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.

PP029. Gestational hypertension and birth weight in twin pregnancies.

INTRODUCTION: It is well known that hypertensive disorders of pregnancy are most frequent in twin pregnancies than in singleton ones. As demonstrated by a previous work of our group, twin pregnancies complicated by preeclampsia are associated with a higher rate of "small for gestational age" (SGA) neonates and inter-twin weight discordance than normotensive ones. OBJECTIVES: The present study investigates the effect of gestational hypertension (GH) on neonatal birth weight, inter-twin weight discordance and growth restriction rate among twin pregnancies. METHODS: A 26 year retrospective study was undertaken by examining 196 twin pregnancies complicated by GH, from January 1, 1980 to December 31, 2006, and comparing them to 912 normotensive twin pregnancies. RESULTS: No significant differences were observed between the two groups in relationship to birth weight, inter-twin weight discordance and growth restriction rate, with a trend towards a higher birth weight in GH group. In normotensive group, the discordance >25% was associated with a lower gestational age at the delivery (p<0.00001). Moreover, the rate of pregnancies with SGA second twin gradually rose while paralleling the degree of discordance. CONCLUSION: Contrary to preeclampsia in twin pregnancies the outcome of those complicated by GH is similar to normotensive ones. The trend towards a higher birth weight in GH seems apparently paradoxical, but it may reflect the role of uncomplicated hypertension in twin pregnancies: the increased blood pressure could be a physiologic response for more blood nutrient supply to the fetuses.

PP158. Hypertensive disorders in pregnant women affected by type I diabetes.

INTRODUCTION: Type I diabetes in pregnancy is associated with an increased incidence of hypertensive disorders. OBJECTIVES: The aim of the present study was to evaluate the incidence of hypertensive disorders in pregnant women affected by type I diabetes and pregnancy outcome in women with and without hypertension. METHODS: One hundred seventy two pregnancies in 150 women affected by type I diabetes were assessed. Twelve pregnancies were excluded (8 because of spontaneous abortions, 1 for voluntary abortion and 3 twin pregnancies), and 160 pregnancies were considered for the study. RESULTS: Twenty-five pregnancies (15.6%) were complicated by hypertensive disorders: 4.4% by chronic hypertension (CH), 5% by gestational hypertension (GH), 4.4% by preeclampsia (PE) and 1.8% by preeclampsia superimposed on chronic hypertension (PE+CH); 32% of the women presented a vascular disease (renal or retinal disease). The diabetic women with hypertensive complications were compared with diabetic women without hypertension. The main results are shown in Table 1. Significant differences in mean birth weight and mean gestational age were found. The group affected by preeclampsia showed 14.7% of small for gestational age (SGA) neonates (birth weight percentile less than 10th pc), and 57.1% of large for gestational age (LGA) neonates (birth weight percentile greater than 90th pc), two of them were over 4000 g. Only one case of very preterm delivery (<32 weeks) was observed in the sample. CONCLUSION: As expected, the incidence of hypertensive disorders in population affected by type 1 diabetes is higher than in general population and a poor pregnancy outcome was observed in this group of women. However, the neonatal outcome of women affected by preeclampsia is not different from that observed in women without hypertensive complications (diabetic controls) in terms of mean birth weight despite a significantly lower mean week gestation at delivery.

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.

[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.

Celiac disease and inflammatory bowel disease in pregnancy.

An adverse influence on reproductive life and obstetric complications are known to occur in women with celiac disease (clinical and subclinical disease) or inflammatory bowel diseases. Treatment can improve the pregnancy outcome; therefore, it is advisable that a clinical evaluation is performed by a joint team of obstetricians, internists and surgeons. The preconception clinical evaluation of the affected women is useful to focus on the different clinical aspects of the disease and to indicate specific therapeutic strategies. In this study a review of the literature regard to celiac disease and inflammatory bowel disease in pregnancy is presented.

Uterine myomectomy in pregnant women.

OBJECTIVE: To determine whether myomectomy during pregnancy in selected patients improves outcome. METHODS: Retrospective analysis of 18 patients who underwent myomectomy between the 6th and 24th week of gestational age. Surgical management of tumors was required on the basis of the characteristics of the myomas and symptoms. The dimensions and site of myomas, symptoms of the patients, time and mode of delivery, and pregnancy outcome were analyzed. RESULTS: One woman was lost to follow-up, and one suffered a miscarriage. The remaining 16 patients delivered healthy babies between the 36th and 41st week; 14 delivered by cesarean section, and 2 vaginally. CONCLUSION: We suggest that myomectomy during pregnancy may be considered safe in selected patients. Moreover, it permits good pregnancy outcome with healthy babies delivered at term.

There is poor agreement between manual auscultatory and automated oscillometric methods for the measurement of blood pressure in normotensive pregnant women.

