Mara Sobel

Angiogenic response of placental villi to heparin

OBJECTIVE: To estimate the angiogenic effect of heparin on human umbilical vein endothelial cells cultured in conditioned media from normal and severely pre-eclamptic human placental villi. METHODS: Normal first- and second-trimester floating placental villi were explanted in control conditions and increasing concentrations of heparin (unfractionated and low molecular weight heparin) across the clinical prophylactic and therapeutic range (0.025–25 units/mL). At 96 hours, the placenta-conditioned media was tested for angiogenic activity in a human umbilical vein endothelial cell in vitro angiogenesis assay. Total capillary-like tube length and number of branch points were determined from photographs that did not contain information about experimental conditions. The response of placenta-conditioned media from preterm severely preeclamptic pregnant women exposed to low molecular weight heparin also was assessed and compared with both preterm and term control groups. RESULTS: Unfractionated heparin significantly promoted angiogenesis (0.25 units/mL compared with control: relative branch points 185±32% [mean±standard error of the mean], P<.05), whereas low molecular weight heparin had no significant effect. Addition of unfractionated or low molecular weight heparin to first- and second-trimester placenta-conditioned media significantly promoted angiogenesis with the response to low molecular weight heparin more than double that of unfractionated heparin (low molecular weight compared with unfractionated heparin at 2.5 units/mL: relative branch points 930±158% compared with 398±90%, P<.05). Placenta-conditioned media from pregnancies with severe preeclampsia arrested angiogenesis in comparison with both preterm and term pregnancies and was not significantly restored by the addition of low molecular weight heparin. CONCLUSION: Unfractionated and low molecular weight heparin promote in vitro angiogenesis in healthy first- and second-trimester placenta-conditioned media. The nonanticoagulant actions of heparin may be relevant to the prevention of severe preeclampsia.

Heparin promotes soluble VEGF receptor expression in human placental villi to impair endothelial VEGF signaling

Summary.  Background: Severe preeclampsia is characterized by hypertension, renal injury and placental dysfunction. Prothrombotic disorders are discovered in 10–20% of women with preeclampsia, providing the rationale for prescribing low‐molecular‐weight heparin (LMWH) in future pregnancies. Heparin has diverse molecular actions and appears to reduce the recurrence risk of preeclampsia in women without prothrombotic disorders. The placenta‐derived anti‐angiogenic splice‐variant protein soluble vascular endothelial growth factor (VEGF) receptor‐1 (sFLT1) is strongly implicated in the pathogenesis of the underlying endothelial dysfunction. As the placental syncytiotrophoblast is the principal source of sFLT1, we tested the hypothesis that heparin suppresses placental sFLT1 secretion. Methods and Results: First trimester placental villi exposed to LMWH (0.25–25 IU mL−1) in an in vitro explant model significantly increased the expression and release of sFLT1 by the syncytiotrophoblast into culture media, reducing phosphorylation of FLT1 and KDR receptors in cultured human umbilical vein endothelial cells. This response was significantly diminished in placental villi from healthy term pregnancies. Placental villi from severely preeclamptic pregnancies had a higher baseline sFLT1 release, compared with first trimester placental villi and did not respond to LMWH treatment. LMWH promoted villous cytotrophoblast proliferation (BrdU incorporation) and impaired syncytial fusion‐differentiation, causing syncytiotrophoblast apoptosis (by caspase 3&7 activity and TUNEL staining) and necrosis (ADP/ATP ratio). Conclusion: LMWH promotes sFLT1 synthesis and release from first trimester placental villi in a manner similar to that of severely preeclamptic placental villi, which antagonizes VEGF signaling in endothelial cells. These effects in part are mediated by an interaction between heparin and the cytotrophoblasts that regenerates the overlying syncytiotrophoblast responsible for sFLT1 secretion into the maternal blood.

Propylthiouracil-induced agranulocytosis in the third trimester of pregnancy.

BACKGROUND: Thionamide-induced agranulocytosis in pregnancy is a rare event that poses unique therapeutic challenges. CASE: A 37-year-old woman developed agranulocytosis while taking propylthiouracil in the third trimester. After she took broad-spectrum antibiotics and discontinued propylthiouracil, her neutrophil counts recovered. She was initially managed expectantly but later underwent an uncomplicated total thyroidectomy at 35 weeks of gestation because of patient choice coupled with worsening thyrotoxicosis. CONCLUSION: In circumstances in which thionamides are contraindicated, management options of hyperthyroidism in pregnancy are limited. The proximity to term in the third trimester makes expectant management an attractive approach when maternal thyroid indices are stable, allowing for a choice of postpartum therapies without the worry of fetal implications. However, this strategy carries risks, and thyroidectomy in the third trimester can be a safe alternative.

