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.

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.

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.

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.

Endocrino-metabolic features in women with polycystic ovary syndrome during pregnancy.

To elucidate the mechanism of metabolic adaptation of women with polycystic ovary syndrome (PCOS) during pregnancy, the endocrino-metabolic features of a group of PCOS patients with or without gestational diabetes were studied longitudinally during the three trimesters of gestation. Oral glucose tolerance test (OGTT, 100 g) and hyperinsulinaemic-euglycaemic clamp were performed throughout the study. Plasma concentrations of insulin and glucose were determined by radioimmunoassay and glucose oxidase technique, respectively. Five of 13 PCOS patients developed gestational diabetes (GD) at the third trimester (PCOS-GD), while the other eight patients did not develop any alteration of glucose metabolism (PCOS-nGD). Both fasting glucose and insulin plasma concentrations did not change significantly during pregnancy and no difference was seen between the two groups. On the contrary PCOS-GD group early exhibited higher values of area under the curve (AUC) for glucose and insulin response to OGTT with respect to those found in PCOS-nGD group. This difference was already significant in the first gestational trimester. Moreover insulin sensitivity value (M) was significantly lower in the first trimester of gestation in PCOS-GD as compared with that found in PCOS-nGD group. However, as gestation proceeded, M value decreased in PCOS-nDG group and the difference from PCOS patients developing gestational diabetes was not sustained into the second and third trimesters. Both groups had similar body mass index values and AUC insulin increase from first to third trimester of gestation. It is concluded that early alteration of insulin sensitivity and secretion constitute specific risk factors in PCOS patients for the development of abnormalities of glucose tolerance.

Heparin and low-dose aspirin restore placental human chorionic gonadotrophin secretion abolished by antiphospholipid antibody-containing sera.

This study was conducted to determine whether drugs used for conventional treatments of pregnant women with antiphosholipid syndrome might be able to restore the gonadotrophin-releasing hormone (GnRH)-induced secretion of placental human chorionic gonadotrophin (HCG) in vitro. We tested this hypothesis using a modified enzyme-linked immunosorbent assay (ELISA) and an in-vitro placental culture system. Pharmacological dose of low molecular weight heparin (20 IU/ml) significantly (P < 0.02) reduced the antiphospholipid antibody (aPL) binding in the ELISA and was able to restore GnRH-induced HCG secretion (P < 0.05) in presence of aPL-containing sera. Low-dose aspirin (0.03 M) did not modify aPL binding in the ELISA, but partially restored HCG secretion (P < 0.05). These observations may help to explain the role of these treatments in antiphospholipid syndrome.