or excluding primary infection in pregnant women with no pre-gestational TORCH serology. TORCH is an acronym for Toxoplasmosis, Others (HBV, syphilis, Varicella-Zoster virus, Epstein Barr virus, Coxsackie virus and Parvovirus), Rubella, Cytomegalovirus (CMV) and Herpes Simplex. PATIENTS AND METHODS: Data from 54 pregnancies in women with antiphospholipid syndrome (APS) were assessed in comparison with data from 222 healthy pregnant women as controls. Each woman in both groups was systematically screened for TORCH IgG and IgM during pre-conceptional evaluation and/or at the beginning of pregnancy. The assessment of IgG avidity was also evaluated in order to identify primary infection or false positivity. RESULTS: A significant increase of CMV IgM false positivity in APS in comparison with controls was detected. A worse pregnancy outcome was observed among APS patients having CMV IgM false positivity in comparison with APS patients without false positivity; in particular a statistically significant lower neonatal birth weight and a lower neonatal birth weight percentile were observed. CONCLUSION: Our data suggest that the presence of CMV IgM false positivity could represent a novel prognostic factor for poor pregnancy outcome in APS patients.

False-positive IgM for CMV in pregnant women with autoimmune disease: a novel prognostic factor for poor pregnancy outcome.

Our aims were to assess the frequency of false-positive IgM antibodies for cytomegalovirus in pregnant women with autoimmune diseases and in healthy women (controls) and to determine their relationship with pregnancy outcome. Data from 133 pregnancies in 118 patients with autoimmune diseases and from 222 pregnancies in 198 controls were assessed. When positive IgM for cytomegalovirus was detected, IgG avidity, cytomegalovirus isolation and polymerase chain reaction for CMV-DNA in maternal urine and amniotic fluid samples were performed in order to identify primary infection or false positivity. A statistically significantly higher rate of false-positive IgM was found in pregnancies with autoimmune diseases (16.5%) in comparison with controls (0.9%). A worse pregnancy outcome was observed among patients with autoimmune disease and false cytomegalovirus IgM in comparison with those without false positivity: earlier week of delivery (p = 0.017), lower neonatal birth weight (p = 0.0004) and neonatal birth weight percentile (p = 0.002), higher rate of intrauterine growth restriction (p = 0.02) and babies weighing less than 2000 g (p = 0.025) were encountered. The presence of false cytomegalovirus IgM in patients with autoimmune diseases could be used as a novel prognostic index of poor pregnancy outcome: it may reflect a non-specific activation of the immune system that could negatively affect pregnancy outcome. Lupus (2010) 19, 844-849.

Low-molecular weight heparin induces in vitro trophoblast invasiveness: role of matrix metalloproteinases and tissue inhibitors.

Heparin is used widely for the prevention of pregnancy loss in pregnant women with thrombophilia. However, it is still unknown if heparin may be able to affect trophoblast functions. Therefore, we investigated the hypothesis that low-molecular weight heparin (LMWH) might regulate in vitro trophoblast invasiveness and placental production of matrix metalloproteinases (MMPs) and tissue inhibitors (TIMPs). In the first-trimester placental tissue, the MMP-9 expression was observed in both villous and extravillous cytotrophoblast cells, and MMP-2 mainly in villous cytotrophoblast. In human choriocarcinoma cells (JAR), MMP-2 was the dominant form. Heparin significantly enhanced both pro-MMPs and the active forms, and increased Matrigel invasiveness of extravillous trophoblast and choriocarcinoma cells. In choriocarcinoma cells the heparin effect was also indirect, inducing a significant decrease in TIMP-1 and TIMP-2 protein expressions and mRNAs. The present data suggest that the increase in trophoblast invasion by heparin is due to a specific protein playing a role in placental invasion. These observations may help in understanding the effects of heparin treatment during pregnancy.

[Postpartum hemorrhage]. / L'emorragia del postpartum.