Surgical Management Algorithm for Caesarean Scar Pregnancy

OBJECTIVES To report our experience with the management of Caesarean scar pregnancy (CSP) in the first trimester and to develop a unique treatment algorithm allowing physicians to customize their management based on clinical patient characteristics. METHODS A retrospective review of 12 patients diagnosed with CSP between December 2012 and June 2016 was conducted in a tertiary care hospital in Toronto. All patients were diagnosed with CSP by transvaginal ultrasound using radiologic criteria. Patients were initially treated with an ultrasound-guided embryocidal injection when fetal heart activity was present. Next, patients underwent medical management with systemic multidose methotrexate (MTX) or surgical management using a laparoscopic or transcervical approach depending on CSP characteristics. RESULTS The mean age at diagnosis was 35.6 years. The median number of previous CSs was one. The mean serum human chorionic gonadotropin level was 59 938 IU/L. The mean GA at presentation was 8+1 weeks. Two-thirds of patients received medical management with systemic multidose methotrexate. Of these, 50% required additional surgical treatment for the resolution of their CSP. One-third of patients underwent primary surgical treatment, resulting in complete resolution of CSP with no complications. Given the improved outcomes of surgical management in our series, we suggest a treatment algorithm that tailors the surgical approach, either laparoscopic or transcervical, to the characteristics of the CSP. CONCLUSION This constitutes the largest case series of CSP in Canada. Based on our results, CSP can be safely and effectively managed using the suggested surgical algorithm, which accounts for individual patient characteristics.

Pregnancy outcomes in women with elevated levels of fetal hemoglobin

Objective. Elevated maternal levels of fetal hemoglobin (HbF) present a unique situation where both mother and fetus produce hemoglobin with equivalent oxygen affinities. We aimed to determine pregnancy outcomes in women with persistently elevated HbF. Methods. In this retrospective cohort study, women with HbF levels exceeding 10% were identified by searching a provincial database. Maternal, obstetric, and neonatal outcomes were extracted from chart reviews performed at two hospitals. Results. Twenty-two women with a total of 43 pregnancies and 33 live births were identified. Maternal levels of HbF ranged between 11 and 100%. Women with HbF ≥ 70% were significantly more likely to deliver growth-restricted or small for gestational age (SGA) fetuses compared to the group of women with HbF <70% (100% versus 8%; p <0.01). Three women (4/32 pregnancies) received blood transfusions, which was unrelated to HbF levels. Conclusions. Pregnancies complicated by maternal HbF levels ≥ 70% are at increased risk of intra-uterine growth restriction or SGA fetuses. Increased antenatal surveillance is suggested.

Implementation of a Same-Day Discharge Protocol Following Total Laparoscopic Hysterectomy

OBJECTIVE Previous studies have demonstrated that outpatient total laparoscopic hysterectomy (TLH) is both safe and feasible. Our objective was to decrease length of stay for patients undergoing TLH by implementing a same-day discharge protocol at two Canadian teaching hospitals. METHODS We conducted a prospective cohort study assessing length of stay (primary outcome), perioperative complications, and readmission rates over a 12-month period following implementation of a same-day discharge protocol for TLH. These data were compared with pre-intervention baseline data collected retrospectively over a 12-month period immediately before protocol introduction. Our protocol consisted of patient education, instructions for perioperative care, and close follow-up. RESULTS In the year prior to our protocol, 256 TLHs were performed. Forty-seven patients (18.3%) were discharged the same day, 191 patients (74.5%) were discharged on the first postoperative day, and 18 patients (7%) were admitted for 2 or more days. In the year following implementation, 215 patients underwent TLH of which 129 were enrolled in our study. The overall outpatient hysterectomy rate during that time period was 62% (134/215 patients). Among study participants, 102 patients (79.1%) were discharged the same day, 22 patients (17.0%) were discharged on the first postoperative day, and 5 patients (3.9%) were admitted for 2 or more days. There were no significant differences in perioperative complications or readmission rates and patient satisfaction scores were high. CONCLUSION Implementation of a same-day discharge protocol successfully increased the rate of outpatient TLH without impacting patient safety. This protocol was acceptable to both surgeons and patients and can be easily adapted for use at other centres.

Arteriovenous Malformation Following Conservative Management of Cervical Pregnancy

BACKGROUND Medical management using potassium chloride feticide and methotrexate is often the first-line approach to cervical pregnancies. CASE A 25-year-old woman presenting with a cervical ectopic pregnancy was unsuccessfully managed with conservative therapy, resulting in an arteriovenous malformation requiring a laparoscopic hysterectomy. CONCLUSION Conservative management of ectopic pregnancies is the treatment of choice for young women looking to preserve fertility. However, medical management is not without risk, and this case illustrates one such complication.

Diagnosing ovarian cancer

Women with persistent abdominal or pelvic pain, bloating, early satiety, urinary urgency or frequency, or constitutional symptoms require further investigation.[1][1] Annual screening in asymptomatic women with a pelvic examination, serum assay for cancer antigen 125 (CA 125) or transvaginal

Bowel obstruction and pelvic mass

A 42-year-old woman presented to the emergency department with a four-day history of severe constipation, bilious vomiting and colicky abdominal pain. Her symptoms started with the onset of menses but differed from the crampy dysmenorrhea for which she had taken over-the-counter analgesics for many