Can we predict peritoneal adhesions formation after cesarean delivery?

OBJECTIVE: To examine demographic and obstetrical factors that are associated with adhesion formation following cesarean delivery. METHODS: We conducted a population-based study that included all women over 18 years og age who underwent two cesarean deliveries between the years 1988 and 2016 in a large tertiary medical center. We excluded women with adhesions already diagnosed during the first cesarean delivery, history of other abdominal or pelvic surgery, history of pelvic infection or pelvic inflammatory disease, history of endometriosis and history of uterine Müllerian anomalies. In addition, women with a classical or T-shaped uterine incision, non-singleton pregnancies, and fetal chromosomal or structural abnormalities were excluded. RESULTS: During the study period, 32.6% (n = 2283) of women were diagnosed with peritoneal adhesions during the second cesarean delivery. Factors found to be significantly associated with peritoneal adhesions were maternal age 35 years or older at the first cesarean delivery, Bedouin Arab ethnicity, composite of intrapartum and postpartum infectious morbidity, and cesarean deliveries that were performed after the onset of labor. In contrast, having a previous vaginal birth was found to be protective. CONCLUSIONS: Our results suggest that a woman's characteristics at her first cesarean delivery and her obstetrical history may be predictive of the likelihood of adhesion formation.

Resistant prolactinomas: a case series of 26 patients.

PURPOSE: Prolactin (PRL)-secreting tumors are the most common functional pituitary adenomas. They usually respond to dopamine agonist (DA) treatment, with PRL normalization and adenoma shrinkage. Our aim was to characterize patients with prolactinoma resistant to DA treatment. METHODS: This retrospective case series included patients diagnosed with DA-resistant prolactinomas between 1993-2017 in three medical centers. Resistance was defined as PRL levels above three times the upper limit of normal (ULN) despite a weekly dose of ≥2 mg cabergoline (CAB). Clinical and biochemical information, and response to treatment, were retrieved from medical records. RESULTS: Twenty-six patients were identified; 20 males. Of 25 macroadenomas, three were giant tumors (>40 mm) and 15 (57.7%) were invasive. The mean age at diagnosis was 31.8 ± 14.9 years (range: 13-62). The median maximal CAB dose was 3.5 mg/week (IQR, 2.5-5). Half the patients received only CAB in escalating doses, nine received CAB and underwent transsphenoidal surgery, and four underwent surgery and radiotherapy in addition to CAB treatment. PRL levels at baseline between patients treated only with CAB and those operated were (91.6 [51.1-296.7] vs. 73.1 [22.6-170.9] XULN p = 0.355), and under maximal CAB dose PRL levels between patients treated only with CAB and those operated were similar (5.77 [1.27-11.27] vs 5.27 (2.9-26) XULN p = 0.317). At the last visit patients who received combined therapy achieved lower PRL levels than those treated with DA only (5.22 [1.7-21.6] vs 1.1 [0.44-3.99] XULN p = 0.017) PRL normalization was attained in seven patients and levels below 3 × ULN in fourteen patients; the overall response was 56%. CONCLUSIONS: Resistant prolactinomas usually require a multi-modal treatment strategy. We were able to control 14/25 (56%) of resistant tumors.

Cannabidiol changes P-gp and BCRP expression in trophoblast cell lines.

Objectives. Marijuana is the most commonly used illicit drug during pregnancy. Due to high lipophilicity, cannabinoids can easily penetrate physiological barriers like the human placenta and jeopardize the developing fetus. We evaluated the impact of cannabidiol (CBD), a major non-psychoactive cannabinoid, on P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) expression, and P-gp function in a placental model, BeWo and Jar choriocarcinoma cell lines (using P-gp induced MCF7 cells (MCF7/P-gp) for comparison). Study design. Following the establishment of the basal expression of these transporters in the membrane fraction of all three cell lines, P-gp and BCRP protein and mRNA levels were determined following chronic (24-72 h) exposure to CBD, by Western Blot and qPCR. CBD impact on P-gp efflux function was examined by uptake of specific P-gp fluorescent substrates (calcein-AM, DiOC2(3) and rhodamine123(rh123)). Cyclosporine A (CsA) served as a positive control. Results. Chronic exposure to CBD resulted in significant changes in the protein and mRNA levels of both transporters. While P-gp was down-regulated, BCRP levels were up-regulated in the choriocarcinoma cell lines. CBD had a remarkably different influence on P-gp and BCRP expression in MCF7/P-gp cells, demonstrating that these are cell type specific effects. P-gp dependent efflux (of calcein, DiOC2(3) and rh123) was inhibited upon short-term exposure to CBD. Conclusions. Our study shows that CBD might alter P-gp and BCRP expression in the human placenta, and inhibit P-gp efflux function. We conclude that marijuana use during pregnancy may reduce placental protective functions and change its morphological and physiological characteristics.