Postpartum hemorrhage, frequently due to uterine atony, is an important cause of maternal death and morbidity. The knowledge of causes, of antenatal and intrapartum risk factors and of physiopathological changes in hemodynamics and coagulation during pregnancy are essential for the management of the condition. At the present time, many efforts are made to organize a multidisciplinary approach to this complication of delivery involving clinical and laboratory staffs, since the rapid correction of hypovolemia, the diagnosis and treatment of defective coagulation, the surgical and pharmacological control of bleeding are mandatory. Several medical options have been developed and the surgical management includes traditional and newer conservative procedures with variable success rates. The developments in the treatment of postpartum hemorrhage may reduce hysterectomy that is to be considered the last resort to resolve the hemorrhage in some cases. In the modern management of postpartum hemorrhage protocols and guidelines should be available in every delivery room.

Pregnancy outcome in relation to uterine artery flow velocity waveforms and clinical characteristics in women with antiphospholipid syndrome.

OBJECTIVE: To determine whether uterine artery velocimetry is a useful tool for identifying pregnancies with antiphospholipid syndrome at risk for adverse outcome. METHODS: Twenty-four women with antiphospholipid syndrome, who had experienced 56 fetal losses in 63 previous pregnancies (88.9%), were treated with prednisone (40 mg/day) and aspirin (100 mg/day) during 28 pregnancies. Color Doppler ultrasound was performed at 18-24 weeks' gestation to investigate the resistance index of the uterine arteries. RESULTS: Treated women delivered 23 live infants in the 28 pregnancies (82.1%). Three infants weighed less than the tenth percentile (13%). Five pregnancies were complicated by preeclampsia and ten by nonproteinuric gestational hypertension. Positive results for all three assays for antiphospholipid antibodies (anticardiolipin antibodies, lupus anti-coagulant, VDRL) at conception identified pregnancies destined to have poor fetal outcome and a significantly lower birth weight compared to pregnancies not having all three assays positive. An abnormal resistance index of the uterine arteries predicted pregnancies with poor fetal outcome in terms of week of delivery, birth weight, and birth percentile, as well as four of five cases of preeclampsia. CONCLUSIONS: Three assays positive for antiphospholipid antibodies at conception and an abnormal resistance index of the uterine arteries at 18-24 weeks' gestation predicted pregnancies at major risk for obstetric complications. Future studies should determine whether treatment can be modulated based on the Doppler findings.

Carbohydrate metabolism in gestational diabetes: effect of chronic hypertension.

OBJECTIVE: To evaluate whether the coexistence of chronic hypertension and gestational diabetes mellitus (GDM) is characterized by a greater impairment of carbohydrate metabolism than GDM alone. METHODS: Carbohydrate metabolism of eight women with chronic hypertensive GDM and 15 normotensive women with GDM was evaluated in the third trimester using the oral glucose tolerance test (GTT) and hyperinsulinemic-euglycemic clamp technique. Controls were ten normotensive, glucose-tolerant, pregnant women in the third trimester. RESULTS: Insulin sensitivity of women with chronic hypertension and GDM was approximately twofold lower than those with GDM only (1.54+/-0.35 versus 4.15+/-0.31, P < .001) and approximately fivefold lower than controls (1.54+/-0.35 versus 7.65+/-0.66, P < .001). Women with chronic hypertension and concomitant GDM had higher insulin levels in response to GTT than controls (P < .001 repeated measures analysis of variance). In all subjects, mean arterial pressure (MAP) had a strong negative correlation with maternal insulin sensitivity (r = -0.62, P < .001). Significant correlation was also found between percent of body fat and insulin sensitivity (r = -0.53, P < .002). Those regressions were still significant when adjusted for percent of body fat and MAP. CONCLUSION: Gravidas with chronic hypertension and GDM are more insulin resistant than those with GDM alone. Blood pressure, in a population of pregnant women with normal and abnormal carbohydrate metabolism, is a stronger predictor of insulin resistance than adiposity.

Effect of maternal carbohydrate metabolism on fetal growth.

