Opioid and benzodiazepine use in gynecologic oncology patients.

OBJECTIVE: The goals of this study were to describe opioid and benzodiazepine prescribing practices in the gynecologic oncology patient population and determine risks for opioid misuse in these patients. METHODS: Retrospective study of opioid and benzodiazepine prescriptions for patients treated for cervical, ovarian (including fallopian tube/primary peritoneal), and uterine cancers within a single healthcare system from January 2016 to August 2018. RESULTS: A total of 7643 prescriptions for opioids and/or benzodiazepines were dispensed to 3252 patients over 5754 prescribing encounters for cervical (n=2602, 34.1%), ovarian (n=2468, 32.3%), and uterine (n=2572, 33.7%) cancer. Prescriptions were most often written in an outpatient setting (51.0%) compared with inpatient discharge (25.8%). Cervical cancer patients were more likely to have received a prescription in an emergency department or from a pain/palliative care specialist (p=0.0001). Cervical cancer patients were least likely to have prescriptions associated with surgery (6.1%) compared with ovarian cancer (15.1%) or uterine cancer (22.9%) patients. The morphine milligram equivalents prescribed were higher for patients with cervical cancer (62.6) compared with patients with ovarian and uterine cancer (46.0 and 45.7, respectively) (p=0.0001). Risk factors for opioid misuse were present in 25% of patients studied; cervical cancer patients were more likely to have at least one risk factor present during a prescribing encounter (p=0.0001). Cervical cancer was associated with a higher number of risk factors (p<0.001). CONCLUSIONS: Opioid and benzodiazepine prescribing patterns differ for cervical, ovarian, and uterine cancer patients. Gynecologic oncology patients are overall at low risk for opioid misuse; however, patients with cervical cancer are more likely to have risk factors present for opioid misuse.

Enhanced recovery after surgery (ERAS) protocol is associated with lower post-operative opioid use and a reduced office burden after minimally invasive surgery.

OBJECTIVE: Enhanced recovery after surgery (ERAS) has decreased hospital opioid use, but less attention has been directed towards its impact on clinic burden with respect to post-operative care. Our objective was to determine the impact of an ERAS protocol on post-operative opioid prescribing, and the subsequent number of pain medication refill requests and unscheduled patient-provider interactions in the 30-day post-operative period. METHODS: IRB-approved retrospective study comparing post-operative opioid prescription practices 10 months before and 10 months after ERAS protocol implementation after minimally invasive gynecologic surgery. Opioid doses in morphine milligram equivalents (MMEs), number of unscheduled visits, and phone calls were compared before and after ERAS implementation. RESULTS: A total of 791 patients were included; 445 without and 346 with ERAS implementation. ERAS was associated with higher rates of same day discharge (49% vs 39%, p = 0.003) and lower readmission rates (2.0% vs 5.6%, p = 0.011). Post-operatively, patients who received the ERAS protocol were prescribed less opioids (197.8 vs. 223.5 MMEs, p = 0.0087). There was a trend towards less refill requests with ERAS (1.7% vs 3.6%, p = 0.11). ERAS was associated with a decreased number of post-operative phone calls (38% vs 46%, p = 0.023), including calls for pain (10% vs 16%, p = 0.021), and fewer unscheduled visits related to pain (1.5% vs 5.8%, p = 0.001). CONCLUSIONS: Implementation of the ERAS protocol resulted in a decrease in post-operative opioid prescribing. Despite the lower amount of prescribed post-operative opioids, the ERAS protocol translated into a decrease in the need for post-operative interactions with the clinic staff, specifically encounters associated with pain.

Placental Pathology in Relation to Uterine Artery Doppler Findings in Pregnancies with Severe Intrauterine Growth Restriction and Abnormal Umbilical Artery Doppler Changes.