Cannabidiol enhances xenobiotic permeability through the human placental barrier by direct inhibition of breast cancer resistance protein: an ex vivo study.

OBJECTIVE: Drugs of abuse affect pregnancy outcomes, however, the mechanisms in which cannabis exerts its effects are not well understood. The aim of this study was to examine the influence of short-term (1-2 hours) exposure to cannabidiol, a major phytocannabinoid, on human placental breast cancer resistance protein function. STUDY DESIGN: The in vitro effect of short-term exposure to cannabidoil on breast cancer resistance protein in BeWo and Jar cells (MCF7/P-gp cells were used for comparison) was tested with mitoxantrone uptake, and nicardipine was used as positive control. The ex vivo perfused cotyledon system was used for testing the effect of cannabidoil on glyburide transport across the placenta. Glyburide (200 ng/mL) was introduced to maternal and fetal compartments through a recirculating 2 hour perfusion, and its transplacental transport was tested with (n = 8) or without (n = 8) cannabidoil. RESULTS: (1) Cannabidoil inhibition of breast cancer resistance protein-dependent mitoxantrone efflux was concentration dependent and of a noncell type specific nature (P < .0001); (2) In the cotyledon perfusion assay, the administration of cannabidoil to the maternal perfusion media increased the female/male ratio of glyburide concentrations (1.3 ± 0.1 vs 0.8 ± 0.1 at 120 minutes of perfusion, P < .001). CONCLUSION: (1) Placental breast cancer resistance protein function is inhibited following even a short-term exposure to cannabidoil; (2) the ex vivo perfusion assay emphasize this effect by increased placental penetration of glyburide to the fetal compartment; and (3) these findings suggest that marijuana consumption enhances placental barrier permeability to xenobiotics and could endanger the developing fetus. Thus, the safety of drugs that are breast cancer resistance protein substrates is questionable during cannabis consumption by pregnant women.

The effects of magnesium sulfate on placental vascular endothelial growth factor expression in preeclampsia.

OBJECTIVE: To evaluate the effect of magnesium sulfate (MgSO(4)) on placental expression levels of vascular endothelial growth factor (VEGF). MATERIALS AND METHODS: Cotyledons of term normotensive and preeclamptic placentas were dually perfused for 6 h, with MgSO(4) (6-7 mg%) in the maternal reservoir [normotensive (n = 3); preeclamptic (n = 4)] and with the control medium (without MgSO(4)) [normotensive (n = 3); preeclamptic (n = 6)]. After perfusion, placental tissue samples were collected from four different placental compartments (amnion, chorion, placental villous and decidua). The collected placental tissues were homogenized and examined for VEGF by ELISA. Statistical significance was determined using a two-way analysis of variance. RESULTS: After perfusion with control medium, significantly lower levels of VEGF were detected in the chorion and placental villous compartments of preeclamptic placentas (70 ± 24 pg/g protein and 29 ± 11 pg/g protein; respectively), as compared with normotensive placentas (172 ± 80 pg/g protein and 51 ± 17 pg/g protein; respectively; p < 0.05). Exposure of preeclamptic placentas to MgSO(4) resulted in decreased VEGF levels by the amnion (57 ± 26 pg/g protein), as compared with the control group (153 ± 62 pg/g protein) (p < 0.05). On the other hand, MgSO(4) significantly increased VEGF levels by the placental villous and the decidua (58 ± 15 pg/g protein, 70 ± 29 pg/g protein; respectively), as compared with the control group (29 ± 11 pg/g protein, 33 ± 14 pg/g protein; respectively) (p < 0.01, p < 0.05; respectively). Exposure to MgSO(4) did not affect VEGF levels in normotensive placentas. CONCLUSION: Reduced levels of VEGF are expressed by some placental compartments in preeclampsia compared with normotensive pregnancy. Perfusion with MgSO(4) affects VEGF expression differently by preeclamptic and normotensive placentas. Increased production of placental VEGF in preeclampsia may play a role in the therapeutic action of MgSO(4).

