HIV antiretroviral exposure in pregnancy induces detrimental placenta vascular changes that are rescued by progesterone supplementation.

Adverse birth outcomes are common in HIV-positive pregnant women receiving combination antiretroviral therapy (cART), especially when cART is initiated in early pregnancy. The mechanisms remain poorly understood. Using a mouse model we demonstrate that protease inhibitor based-cART exposure beginning on day 1 of pregnancy was associated with a pro-angiogenic/pro-branching shift in the placenta driven by lower Flt-1 levels and higher Gcm-1 expression. Micro-CT imaging revealed an increase in the number of arterioles in cART-treated placentas, which correlated with fetal growth restriction. Delaying initiation of cART, or supplementing cART-treated mice with progesterone, prevented the pro-angiogenic/pro-branching shift and the associated placenta vascular changes. In agreement with our mouse findings, we observed an increase in the number of terminal-villi capillaries in placentas from HIV-positive cART-exposed women compared to HIV-negative controls. Capillary number was inversely correlated to maternal progesterone levels. Our study provides evidence that cART exposure during pregnancy influences placenta vascular formation that may in turn contribute to fetal growth restriction. Our findings highlight the need for closer investigation of the placenta in HIV-positive pregnancies, particularly for pregnancies exposed to cART from conception, and suggest that progesterone supplementation could be investigated as a possible intervention to improve placenta function in HIV-positive pregnant women.

Vitamin D3 inhibits lipopolysaccharide-induced placental inflammation through reinforcing interaction between vitamin D receptor and nuclear factor kappa B p65 subunit.

It is increasingly recognized that vitamin D3 (VitD3) has an anti-inflammatory activity. The present study investigated the effects of maternal VitD3 supplementation during pregnancy on LPS-induced placental inflammation and fetal intrauterine growth restriction (IUGR). All pregnant mice except controls were intraperitoneally injected with LPS (100 µg/kg) daily from gestational day (GD)15-17. In VitD3 + LPS group, pregnant mice were orally administered with VitD3 (25 µg/kg) before LPS injection. As expected, maternal LPS exposure caused placental inflammation and fetal IUGR. Interestingly, pretreatment with VitD3 repressed placental inflammation and protected against LPS-induced fetal IUGR. Further analysis showed that pretreatment with VitD3, which activated placental vitamin D receptor (VDR) signaling, specifically suppressed LPS-induced activation of nuclear factor kappa B (NF-κB) and significantly blocked nuclear translocation of NF-κB p65 subunit in trophoblast gaint cells of the labyrinth layer. Conversely, LPS, which activated placental NF-κB signaling, suppressed placental VDR activation and its target gene expression. Moreover, VitD3 reinforced physical interaction between placental VDR and NF-κB p65 subunit. The further study demonstrates that VitD3 inhibits placental NF-κB signaling in VDR-dependent manner. These results provide a mechanistic explanation for VitD3-mediated anti-inflammatory activity. Overall, the present study provides evidence for roles of VDR as a key regulator of placental inflammation.

Disposition of desfuroylceftiofur acetamide in serum, placental tissue, fetal fluids, and fetal tissues after administration of ceftiofur crystalline free acid (CCFA) to pony mares with placentitis.

