Altered placental ion channel gene expression in preeclamptic high-altitude pregnancies.

High-altitude (>2,500 m) residence increases the risk of pregnancy vascular disorders such as fetal growth restriction and preeclampsia, each characterized by impaired placental function. Genetic attributes of highland ancestry confer relative protection against vascular disorders of pregnancy at high altitudes. Although ion channels have been implicated in placental function regulation, neither their expression in high-altitude placentas nor their relationship to high-altitude preeclampsia has been determined. Here, we measured the expression of 26 ion-channel genes in placentas from preeclampsia cases and normotensive controls in La Paz, Bolivia (3,850 m). In addition, we correlated gene transcription to maternal and infant ancestry proportions. Gene expression was assessed by PCR, genetic ancestry evaluated by ADMIXTURE, and ion channel proteins localized by immunofluorescence. In preeclamptic placentas, 11 genes were downregulated (ABCC9, ATP2A2, CACNA1C, KCNE1, KCNJ8, KCNK3, KCNMA1, KCNQ1, KCNQ4, PKD2, and TRPV6) and two were upregulated (KCNQ3 and SCNN1G). KCNE1 expression was positively correlated with high-altitude Amerindian ancestry and negatively correlated with non-high altitude. SCNN1G was negatively correlated with African ancestry, despite minimal African admixture. Most ion channels were localized in syncytiotrophoblasts (Cav1.2, TRPP2, TRPV6, and Kv7.1), whereas expression of Kv7.4 was primarily in microvillous membranes, Kir6.1 in chorionic plate and fetal vessels, and MinK in stromal cells. Our findings suggest a role for differential placental ion channel expression in the development of preeclampsia. Functional studies are needed to determine processes affected by these ion channels in the placenta and whether therapies directed at modulating their activity could influence the onset or severity of preeclampsia.

An exploratory study on the possible association of serum etonogestrel concentrations with mood concerns and symptoms among contraceptive implant users.

OBJECTIVE: To evaluate if inter-individual variability in serum etonogestrel (ENG) concentrations accounts for variability in mood-related side effects among ENG implant users. STUDY DESIGN: Participants underwent a single-time blood draw for measurement of serum ENG concentrations using a liquid-chromatography mass-spectrometry assay, and completed a questionnaire at enrollment that retrospectively assessed mood-related side effects during the period of implant use. For a subset of participants, Patient Health Questionnaire-9 (PHQ-9) scores, obtained for other clinical purposes, were also compared. We used independent medians tests and linear regression to evaluate associations between mood symptoms and serum ENG concentrations as our primary outcome. RESULTS: Among 900 enrolled participants, 34% (306/900) reported mood changes on the baseline questionnaire. Of these, 31 (3.4%) participants also had documented PHQ-9 scores. Serum ENG concentrations (median 126.9 pg/mL [range 39.4-695.1]) were not associated with reported mood changes on the questionnaire (p = 0.19) or on the PHQ-9 (ß = 0.00, 95% CI -0.03, 0.03). CONCLUSION: Pharmacokinetic variability does not explain the inter-individual variability in mood-related side effects among ENG implant users. IMPLICATIONS: Mood-related side effects and altered mental health metrics are commonly reported by etonogestrel contraceptive implant users but demonstrate wide inter-individual variability. Individual differences in serum drug levels do not appear to account for this variability in mood-related side effects, and so future research should focus on novel personal factors.