Can we find the perfect oil to protect the perineum? A randomized-controlled double-blind trial.

OBJECTIVE: To determine whether perineal massage during the second stage of labor using oil enriched with vitamins, increases the chances of delivering with an intact perineum as compared to perineal massage using pure liquid wax. METHOD: A prospective, randomized, double-blind study was conducted. Women were assigned to liquid wax (jojoba oil) versus purified formula of almond and olive oil, enriched with vitamin B1, B2, B6, E and fatty acids. The caregivers used the oils during the second stage of labor. RESULTS: A total of 164 women undergoing vaginal delivery were recruited. No significant differences regarding perineal lacerations, number of sutures and length of suturing were noted between the two groups. Likewise, while analyzing separately nulliparous and multiparous women, no significant differences were noted. Controlling for birth weight >4000 g, using the Mantel-Haenszel technique, no association was noted between perineal lacerations and the type of oil used (weighted OR = 0.9, 95% CI 0.3-2.4; p = 0.818). CONCLUSION: The type of the oil used during the second stage of labor for prevention of perineal tears has no effect on the integrity of the perineum. Accordingly, it seems that there is no perfect oil.

Perfusion with magnesium sulfate increases sFlt-1 secretion only in the fetal side of placenta of women with preeclampsia.

OBJECTIVE: To examine the effect of magnesium sulfate (MgSO(4)) on sFlt (soluble fms-like tyrosine kinase)-1 in the fetal and maternal compartments of normotensive and preeclamptic placentas. METHODS: Cotyledons of term normotensive and preeclamptic placentas were dually perfused for six hours, with control medium and MgSO(4) (6-7 mg %) in the maternal reservoir. Perfusate sFlt-1 concentrations were measured. RESULTS: Median sFlt-1 concentration was higher in the maternal than in the fetal side in both groups and perfusion media (p < 0.0001). When perfused with control medium, the maternal side median sFlt-1 concentration was higher in the preeclampsia than in the control group (p < 0.0001). After perfusion with MgSO(4), the median maternal and fetal sides perfusate sFlt-1 concentration were higher in the preeclampsia than in the control group (p < 0.0001). In comparison to perfusion with control medium, the median sFlt-1 concentration of normal pregnant women decreased in the fetal and increased in the maternal side. In the preeclampsia group, only median fetal side sFlt-1 concentration increased. CONCLUSION: In contrast to normal pregnant women, perfusion with MgSO(4) of preeclamptic placentas did not increase their sFlt-1 concentration. This may indicate that MgSO(4) role may be limited to its anti-eclamptic and does not affect the anti-angiogenic state associated with preeclampsia.

Drug transport across the placenta.

It has become clear that almost any drug or chemical substance administered to the mother is able to cross the placenta to some extent, unless it is metabolized or altered during passage, or else its molecular size and low lipid solubility do not allow transplacental transfer. A number of transport systems have been identified in the placenta, which recognizes a wide variety of pharmacological active drugs as substrates. In recent years, research on human placental transporters has been developing due to the increase of knowledge technology in pharmacology. In this review we will focus on the main placental transporters which are known today. The P-glycoprotein (P-gp), Breast cancer resistance protein (BCRP/ABCG2) and Multidrug resistance associated protein 2 (MDR2) transporters are expressed at the apical surface of the syncytiotrophoblast, and have a protective effect. Transporters for 5-HT (SERT) and NE (NET) are also expressed at the apical surface and regulate extracellular concentrations of monoamines. The physiologic function of Multidrug resistance associated protein (MRP) transporters (which is expressed at the basal surface of the syncytiotrophoblast) may be the removal of metabolic end products from the fetus. Some of the members of the organic anion transporters are also expressed at the basolateral surface of the syncytiotrophoblast.