OBJECTIVE: To determine the effect of maternal carbohydrate metabolism and anthropometric characteristics on fetal growth. METHODS: Eight pregnant women in the third trimester with unexplained fetal growth restriction (FGR) and 11 women with normal pregnancies in the third trimester were evaluated for maternal carbohydrate metabolism, using oral glucose tolerance tests and hyperinsulinemic-euglycemic clamps. These data and maternal anthropometric characteristics subsequently were related to relative birth weight, defined as observed birth weight x 100/50th percentile birth weight. RESULTS: The women with FGR pregnancies were more insulin sensitive than were controls (21.6+/-4.4 versus 16.7+/-4.8 micromol/kg x min, P < .05) and showed reduced insulin and glucose areas under the curve (96,293+/-25,870 versus 145,291+/-49,356 pmol/L, P < .03; 1057.0+/-184.7 versus 1210.1 +/-85.9 mmol/L, P < .05, respectively). No differences were seen in fasting plasma glucose, insulin and human placental lactogen samples, age, height, pregravid weight, weight gain, and parity. In all patients, maternal insulin sensitivity and weight gain correlated well with relative birth weight (r =-.65, P < .002; r=.68, P < .001, respectively). When the same analysis was computed separately in the groups, insulin sensitivity exhibited a strong negative correlation with relative birth weight in the FGR group but not in controls (r=-.84, P < .007; r=-.54, P=.08, respectively). Conversely, in control women the best correlation between relative birth weight and the other variables studied was seen with maternal weight gain (r=.82, P < .002). CONCLUSION: Women with unexplained FGR have a different glucose metabolic pattern than do normals. We speculate that increased insulin sensitivity leads to a reduction in metabolic substrates for fetal growth.

Interleukin-3 and human trophoblast: in vitro explanations for the effect of interleukin in patients with antiphospholipid antibody syndrome.

OBJECTIVE: To examine the effect of interleukin (IL)-3 on in vitro trophoblast differentiation, hormone production, and invasiveness affected by antiphospholipid antibodies. DESIGN: Primary cytotrophoblast cell cultures. SETTING: Obstetrics and Gynecology Department of the Catholic University, Rome, Italy. PATIENT(S): Five normal pregnant women underwent uncomplicated vaginal delivery at 36 weeks of gestation. INTERVENTION(S): Immunoglobulin (Ig) G antibodies were isolated from the plasma of two patients with antiphospholipid syndrome and two normal control subjects with the use of protein-G Sepharose columns. Cytotrophoblast cells were dispersed in Ringer's bicarbonate buffer containing trypsin and DNAseI, filtered, and layered over a Percoll gradient in Hank's balanced salt solution. MAIN OUTCOME MEASURE(S): We investigated the effects of IL-3 and antiphospholipid antibodies on trophoblast cell invasiveness, differentiation, and hormone secretion. RESULT(S): IgG obtained from patients with antiphospholipid syndrome bound to trophoblast cells, with inhibitory effects on the cells' invasiveness, differentiation, and hCG secretion. IL-3 was able to restore in vitro placental functions. CONCLUSION(S): These results imply that IL-3 favorably affects human trophoblast implantation and development.

Pregnancy outcome in women with cardiac valve prosthesis.

Twenty-one pregnancies in 16 women who conceived after cardiac valve replacement were reviewed. Oral anticoagulants were discontinued before conception or as soon as possible for subcutaneous heparin treatment (8000-14,000 IU every 8-12 h) and resumed in the second trimester until the last period of pregnancy when oral anticoagulants were replaced again by heparin. No therapeutic abortion was performed. The spontaneous abortion rate was found to be 14.3% (3/21). Preterm delivery (< or = 37 weeks) and low birth weight babies (< 2500 g) were 29.4% (5/17) and 35.3% (6/17), respectively, significantly more frequent than those of the control group (P < 0.02 and P < 0.0005). No significant statistical difference was found when the rate of spontaneous abortion [14.3% (3/21)] and the rate of fetal growth retardation [11.8% (2/17)] were compared with the control group. The majority of thromboembolic events (6/7) occurred during heparin regimen in three mothers; one of them subsequently died. No coumarin embryopathy was observed and the physical and mental development in the 16 surviving children was good. This study confirms: (1) the increased rate of preterm delivery and infants weighing < 2500 g; (2) the increased risk of maternal thrombosis related to heparin use; and (3) the good follow-up in the surviving children.

