Clinical Validation of a Proteomic Biomarker Threshold for Increased Risk of Spontaneous Preterm Birth

AbstractPreterm births are prevalent and a leading cause of neonatal death in the United States. Despite the availability of effective interventions, to date there is not a robust and widely applicable test to identify pregnancies at high risk for spontaneous preterm birth (sPTB). Previously, a sPTB predictor based on the ratio of two proteins, IBP4/SHBG, was validated as an accurate predictor of sPTB in the observational study Proteomic Assessment of Preterm Risk (PAPR). Here it is demonstrated that the same predictor threshold associated with 2-fold increased risk of sPTB, namely −1.4, is also statistically significant for predicting elevated risk of sPTB in the observational study Multicenter Assessment of a Spontaneous Preterm Birth Risk Predictor (TreeToP).

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Clinical Validation of a Proteomic Biomarker Threshold for Increased Risk of Spontaneous Preterm Birth and Associated Clinical Outcomes: A Replication Study

Journal of Clinical Medicine ◽

10.3390/jcm10215088 ◽

2021 ◽

Vol 10 (21) ◽

pp. 5088

Author(s):

Julja Burchard ◽

Ashoka D. Polpitiya ◽

Angela C. Fox ◽

Todd L. Randolph ◽

Tracey C. Fleischer ◽

...

Keyword(s):

Preterm Birth ◽

Preterm Births ◽

Neonatal Morbidity ◽

Fold Increase ◽

The United States ◽

Independent Study ◽

Adverse Outcomes ◽

Spontaneous Preterm Birth ◽

Increased Risk ◽

Adverse Pregnancy

Preterm births are the leading cause of neonatal death in the United States. Previously, a spontaneous preterm birth (sPTB) predictor based on the ratio of two proteins, IBP4/SHBG, was validated as a predictor of sPTB in the Proteomic Assessment of Preterm Risk (PAPR) study. In particular, a proteomic biomarker threshold of −1.37, corresponding to a ~two-fold increase or ~15% risk of sPTB, significantly stratified earlier deliveries. Guidelines for molecular tests advise replication in a second independent study. Here we tested whether the significant association between proteomic biomarker scores above the threshold and sPTB, and associated adverse outcomes, was replicated in a second independent study, the Multicenter Assessment of a Spontaneous Preterm Birth Risk Predictor (TREETOP). The threshold significantly stratified subjects in PAPR and TREETOP for sPTB (p = 0.041, p = 0.041, respectively). Application of the threshold in a Kaplan–Meier analysis demonstrated significant stratification in each study, respectively, for gestational age at birth (p < 001, p = 0.0016) and rate of hospital discharge for both neonate (p < 0.001, p = 0.005) and mother (p < 0.001, p < 0.001). Above the threshold, severe neonatal morbidity/mortality and mortality alone were 2.2 (p = 0.0083,) and 7.4-fold higher (p = 0.018), respectively, in both studies combined. Thus, higher predictor scores were associated with multiple adverse pregnancy outcomes.

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PREMATURE CERVICAL CHANGE AND THE USE OF CERVICAL CERCLAGE

Fetal and Maternal Medicine Review ◽

10.1017/s0965539507001878 ◽

2007 ◽

Vol 18 (1) ◽

pp. 25-52 ◽

Cited By ~ 5

Author(s):

MANJU CHANDIRAMANI ◽

ANDREW H SHENNAN

Keyword(s):