Objectives Current guidelines for diagnosis and management of early-onset intrauterine growth restriction (IUGR) rely on umbilical artery Doppler (UAD), without including uterine artery Doppler (UtAD). We hypothesized that IUGR cases with abnormal UAD but normal UtAD has a different spectrum of placental pathology compared with those with abnormal UtAD. Study Design Retrospective review of pregnancies with sonographic evidence of IUGR and abnormal UAD prior to delivery. Cases with ≥ 1 UtAD record(s) after 18+0 weeks' gestation and placental pathology were included. Cases were stratified according to initial UtAD pulsatility index (PI) values (n = 196): normal (n = 19; PI < 95th centile for gestational age/no notching), intermediate (n = 69; PI ≥ 95th centile/no/unilateral notching) and abnormal (n = 108; PI ≥ 95th centile/bilateral notching). Pregnancy outcomes and placental pathology were compared between groups. Results Women in the normal group delivered later than those in the abnormal group (30.1 ± 3.5 vs. 28.0 ± 3.5 weeks; mean ± standard deviation; p = 0.03). Their placentas exhibited higher rates of chronic intervillositis (15.8 vs. 0.9%; p = 0.01), chorangiosis (15.8 vs. 0.9%; p < 0.0001), and massive perivillous fibrin deposition (21.1 vs. 7.4%; p = 0.05), but had lower rates of uteroplacental vascular insufficiency (26.3 vs. 79.6%; p < 0.0001). Conclusion Approximately 10% of pregnancies with early-onset IUGR and abnormal UAD exhibited normal UtAD waveforms. They delivered later, and their placentas exhibited unusual placental pathologies.

Status of medical genomics and genetics education in maternal-fetal medicine: survey of program directors and clinical fellows in the USA.

OBJECTIVE: The study aimed to assess the current state of medical genetics and genomics (MGG) education amongst maternal-fetal medicine (MFM) program directors (PDs) and clinical fellows. METHODS: An online questionnaire was generated and distributed to all current program directors and fellows in ACGME-accredited MFM fellowships across the USA in 2018. RESULTS: A total of 13 program directors and 54 MFM fellows responded to our survey. Of the respondents, 73% of the MFM fellows mentioned having dedicated structured MGG rotations as part of their training. Only 12% of fellows reported a high level of satisfaction with their programs' structured MGG rotations and almost 40% reported dissatisfaction, compared to 56% of PDs who reported very high satisfaction. Furthermore, 84% of PDs reported high levels of satisfaction with MGG didactics currently in place compared to only 24% of fellows sharing the same opinion. When compared to PDs, fellows reported a significantly lower satisfaction score toward their MGG rotations (p < .05) and didactic sessions (p < .05). More than 62% of PDs were satisfied with the number of MGG-faculty in their division compared to 80% of fellows who thought more faculty is needed. Thirty-eight percent of PDs quoted curricular overload and lack of time as the most important obstacles to MGG education, compared to 43% of fellows citing a limited number of genetics services providers as the most important obstacles to their MGG education. CONCLUSION: MFM fellows and PDs differ in their satisfaction with the current state of MGG didactics and rotations in their programs, the number of MGG faculty in their divisions, and the perceived obstacles to MGG education . Our study illustrates the need for MGG curriculum development in MFM fellowships as this subspecialty relies heavily on the use of genetics and genomics services.

Multisystem inflammatory syndrome in children (MIS-C) in pregnancy can mimic new-onset pre-eclampsia: A case report.

Introduction: Pregnant women affected by coronavirus disease 2019 (COVID-19) are at increased risk of severe disease, admission to an intensive care unit, and adverse pregnancy outcomes. In contrast, children typically experience a mild form of COVID-19. Nonetheless, there is a risk of multisystem inflammatory syndrome in children (MIS-C) following a SARS-CoV-2 infection. Case: A healthy 16-year-old, G1P0, presented with MIS-C in the second trimester and was treated with intravenous immunoglobulin. She subsequently developed transient mild hypertension, proteinuria, and transaminitis, which ultimately was thought to be secondary to MIS-C rather than pre-eclampsia. Discussion: MIS-C is an important COVID-19 complication in pediatric patients. This case offers guidance on expectant management of hypertension, transaminitis, and proteinuria during an episode of MIS-C in pregnant patients, as opposed to preterm delivery for a misdiagnosis of severe pre-eclampsia.

Parental ethnicity and placental maternal vascular malperfusion pathology in healthy nulliparous women.

