Dysregulation of the Fas/FasL system in an experimental animal model of HELLP syndrome.

INTRODUCTION: Placental FasL is up-regulated in women with HELLP (hemolysis elevated liver enzyme and low platelet) syndrome and has been proposed to contribute to the liver damage seen in these patients. OBJECTIVE: This study aimed to determine if an experimental rodent model of HELLP also had dysregulation of Fas/FasL compared to normal pregnant (NP) rats. We also set out to determine if blockade of the endothelin system regulated Fas/FasL expression in HELLP rats. STUDY DESIGN: On gestational day (GD) 12, sEng (7ug/kg) and sFlt-1 (4.7ug/kg) infusion began via mini-osmotic pump into NP rats. On GD19 plasma and tissue were collected and FasL and Fas were measured via enzyme linked immunosorbent assay and gene expression via real-time PCR. RESULTS: HELLP rats had significantly more circulating and placental FasL compared to NP rats, whereas hepatic FasL was decreased and placental Fas was increased compared to NP rats. Administration of an endothelin A receptor antagonist (ETA) beginning on GD12 significantly decreased placental expression of Fas in HELLP rats. Liver mRNA transcript of Fas was significantly increased in HELLP rats compared to NP rats. CONCLUSION: These data suggest that rats in this experimental model of HELLP syndrome have abnormal expression of the Fas/FasL system. Future studies will examine the sources of Fas/FasL dysregulation in this model and if blockade could reduce some of the inflammation and hypertension associated with HELLP syndrome.

Hypertension, inflammation and T lymphocytes are increased in a rat model of HELLP syndrome.

OBJECTIVE: An animal model of hemolysis, elevated liver enzymes, low platelet count (HELLP) was used to determine if T lymphocytes accompany hypertension and increased inflammatory cytokines. METHODS: sFlt-1 (4.7 µg/kg/day) and sEndoglin (7 µg/kg/day) were infused into normal pregnant rats (HELLP rats) for 8 days. RESULTS: HELLP was associated with increased mean arterial pressure (p = 0.0001), hemolysis (p = 0.044), elevated liver enzymes (p = 0.027), and reduced platelets (p = 0.035). HELLP rats had increased plasma levels of TNFα (p = 0.039), IL-6 (p = 0.038) and IL-17 (p = 0.04). CD4(+) and CD8(+) T lymphocytes were increased. CONCLUSION: These data support the hypothesis that T cells are associated with hypertension and inflammation.

Pre-eclampsia following chemotherapy for breast cancer during pregnancy: case report and review of the literature.

PURPOSE: There has been some discussion about the effect of antineoplastic agents on the trophoblast, and whether this is associated with abnormal placental function such as an increased risk of pre-eclampsia/eclampsia. We discuss a possible causal relationship between chemotherapy for breast cancer during pregnancy and the development of pre-eclampsia based on the occurrence of both in a recent pregnancy. METHODS: We report the case of a 34-year-old gravida 4, para 1 with unilateral ductal invasive breast cancer, treated by surgery and subsequent chemotherapy during pregnancy. At 36 + 2 weeks of gestation a growth restricted male infant (1,680 g, <5th percentile) was born by urgent caesarean section because of acute pre-eclampsia, pathologic CTG and umbilical end-diastolic reverse flow. This case is reported in detail, and literature and databases reviewed. RESULTS: So far there have been no reports suggesting an increased risk of pre-eclampsia following chemotherapy for breast cancer in pregnancy from the second trimester onwards, and the most probable is an accidental occurrence from pre-eclampsia and chemotherapy. CONCLUSIONS: Whenever possible, pregnant patients with breast cancer should receive the same treatment as those who are not pregnant. Should chemotherapy for breast cancer be indicated in pregnancy from the second trimester onwards only, contraindications would be other risks for pre-eclampsia and intrauterine growth restriction, such as smoking and gestational diabetes.

Metformin, pre-eclampsia, and pregnancy outcomes in women with polycystic ovary syndrome.

AIMS: Was metformin during pregnancy in women with polycystic ovary syndrome (PCOS) associated with pre-eclampsia, and was it safe for mother and neonate? METHODS: In the current study, pre-eclampsia and other pregnancy outcomes were prospectively studied in 90 women with PCOS who conceived on metformin 1.5-2.55 g/day, and had > or = 1 live birth (97 pregnancies, 100 live births) compared with 252 healthy women (not known to have PCOS) with > or = 1 live birth, consecutively delivered in a community obstetrics practice. RESULTS: Women with PCOS were older than controls (33 +/- 5 vs. 29 +/- 6 years, P < 0.0001), more likely to be > 35 years old at conception (23 vs. 13%, P = 0.028), much heavier (93 +/- 23 vs. 72 +/- 18 kg, P < 0.0001, BMI 33.8 +/- 7.8 kg/m2 vs. 25.6 +/- 5.9, P < 0.0001), and more likely to be Caucasian (97 vs. 90%, P = 0.05), but there were similar numbers with preconception Type 2 diabetes mellitus [2/90 (2.2%) vs. 1/252 (0.4%), P = 0.17]. Pre-eclampsia in PCOS (5/97 pregnancies, 5.2%), did not differ (P = 0.5) from controls (9/252, 3.6%), nor did it differ (P = 1.0) in PCOS vs. control primigravidas [2/45 (4.4%) vs. 4/91 (4.4%)]. Development of gestational diabetes in PCOS did not differ from controls [9/95 pregnancies (9.5%) vs. 40/251 (15.9%), P = 0.12]. Of the 100 live births to 90 women with PCOS, there were no major birth defects. Mean +/- sd birth weight of the 80 live births > or = 37 weeks gestation in women with PCOS (3414 +/- 486 g) did not differ from controls' 206 live births > or = 37 weeks (3481 +/- 555 g), P = 0.34, nor did the percentage of > or = 37 week gestation neonates > or = 4000 g (12.5 vs. 17.5%, P = 0.3) or > or = 4500 g (1.3 vs. 2.9%, P = 0.7). CONCLUSIONS: Metformin is not associated with pre-eclampsia in pregnancy in women with PCOS, and appears to be safe for mother and fetus.

HELLP syndrome-like biochemical parameters obtained with endothelin-1 injections in rabbits.

We studied the effects of bolus injections and infusion of endothelin-1 (ET-1) in female rabbits by measuring serum glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), lactic dehydrogenase (LDH), antithrombin III (AT-III), thrombin antithrombin (TAT) complexes, platelet counts and indirect bilirubin. Two successive bolus doses of 0.125 and 0.25 nmol/kg of ET-1 with an interval of 30 min were given to conscious non-pregnant female rabbits (n = 8). GOT, GPT and LDH were found to be significantly increased after injections of ET-1 (p < 0.02, p < 0.04 and p < 0.05, respectively). The percent AT-III activity decreased significantly (p < 0.005). Vasospasm of the hepatic artery was demonstrated by angiography with the same bolus doses in rabbits. There was also an increase in GOT (p < 0.003), GTP (p < 0.05), LDH (p < 0.007), indirect bilirubin (p > 0.07) and TAT complexes (p < 0.02) and a decrease in AT-III (p < 0.03) and platelet counts (p < 0.02) in rabbits (n = 10) after 24 h of continuous infusion of ET-1 (0.6 nmol/kg/h). Histological examination of rabbit liver tissues showed varying degrees of ischemic necrosis of hepatocytes. Thus this study suggests that exogenously administered ET-1 causes vasospasm and liver ischemia resulting in HELLP syndrome-like blood parameters in rabbits.