IMPORTANCE Severe early onset fetal growth restriction caused by placental dysfunction leads to high rates of perinatal mortality and neonatal morbidity. The phosphodiesterase 5 inhibitor, sildenafil, inhibits cyclic guanosine monophosphate hydrolysis, thereby activating the effects of nitric oxide, and might improve uteroplacental function and subsequent perinatal outcomes. OBJECTIVE To determine whether sildenafil reduces perinatal mortality or major morbidity. DESIGN, SETTING, AND PARTICIPANTS This placebo-controlled randomized clinical trial was conducted at 10 tertiary referral centers and 1 general hospital in the Netherlands from January 20, 2015, to July 16, 2018. Participants included pregnant women between 20 and 30 weeks of gestation with severe fetal growth restriction, defined as fetal abdominal circumference below the third percentile or estimated fetal weight below the fifth percentile combined with Dopplers measurements outside reference ranges or a maternal hypertensive disorder. The trial was stopped

Objective-The purpose of this study was to investigate whether the effect of transdermal estrogen therapy in postmenopausal women differs from that of oral therapy with regard to resistance to activated protein C (APC), an important risk factor for venous thrombosis, and levels of related proteins, such as protein S, protein C, and prothrombin. Methods and Results-In a randomized, double-blind, placebo-controlled study, 152 healthy hysterectomized postmenopausal women received daily either placebo (nϭ49), transdermal 17␤-estradiol (E 2 ) 50 g (tE 2 group, nϭ33), oral E 2 1 mg (oE 2 group, nϭ37), or oral E 2 1 mg combined with gestodene 25 g (oE 2 ϩG group, nϭ33) for 13 28-day treatment cycles, followed by 4 cycles of placebo for each group. Plasma samples were collected at baseline and in cycles 4, 13, and 17. In cycle 13, significant increases versus baseline and placebo were found in normalized APC sensitivity ratios (nAPCsr) in all treated groups (tE 2 , ϩ26.9%; oE 2 , ϩ102.7%; oE 2 ϩG, ϩ69.9%). Increases in nAPCsr were significantly higher in the oral treatment groups than in the tE 2 group. In addition, compared with baseline and placebo, after 13 cycles, decreases were observed in total protein S (tE 2 , Ϫ4.1%; oE 2 , Ϫ7.9%; oE 2 ϩG, Ϫ5.8%), free protein S (tE 2 , Ϫ7.1%; oE 2 , Ϫ8.4%; oE 2 ϩG, Ϫ5.2%), and protein C in the oE 2 ϩG group (Ϫ6.4%), but these changes did not explain the increase in nAPCsr. Changes in prothrombin were small and also did not affect the nAPCsr. Conclusions-Increases were observed in resistance to APC, which were more pronounced in the oral treatment groups than in the transdermal group. The increase in resistance to APC was not explained by changes in protein S, protein C, or prothrombin and may contribute to the increased incidence of venous thrombosis in users of hormone replacement therapy. Key Words: resistance to activated protein C Ⅲ protein S Ⅲ protein C Ⅲ estrogen replacement therapy Ⅲ venous thrombosis W omen using oral estrogen containing hormone replacement therapy 1-3 or oral contraceptives 4 have an increased risk of developing venous thrombosis. The risk for oral contraceptive users is higher in women who use ethynylestradiol in combination with so-called third-generation progestogens (desogestrel or gestodene) than among women using ethynylestradiol in combination with the secondgeneration progestogen levonorgestrel. 4 This difference might be explained by a differential effect of the progestogens on resistance to activated protein C (APC), 5,6 a risk factor for venous thrombosis. 7,8 It is plausible that the observed increased risk of venous thrombosis in hormone replacement users can also, at least in part, be explained by an increase in resistance to APC.The effect of hormone replacement therapy on resistance to APC, on protein S, and on protein C has been investigated in several studies. However, only few had a randomized, placebo-controlled design. 9 -16 Only uncontrolled 17,18 and cross-sectional 19 studies on the effect of transdermal estradiol on resistance...

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