United States ◽

Preterm Birth ◽

Economic Burden ◽

Teaching Assistants ◽

Preterm Births ◽

The United States ◽

First Year ◽

Spontaneous Preterm Birth ◽

Cervical Cerclage ◽

First Year Of Life

Preterm birth and its subsequent consequences continue to be a major challenge worldwide. In the United States in 2004, 12.5% of infants were born preterm, making the annual societal economic burden associated with preterm birth in excess of $26.2 billion (and this is a modest estimate). Spontaneous preterm birth accounts for about 75% of all preterm births; however, at earlier gestations iatrogenic preterm birth accounts for a greater proportion of all preterm births; at 27–28 weeks 50% are iatrogenic. The proportion of babies transferred to the neonatal unit is more than 90% for those born before 33 completed weeks of gestation compared with 31% at 36 weeks; delivery between 33 completed weeks and 36 completed weeks has a relatively low morbidity and mortality. Nonetheless, 1 in 3 children born preterm but beyond 32 weeks have educational and behavioural problems at the age of 7, with 1 in 4 children born between 32 and 35 weeks requiring support from non-teaching assistants at school. Although more than 40% of babies at 35 completed weeks show signs of maturity, some still need ventilation at 38 completed weeks. Almost one-fifth of all infants born at less than 32 weeks gestation do not survive the first year of life.

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Unique transcriptomic landscapes identified in idiopathic spontaneous and infection related preterm births compared to normal term births

10.1101/386185 ◽

2018 ◽

Author(s):

Heather M Brockway ◽

Suhas G Kallapur ◽

Irina A Buhimschi ◽

Catalin S Buhimschi ◽

William E Ackerman ◽

...

Keyword(s):

Preterm Birth ◽

Molecular Basis ◽

Preterm Births ◽

The United States ◽

Molecular Signature ◽

Spontaneous Preterm Birth ◽

Igf Binding Proteins ◽

Expression Signature ◽

Term Births ◽

Histopathological Studies

AbstractPreterm birth (PTB) is leading contributor to infant death in the United States and globally, yet the underlying mechanistic causes are not well understood. Histopathological studies of preterm birth suggest advanced villous maturity may have a role in idiopathic spontaneous preterm birth (isPTB). To better understand pathological and molecular basis of isPTB, we compared placental villous transcriptomes from carefully phenotyped cohorts of PTB due to infection or isPTB between 28-36 weeks gestation and healthy term placentasu. Transcriptomic analyses revealed a unique expression signature for isPTB distinct from the age-matched controls that were delivered prematurely due to infection. This signature included the upregulation of three IGF binding proteins (IGFBP1, IGFBP2, and IGFBP6), supporting a role for aberrant IGF signaling in isPTB. However, within the isPTB expression signature, we detected secondary signature of inflammatory markers including TNC, C3, CFH, and C1R, which have been associated with placental maturity. In contrast, the expression signature of the gestational age-matched infected samples included upregulation of proliferative genes along with cell cycling and mitosis pathways. Together, these data suggest an isPTB molecular signature of placental hypermaturity, likely contributing to the premature activation of inflammatory pathways associated with birth and providing a molecular basis for idiopathic spontaneous birth.

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Spontaneous Preterm Birth: Is Prevention with Aspirin Possible?

Geburtshilfe und Frauenheilkunde ◽

10.1055/a-1226-6599 ◽

2021 ◽

Author(s):

Richard Berger ◽

Ioannis Kyvernitakis ◽

Holger Maul

Keyword(s):