INTRODUCTION: Rates of some placental-associated pregnancy complications vary by ethnicity, though the strength of association with underlying placental pathology is presently unknown. Our objective was to determine whether an association between ethnicity and placental pathology occurs in low-risk pregnancies. METHODS: 829 low-risk nulliparous pregnant women were prospectively studied. Data were obtained from standardized obstetrical appointments (clinical history, serum biomarkers, placental ultrasound) and hospital delivery records (pregnancy complications, delivery details and perinatal outcomes). Placental pathology was performed in all subjects using standard criteria. RESULTS: In our cohort, 72% of women were Caucasian, 14% East Asian, 8% South Asian, 4% Afro-Caribbean and 3% Hispanic women. 81% of couples were concordant (same ethnic background) and 19% discordant (mixed ethnicities). South Asian women had the highest rate of small for gestational age (SGA) birth (customized birthweight <10th percentile) (24.2%), which was associated with the placental features of uteroplacental vascular insufficiency (placental weight <10th percentile with decidual vasculopathy, focal infarction, and/or syncytial knot formation) (p = 0.05). Placental efficiency varied significantly by ethnicity; Caucasian women had the highest efficiency (7.1 ±â€¯1.2) and Afro-Caribbean women the lowest (6.5 ±â€¯0.9) (p < 0.003). Afro-Caribbean women had the highest rate of marginal cord insertion. Placental efficiency, was higher in concordant vs. discordant couples (7.0 ±â€¯1.2 vs. 6.8 ±â€¯1.1; p < 0.05). Placental histopathology was not affected by parental ethnic discordance. DISCUSSION: Maternal ethnicity influences placental efficiency and relationship between uteroplacental vascular insufficiency and SGA birth, but was not associated with other placental pathologies. Discordant parental ethnicity did not affect the development of placental pathologies or adverse pregnancy outcomes.

SUMO-4: A novel functional candidate in the human placental protein SUMOylation machinery.

BACKGROUND: Small ubiquitin-like modifiers (SUMOs) conjugate to proteins post-translationally, thereby affecting target localization, activity and stability. Functional SUMO family members identified in the human placenta include SUMO-1 to SUMO-3, which are elevated in pre-eclampsia. Whether the fourth isoform, SUMO-4, plays a role in placental development and function remains unknown. OBJECTIVES: We tested the hypothesis that SUMO-4 is expressed in the human placenta and demonstrates altered SUMOylation in pre-eclamptic pregnancies. METHODS: SUMO-4 mRNA (qRT-PCR) and protein (Western blot and immunohistochemistry) were measured in Jar cells, BeWo cells, first trimester placental villous explants and placental tissues across normal gestation and in pre-eclampsia. SUMO-4 expression in response to oxidative stress (H2O2: 0, 0.1, 1 and 5mM), as well as, hypoxia-reperfusion (O2: 1%, 8% and 20%) was measured. Lastly, SUMO-4 binding (covalently vs. non-covalently) to target proteins was investigated. RESULTS: SUMO-4 mRNA and protein were unchanged across gestation. SUMO-4 was present in the villous trophoblast layer throughout gestation. SUMO-4 mRNA expression and protein levels were increased ~2.2-fold and ~1.8-fold in pre-eclamptic placentas compared to age-matched controls, respectively (p<0.01). SUMO-4 mRNA and protein expression increased in Jars, BeWos and first trimester placental explants with 5mM H2O2 treatment, as well as with exposure to hypoxia-reperfusion. SUMO-1 to SUMO-3 did not show consistent trends across models. SUMO-4 hyper-SUMOylation was predominantly covalent in nature. CONCLUSIONS: SUMO-4 is expressed in normal placental development. SUMO-4 expression was increased in pre-eclamptic placentas and in models of oxidative stress and hypoxic injury. These data suggests that SUMO-4 hyper-SUMOylation may be a potential post-translational mechanism in the stressed pre-eclamptic placenta.

Classifying neonatal growth outcomes: use of birth weight, placental evaluation and individualized growth assessment.