The objective of this study was to determine the pharmacokinetics of CCFA in mares with placentitis and evaluate the disposition of the drug in fetal fluids, fetal membranes, colostrum, and serum of foals. A secondary objective was to obtain pilot data regarding the efficacy of CCFA for improving foal survival in mares with placentitis. Twelve pregnant pony mares were enrolled in the study, inoculated with Streptococcus zooepidemicus, intracervically and assigned to one of three groups: CEFT (n = 3; administered CCFA only; 6.6 mg/kg, i.m., q96h); COMBO (n = 6; administered combination therapy of CCFA, altrenogest, and pentoxifylline); UNTREAT (n = 3, no treatment). Treatment was initiated at the onset of clinical signs. Concentrations of desfuroylceftiofur acetamide (DCA), the acetamide derivative of ceftiofur and desfuroylceftiofur metabolites, were measured using high-performance liquid chromatography. Maximum and minimum serum concentrations of DCA at steady state in treated mares were 2.40±0.40 µg/mL and 1.06±0.29 µg/mL, respectively. Concentration of DCA in colostrum was 1.51±0.60 µg/mL. DCA concentrations in placenta and fetal tissues were very low (median = 0.03 µg/mL) and below the minimum inhibitory concentration of relevant pathogens. DCA was not detected in amniotic fluid or foal serum. Treatment did not appear to improve foal survival (CEFT: 0/3; COMBO: 2/6; UNTREAT: 2/3). Bacteria were recovered from the uterus of most mares postpartum and from blood cultures of most foals regardless of treatment.

Efficacy of the Kampo medicine Xiong-gui-jiao-ai-tang, a traditional herbal medicine, in the treatment of threatened abortion in early pregnancy.

This study was carried out to evaluate the clinical efficacy of Xiong-gui-jiao-ai-tang (Kyuki-kyogai-to), a traditional Chinese herbal medicine, in the treatment of threatened abortion in early pregnancy. We enrolled 72 women diagnosed with threatened abortion at Osaka Medical College Hospital and assigned them at random to the following two groups: a group of 36 women who received Xiong-gui-jiao-ai-tang at a dose of 7.5 g/day and another group of 36 women who received human chorionic gonadotropin (hCG)(control group). We found that in the Xiong-gui-jiao-ai-tang group (2.9 + or - 3.5 days), the number of days required before hemostasis was reached in the uterus was significantly shorter than in the control group (10.8 + or - 8.2 days, p < 0.0001). Furthermore, the number of days required for retroplacental hematoma in the vicinity of the gestational sac to disappear was significantly shorter in the Xiong-gui-jiao-ai-tang group (9.9 + or - 7.1 days) than in the control group (23.2 + or - 12.8 days) (p < 0.0001). In retroplacental hematoma size, significant rates of reduction were obtained in both major and minor axis measurements at the 7th day of treatment for the Xiong-gui-jiao-ai-tang group compared to the control group (control vs Xiong-gui-jiao-ai-tang: major axis: 7.5 + or - 3.8% vs 42.3 + or - 10.5%; minor axis: 15.3 + or - 16.8% vs 71.5 + or - 48.2%)(p < 0.0001, each case). The results of this study demonstrated the beneficial effects of Xiong-gui-jiao-ai-tang in stabilizing early pregnancy. Xiong-gui-jiao-ai-tang can be expected to improve unstable early pregnancy with uterine bleeding and to prevent abortion.

[Carnitine in therapy of placental insufficiency--initial experiences]. / Carnitin als Therapie der Plazentainsuffizienz--erste Erfahrungen.

Carnitine (3-hydroxy and 4-trimethylaminobutyrate) present in all living cells, plays an important role in the oxidation of fatty acids. It is known that high dose carnitine activates surfactant synthesis. Given to women with imminent premature delivery, its benefit on the post natal period is proved. Own studies showed an increased need of carnitine during pregnancy. Therefore the questions rose if carnitine substitution improves placental insufficiency. 15 pregnant women were treated with 2 x 1 g carnitine orally for one week and with 1 x 1 g carnitine during the following 7 days when their fetus showed a retardation of 1-3 weeks. The control group were 15 untreated patients with the same problems of retardation. The placental insufficiency was diagnosed by fetometry, by blood parameters and the doppler ultrasound flow measurement. In the group of the treated patients 11 out of 15 showed an improvement, in 4 patients no effect of carnitine was seen and in 1 patient the retardation increased. In the control group 8 out of 15 patients showed a spontaneous improvement of fetal growth, 2 women did not have a change in their retardation and 5 patients had to be hospitalized because of increasing placental insufficiency. Inspite of the small number of patients a tendency towards a profit in carnitine treatment for placental insufficiency seems to be real.