Excessive accumulation of misfolded proteins was recently demonstrated in preeclampsia. We examined levels and activity of circulatory proteasome and immunoproteasome (inflammatory subtype) in preeclampsia and hemolysis, elevated liver enzymes, and thrombocytopenia (HELLP) syndrome. We analyzed samples from women with hypertensive pregnancy disorders (n=115), including preeclampsia with severe features (sPE) and HELLP syndrome, and normotensive controls (n=45). Plasma proteasome and immunoproteasome immunoreactivity were determined by quantifying the α-subunit of the 20S core and β5i (proteasome subunit beta 8 [PSMB8]), respectively. Plasma proteasome activity was analyzed with fluorogenic substrates. MG132, lactacystin, and ONX0914 were used to inhibit the circulating proteasome and immunoproteasome, respectively. Plasma cytokine profiles were evaluated by multiplex immunoassay. Placental expression of β5 (constitutive proteasome) and β5i (immunoproteasome) was interrogated by immunohistochemistry. Women with sPE had increased plasma 20S levels ( P <0.001) and elevated lytic activities (chymotrypsin-like 7-fold, caspase-like 4.2-fold, trypsin-like 2.2-fold; P <0.001 for all) compared with pregnant controls. Women with features of HELLP displayed the highest plasma proteasome levels and activity, which correlated with decreased IFN-γ (interferon-γ), and increased IL (interleukin)-8 and IL-10. In sPE and HELLP, chymotrypsin-like activity was suppressed by proteasome inhibitors including ONX0914. Compared with gestational age-matched controls, sPE placentas harbored increased β5 and β5i immunostaining in trophoblasts. β5i signal was elevated in HELLP with predominant staining in villous core, extravillous trophoblasts in placental islands, and extracellular vesicles in intervillous spaces. Pregnancy represents a state of increased proteostatic stress. sPE and HELLP were characterized by significant upregulation in circulating levels and lytic activity of the proteasome that was partially explained by placental immunoproteasome upregulation.
Objective The study aimed to describe the postmortem investigation patterns for perinatal deaths and compare the degree of investigation between stillbirths and early neonatal deaths. Study Design We conducted a single-center retrospective review of all perinatal deaths from 2011 to 2017. Perinatal death was defined as intrauterine fetal death at ≥20 weeks' gestation, plus neonatal deaths within the first 7 days of life. Rates of postmortem investigation were compared. Results There were 97 perinatal deaths, with 54 stillbirths (56%) and 43 neonatal deaths (44%). Stillbirths were significantly more likely to receive autopsy (p = 0.013) and postmortem genetic testing (p = 0.0004) when compared with neonatal deaths. Maternal testing was also more likely in stillbirths than neonatal deaths. A total of 32 deaths (33%) had no postmortem evaluation beyond placental pathology. Conclusion Investigation following perinatal death is more likely in stillbirths than neonatal deaths. Methods to improve postmortem investigation following perinatal death are needed, particularly for neonatal deaths. Key Points
Persuasive clinical trials data suggest that low-risk women identified as having a short cervical length (CL) on midtrimester ultrasound benefit from vaginal progesterone to reduce the risk of preterm birth (PTB). The successful introduction of universal CL screening programs using an "opt-out" approach has been reported. The aim of this study was to compare the risk of PTB among women who did and did not agree to participate in an "opt-in" CL screening program STUDY DESIGN: This was a retrospective cohort study of women carrying a singleton gestation who had an anatomy ultrasound performed between 16w0d-23w6d, and delivered at a single medical center from 7/2014-3/2017. CL screening was offered at time of anatomy ultrasound. Women with CL 20 mm were offered vaginal progesterone; follow-up evaluation in 1-2 weeks was recommended with CL between 21-25 mm. A history of spontaneous PTB and major fetal anomalies were exclusion criteria. Demographic characteristics were compared between screened and unscreened women. Rates of CL 20mm and CL 21-25mm, and progesterone use in the screened group were assessed. Rates of PTB <37 weeks were compared in the two groups. The rates of PTB <34 and <28 weeks gestation, and spontaneous PTB, were also analyzed. Multivariable logistic regression was used to adjust for confounding. RESULTS: Of the 6,170 women included in the study, 2,410 (39.1%) opted-in for CL screening. Screened women were more likely to be nulliparous, to have conceived with fertility treatment, and to have a prior cervical excisional procedure. Unscreened women were more likely to have public insurance. Overall incidence of CL 20 mm among screened women was 1.7% (40/2,410), and 38 of these women started progesterone. 33 women (1.4%) had a CL 20 mm on initial scan. 40 women (1.7%) had CL 21-25 mm; 31 of these women had a follow-up CL of whom 7 (22.6%) had a CL 20 mm. Rates of PTB and spontaneous PTB <37, <34, and <28 did not differ among screened and unscreened women after adjusting for parity, black race, insurance type, tobacco use, and history of cervical excisional procedure (Table). CONCLUSION: No difference in PTB rates were seen among women undergoing universal CL screening using an "opt-in" approach. This contrasts with prior studies reporting decreased PTB rates in women screened using an "optout" approach. Further research comparing these two approaches to CL screening is recommended.
OBJECTIVE: Ultrasound (US) is under increased scrutiny due to perceived overutilization for the 4 million pregnancies/yr in the United States. Historically, overutilization of healthcare services has prompted controls such as insurance authorization, limitation of testing, and calls for changes in provider payment models. In response, the SMFM has worked with payers to set defined ICD-9 codes for appropriate US use. This study was an analysis of US utilization of UAD, which has perceived wide variation. We hypothesized large variation exists in coding by MFM subspecialists UAD still exists despite current payer and organizational efforts. STUDY DESIGN: The AMFMM RVU Study examined productivity of MFM practitioners. Members of the SMFM were asked via email to submit CPT coding data, practice and provider information with a form via the Internet. Participants supplied data for a six-month period from January 1-June 30 of 2014. CPT utilization for UAD (76820) was assessed. UAD is commonly performed as an adjunct test with other fetal examinations (76805, 76811, and 76816). Hence, a ratio was created to assess utilization based upon the number of times a code was used: 76820 ratio-76820/ (76805+76811+76816). RESULTS: Data was obtained from 166 MFM subspecialists with UAD being performed by 154 MFM providers. A wide variation in UAD utilization was seen (Table 1 and Figure 1). The overall group exhibited a 76820 ratio median performance of 0.108 with a range of the 10th-90th percentile at 0.051-0.302 respectively. As the data were not normally distributed, bootstrap analysis was performed to assess the accuracy of the median with the 95% CI for the 76820 ratio of 0.095-0.117. CONCLUSION: Wide variation in UAD coding exists despite payer efforts to curb overutilization and SMFM efforts to standardize indications. This disparity and instances of provider overutilization represent a financial burden to the healthcare system and point toward a continued need to educate MFM providers on appropriate examination criteria. Payers may use numbers from this study as a benchmark to assist in claims management. A shift from a fee for service system may assist in elimination of overutilization.
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