OBJECTIVE: To compare neonatal growth outcomes determined by birth weight (BW), placental assessment (Plac Assess) and individualized growth assessment (IGA). METHODS: This retrospective analysis was carried out in 45 selected pregnancies at risk for fetal growth restriction. Serial fetal biometry was carried out in the 2nd and 3rd trimester. First and second trimester placental biomarkers, 2nd trimester uterine artery (Ut A) velocimetry and postnatal placental pathology were evaluated as indicators of placental insufficiency. At delivery, weight (WT), head circumference (HC) and crown-heel length (CHL) were measured. BWs were categorized as large-for-gestational-age (LGA), appropriate-for-gestational-age (AGA) and small-for-gestational age (SGA) (<10th, 10th-90th and >90th percentiles). In these categories, neonatal growth outcomes were classified as growth restricted (GR), normal (NORMAL) or macrosomic (MACRO) based on BW plus Plac Assess (Ut A velocimetry, biomarkers, pathology) or IGA [growth potential realization index profile (WT, HC and CHL)]. RESULTS: There were 6 LGA, 14 AGA and 25 SGA neonates in this sample. All 14 AGA neonates were considered NORMAL by both IGA and BW + Plac Assess. All six LGA neonates were classified as MACRO by BW + Plac Assess but only four by IGA (the remaining two were NORMAL and high NORMAL). The 25 SGA cases could be divided into five subgroups based on IGA and BW + Plac Assess. The largest subgroup (56%) was GR and the next largest (24%) was NORMAL by both classification methods. In the remaining 20%, there was some evidence of GR but IGA and BW + Plac Assess were not in complete agreement. CONCLUSIONS: Agreement was good for all three methods in the LGA and AGA groups. The SGA group was heterogeneous but agreement between IGA and BW + Plac Assess was 89%. These results, using more sophisticated growth assessment methods, confirm placental insufficiency as a primary cause of growth restriction. Most normal and GR SGA neonates can be identified with conventional anatomical measurements if IGA is used.

PPAR- γ Regulates Trophoblast Differentiation in the BeWo Cell Model.

Common pregnancy complications, such as severe preeclampsia and intrauterine growth restriction, disrupt pregnancy progression and impair maternal and fetal wellbeing. Placentas from such pregnancies exhibit lesions principally within the syncytiotrophoblast (SCT), a layer in direct contact with maternal blood. In humans and mice, glial cell missing-1 (GCM-1) promotes differentiation of underlying cytotrophoblast cells into the outer SCT layer. GCM-1 may be regulated by the transcription factor peroxisome proliferator-activated receptor-gamma (PPAR- γ ); in mice, PPAR- γ promotes labyrinthine trophoblast differentiation via Gcm-1, and, as we previously demonstrated, PPAR- γ activation ameliorates disease features in rat model of preeclampsia. Here, we aimed to characterize the baseline activity of PPAR- γ in the human choriocarcinoma BeWo cell line that mimics SCT formation in vitro and modulate PPAR- γ activity to study its effects on cell proliferation versus differentiation. We report a novel negative autoregulatory mechanism between PPAR- γ activity and expression and show that blocking PPAR- γ activity induces cell proliferation at the expense of differentiation, while these remain unaltered following treatment with the agonist rosiglitazone. Gaining a deeper understanding of the role and activity of PPAR- γ in placental physiology will offer new avenues for the development of secondary prevention and/or treatment options for placentally-mediated pregnancy complications.

DREAM mediated regulation of GCM1 in the human placental trophoblast.

The trophoblast transcription factor glial cell missing-1 (GCM1) regulates differentiation of placental cytotrophoblasts into the syncytiotrophoblast layer in contact with maternal blood. Reduced placental expression of GCM1 and abnormal syncytiotrophoblast structure are features of hypertensive disorder of pregnancy--preeclampsia. In-silico techniques identified the calcium-regulated transcriptional repressor--DREAM (Downstream Regulatory Element Antagonist Modulator)--as a candidate for GCM1 gene expression. Our objective was to determine if DREAM represses GCM1 regulated syncytiotrophoblast formation. EMSA and ChIP assays revealed a direct interaction between DREAM and the GCM1 promoter. siRNA-mediated DREAM silencing in cell culture and placental explant models significantly up-regulated GCM1 expression and reduced cytotrophoblast proliferation. DREAM calcium dependency was verified using ionomycin. Furthermore, the increased DREAM protein expression in preeclamptic placental villi was predominantly nuclear, coinciding with an overall increase in sumolylated DREAM and correlating inversely with GCM1 levels. In conclusion, our data reveal a calcium-regulated pathway whereby GCM1-directed villous trophoblast differentiation is repressed by DREAM. This pathway may be relevant to disease prevention via calcium-supplementation.