Urinary kallikrein and kininase activity in normal and complicated by hypertension pregnancy.

Kallikrein and kininase activities were determined in urine of 58 hospitalized pregnant patients: 15 with E.P.H. gestosis, 10 with chronic hypertension, 18 with non proteinuric pregnancy induced hypertension, 15 with no hemodynamic disease as controls. All our cases with hypertension were treated with alpha-methyl-dopa. A significant increase in urinary kininase activity was shown by only E.P.H. gestosis group vs. controls. In the same group we found a significant decrease in urinary kallikrein activity vs. controls, in contrast with the results obtained previously, perhaps because of the different measuring method. The kininase/kallikrein ratio, theoretically indicative of kinins activity, increased significantly only in the E.P.H. gestosis group.

Low-dose aspirin and vascular response in pregnant patients sensitive to angiotensin II.

The angiotensin sensitivity test was performed in 25 high risk pregnant women before and after administration of low-dose aspirin (100 mg/day for 7 days). After aspirin administration there was a significant decrease in AII sensitivity in sensitive patients with no change in nonsensitive patients. Low-dose aspirin favorably affects sensitivity to AII in sensitive patients, thus indicating a reduced vascular reactivity as a consequence of this regimen.

The use of prostaglandin E2 for cervical ripening in patients requiring induction of labour.

A total of 290 women who required induction of labour for medical or obstetric reasons were given single or multiple doses of prostaglandin E2 gel (0.5 mg) to induce cervical ripening. Onset of labour occurred in 185 (63.8%) of the women treated with the gel, without any further treatment. The overall Caesarean section rate was 27.2% (79/290) and was significantly higher among those with an initially low Bishop score than in those with a higher initial score (34.7% versus 22.1%; P = 0.025). Prostaglandin E2 gel appears to be of considerable clinical benefit, especially where no other options are available except Caesarean section or a very long, difficult labour that may result in significant fetal distress.

[Lipid metabolism in newborn infants at birth. Obstetrical-pediatric aspects]. / Alcune osservazioni sul metabolismo lipidico del neonato alla nascita. Aspetti ostetrico-pediatrici.

Lipid parameters in the cord blood of neonates and that of their mothers at birth were studied in a series of 67 subjects divides in accordance with prior disease or diseases arising during pregnancy. From the results obtained in this albeit restricted study, agreement is expressed with the literature view that there is a common genetic control of lipid metabolism in the foetus, which is unusual and independent of that in the mother. An interesting, though unexplained finding was the absence of prebetalipoproteins in the cord blood of 71.5% of the control group.

[Observations on lipid metabolism in normal pregnancy and in some pathological pregnancy disorders]. / Osservazioni sul metabolismo lipidico nella gravidanza fisiologica e in alcuni quadri di patologia gravidica.

Chemical determination of total and esterified cholesterol and electrophoretic separation of plasma lipoproteins was carried out in a chemico-clinical approach to the pathology of lipide metabolism in pregnancy. In a future study, the investigation will be extended to the neonatal aspect of the problem. 136 women were studied, with 446 samples being taken, specifically: 65 controls, i.e. pregnant women not presenting pathology that might obviously involve lipide metabolism, 36 hypertense pregnant women, 28 diabetic and 7 with gravidic hepatosis. Observation of the data confirms that in pregnancy there is a steady, meaningful increase in cholesterolaemia and that the electrophoretic picture shows a steady reduction in alpha-lipoproteins, with stimulatneous increase in pre-beta proteins, reaching a peak in hepatosis cases, and an increase in beta lipoproteins. All this agrees with functional and teleological modifications in lipide metabolism during gestation.

[Therapy and prevention of obstetric hemorrhage by tamponade using a balloon catheter]. / Terapia e prevenzione dell'emorragia ostetrica mediante tamponamento con catetere a palloncino.