OBJECTIVE: To assess the agreement between manual auscultatory arterial blood pressure values and the values obtained by an automated oscillometric device in normotensive pregnant patients. METHODS: Arterial blood pressure was determined concomitantly by a Dinamap 1846 sx/p device and by one observer (I, IV, V Korotkoff sounds) blinded to the Dinamap values. Agreement between methods was tested and graded according to the protocol of the British Hypertension Society. RESULTS: A total of 490 observations were performed. Differences were observed between the manual auscultatory method and the Dinamap method. In monitoring normotensive pregnant patients with a Dinamap device, an error was made of about 10 mmHg in 22% of the observations for systolic arterial blood pressure (BP); in 11% for diastolic arterial BP (IV sound); and in 15% for diastolic arterial BP (V sound). According to the British Hypertension Society protocol, the overall grade reached was 'C'. CONCLUSIONS: Although an underestimation of only 10 mmHg was shown, this can be of great importance in delaying a correct diagnosis of pre-eclampsia. The assessment of agreement of the Dinamap 1846 sx/p device in hypertensive pregnant patients should also be determined. A prospective study could be useful to determine the effectiveness of an automated device in detecting hypertensive disease in pregnancy.

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.

Emergency cerclage in the presence of protruding membranes: is pregnancy outcome predictable?

BACKGROUND: The aim of this retrospective study is to verify whether some maternal features are related to pregnancy outcome in cases of emergency mid-trimester cerclage when membranes are protruding through the dilated cervix. METHODS: Between 1988 and 1996 twenty-three pregnant patients with dilated cervix and protruding membranes were treated with emergency cerclage. At the time of cerclage, gestational age ranged from 17 to 27 weeks (median 22). RESULTS: Pregnancy was prolonged from 0 to 20 weeks (median 4). Eleven living infants were born (46%); median gestational age at delivery was 25 weeks (range 21-39) and median birth weight 700 g (range 350-3980 g). Obstetric histories, white blood cell count, and vaginal-cervical and urine cultures obtained on admission were analyzed in the two following groups: data from patients with good pregnancy outcome (live births) versus those from patients with poor outcome (stillbirths and neonatal deaths). No significant difference was found between the groups for the above mentioned maternal features. CONCLUSIONS: The possibility of 46% live births is considered a good result for mid-trimester emergency cerclage when the membranes are protruding. Success of the procedure remains unpredictable on the basis of the maternal features investigated.

Birth weight in pre-eclamptic and normotensive twin pregnancies: an analysis of discordance and growth restriction.

The aim of this study was to verify whether twin pregnancies complicated by pre-eclampsia were associated with a higher rate of inter-twin weight discordance or an increased prevalence of small for gestational age (SGA) neonates than in normotensive twin pregnancies. A 17 year retrospective study was undertaken by examining 76 twin pregnancies complicated by pre-eclampsia and comparing them with 400 normotensive twin pregnancies. The case notes were reviewed in reference to birth weight differences, birth order, pregnancy outcome and inter-twin birth weight discordance. Statistical analyses were performed with t-test, contingency tables, regression curves, rank sum test and non-parametric survival plots. Power analysis was also carried out. Pre-eclamptic twin pregnancies were delivered at similar weeks of gestation to normotensive. They resulted in a smaller size for the second twin the earlier the delivery week, while in normotensive twin pregnancies no significant difference occurred at any week. Twin pregnancies complicated by pre-eclampsia showed higher rates of SGA neonates among second twins than those with normal pressure. The >25% discordance was associated with lower gestational age at delivery in each group [mean (range) 33 weeks (27-38) versus 37 (29-41), P < 0.005 pre-eclampsia and 35 weeks (25-41) versus 38 (25-42), P < 0.001 normotensive]. In pre-eclampsia the concomitant occurrence of SGA second twin and the discordance >25% was associated with shorter gestation while the presence of SGA second twin alone was not.

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.

Gestational hypertension but not pre-eclampsia is associated with insulin resistance syndrome characteristics.

The aim of this study was to assess whether the metabolic characteristics of insulin resistance syndrome are present in pre-eclamptic (PE), gestational (GH) and chronic hypertensive (CH) pregnancies. Glucose and insulin serum concentrations, both fasting and after oral administration of a glucose tolerance test, were evaluated in 26 hypertensive pregnant women (10 PE, 10 GH and six CH patients) and in 10 healthy controls during the third trimester of gestation. Insulin sensitivity was assessed using the hyperinsulinaemic-euglycaemic clamp technique. The plasma concentrations of triglyceride (TG), high density (HDL), low density (LDL), and very low density (VLDL) lipoprotein cholesterol, apolipoproteins AI and B, and non-esterified fatty acid (NEFA) were also measured. Women with GH exhibited approximately 40% lower steady-state insulin sensitivity index (ISI) compared to controls (3.75 versus 6.34, P < 0.03), as well as approximately 33% higher mean plasma TG (3.57 versus 2.68 mmol/l, P < 0.01), and approximately 69% higher mean NEFA (0.59 versus 0.35 mmol/l, P < 0.01). Women with PE showed similar ISI but reduced insulin and glucose areas under curve compared to controls (P < 0.006, P < 0.0005 respectively). Women with PE also had higher HDL-cholesterol and apo-AI than controls. Patients with CH had similar lipid and carbohydrate metabolism to control subjects. In conclusion, women with GH exhibit metabolic features similar to those of patients with insulin resistance syndrome, suggesting that similar abnormalities could be involved in the pathogenesis of these disorders. In contrast, our data do not support an association between insulin resistance syndrome and hypertension in pregnant women with PE and chronic hypertension.