The aim of this study was to verify the possibility to use a balloon catheter as hemostatic method in pregnancies at high risk for hemorrhage as an alternative to less conservative surgical procedures. In 4 pregnancies at risk for hemorrhage, a compressive endouterine or endocervical method, consisting of a balloon catheter filled of warm saline solution, was used in order to stop or to prevent otherwise uncontrollable bleeding. In the cases treated the use of the balloon catheter was safe and effective both in the treatment of hemorrhage due to abnormal placentation and in the prevention of hemorrhagic complications due to abnormal implantation of pregnancy. Among novel medical and surgical approaches developed to control obstetric hemorrhage, tamponade using a balloon catheter could be considered a valid option. Moreover, this procedure, by avoiding radical surgical treatments, such as hysterectomy, which are frequently performed in unstable patients, could offer the advantage of preserving fertility.

[Continuous subcutaneous administration of terbutaline in the therapy of threatening premature labour]. / Uso della somministrazione continua sottocutanea di terbutalina nella terapia della minaccia di parto pretermine.

The purpose of this study was to evaluate the tocolytic efficacy of terbutaline, administered subcutaneously in a low-dose continuous infusion, and intermittent high-dose boluses. The population study consisted of 13 women admitted with the diagnosis of Threatened Preterm Labour. Before starting chronic infusion by terbutaline, patients received 48 hour of therapy with intravenous MgSO4 for acute tocolysis. Therapy with microinfusor was continued until the 37th week of gestation or until labor. The mean gestational age at the beginning of therapy was 25.6 +/- 3.5 and pregnancies were prolonged an average of 65.5 +/- 29 days. In any case uterine activity was diminished by terbutaline therapy in all patients. Patient tolerance was excellent and there were no significant complications due to the therapy.

The use of nifedipine as first-line hypotensive therapy in gestational hypertension.

Nifedipine was administered to 49 pregnant women with gestational hypertension as first-line therapy, and were longitudinally studied as paired observations for 3 or 10 day intervals of treatment with nifedipine until delivery. All the patients assumed a slow release formulation of nifedipine at the dose of 40-80 mg/24 hr in 2-3 administrations. Blood pressure was taken at least 4 times a day. The patients were divided in two groups: 32 women with non proteinuric gestational hypertension (NPGH) and 17 women with proteinuric preeclampsia (PP). No statistically significant modification of blood pressure was observed in both groups under treatment. However, NPGH showed a trend to reducing, while PP demonstrated a tendency to worsening both systolic and diastolic blood pressures. After treatment with nifedipine the platelet count of both groups was found unchanged. No adverse fetal or newborn effects imputable to the drug were observed. The present study demonstrates that nifedipine alone, at the doses used, is not effective in reducing blood pressure in long-term treatment. However the treatment could concur to avoid sharp and dangerous increases of blood pressure.

Cocaine during pregnancy: a critical review of the literature.

A number of epidemiological indices suggest that the use of cocaine in Italy is increasing, thus explaining the importance of scientific interest in this field. There is considerable disparity between the scientific papers published in the literature concerning the damaging effects on fetus and mother linked to the use of cocaine during pregnancy. The main problem consists of the method used to identify those patients using cocaine. These methods are burdened by a high level of false negatives: subjects who often use a variety of active pharmacological substances are identified and the methods are not always suitable for classifying subjects according to useful clinical parameters. This is reflected in the poor quality of data concerning the epidemiology and clinical aspects of cocaine abuse during pregnancy. A careful selection of the best scientific papers published in the literature shows that the effects on the maternal organism are slight, whereas those on the fetus are more severe. Compared to controls, the use of cocaine is associated with a high percentage of cardiac malformations, preterm delivery, low birth weight and minor anomalies of the nervous system. Results relating to sudden neonatal death are discordant. This paper shows that the use of cocaine is often underestimated both in epidemiological terms and from the fetal point of view. This behaviour is linked to the belief that the effects of cocaine are benign.