Preterm Birth ◽

Low Dose ◽

Randomized Study ◽

Preterm Births ◽

Spontaneous Preterm Birth ◽

Dose Aspirin ◽

Nulliparous Women ◽

Low Dose Aspirin ◽

Secondary Analyses ◽

Double Blinded

Abstract Background The rate of preterm births in Germany is 8.6%, which is very high compared to other European countries. As preterm birth contributes significantly to perinatal morbidity and mortality rates, the existing prevention strategies need to be optimized and expanded further. About ⅔ of all women with preterm birth have preterm labor or premature rupture of membranes. They are bracketed together under the term “spontaneous preterm birth” as opposed to iatrogenic preterm birth, for example as a consequence of preeclampsia or fetal growth retardation. Recent studies suggest that low-dose aspirin does not just reduce the rate of iatrogenic preterm births but can also further reduce the rate of spontaneous preterm births. This review article presents the current state of knowledge. Method A selective literature search up until April 2020 was done in PubMed, using the terms “randomized trial”, “randomized study”, “spontaneous preterm birth”, and “aspirin”. Results Secondary analyses of prospective randomized studies on the prevention of preeclampsia with low-dose aspirin show that this intervention also significantly reduced the rate of spontaneous preterm births in both high-risk and low-risk patient populations. The results of the ASPIRIN trial, a prospective, randomized, double-blinded multicenter study carried out in six developing countries, also point in this direction, with the figures showing that the daily administration of 81 mg aspirin starting before 14 weeks of gestation lowered the preterm birth rate of nulliparous women without prior medical conditions by around 11% (11.6 vs. 13.1%; RR 0.89; 95% CI: 0.81 – 0.98, p = 0.012). Conclusion Further studies on this issue are urgently needed. If these confirm the currently available results, then it would be worth discussing whether general aspirin prophylaxis for all pregnant women starting at the latest in 12 weeks of gestation is indicated.

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Magnitude of spontaneous preterm birth and its associated factors among preterm birth in NICU wards in Asella Teaching and Referral Hospital, Asella, Oromia, Ethiopia

Journal of International Medical Research ◽

10.1177/03000605211034693 ◽

2021 ◽

Vol 49 (8) ◽

pp. 030006052110346

Author(s):

Techane Sisay Tuji ◽

Addisu Dabi Wake ◽

Gezahegn Badeg Adere ◽

Aselefu Beka Wedajo ◽

Batu Dekeba Obole ◽

...

Keyword(s):

Risk Factors ◽

Preterm Birth ◽

Healthcare Providers ◽

Preterm Births ◽

Cross Sectional Study ◽

Spontaneous Preterm Birth ◽

Related Factors ◽

Cross Sectional ◽

Bivariate Logistic Regression ◽

Associated Risk Factors

Objective To assess the prevalence of spontaneous preterm births and to identify the associated risk factors. Methods This single-centre cross-sectional study enrolled women that experienced a preterm birth as registered on the neonatal log-book between 30 December 2019 and 30 December 2020. A pre-tested structured checklist was used to collect data (sociodemographic characteristics; obstetric-related factors; medical history; and pregnancy-related factors). Bivariate logistic regression analyses were applied to identify factors associated with spontaneous preterm birth. A multivariate model identified significant independent risk factors. Results A total of 310 patients participated in the study. The prevalence of spontaneous preterm birth in this population was 67.1% (208 of 310; 95% confidence interval [CI] 61.5, 71.9). Patients without a partner (adjusted odds ratio [AOR] = 1.470, 95% CI 1.23, 4.42), patients residing in a rural area (AOR = 2.51, 95% CI 1.123, 5.513) and those with a history of PIH during their current pregnancy (AOR = 0.104, 95% CI 0.053, 0.014) were significantly more likely to have a spontaneous preterm birth. Conclusion The prevalence of spontaneous preterm birth in in this study was high. Healthcare providers and all stakeholders should focus on screening pregnant women at the risk of spontaneous preterm birth.

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Women with high plasma levels of PBDE-47 are at increased risk of preterm birth

Journal of Perinatal Medicine ◽

10.1515/jpm-2020-0349 ◽

2020 ◽

Vol 0 (0) ◽

Author(s):

Morgan R. Peltier ◽

Michael J. Fassett ◽

Yuko Arita ◽

Vicki Y. Chiu ◽

Jiaxiao M. Shi ◽

...

Keyword(s):

Preterm Birth ◽

Los Angeles ◽

Polybrominated Diphenyl Ethers ◽

Flame Retardants ◽

Plasma Concentrations ◽

First Trimester ◽

High Plasma ◽

Thyroid Stimulating Hormone ◽

Spontaneous Preterm Birth ◽

Increased Risk

Abstract Objectives Nearly 100% of North American women have detectable levels of flame retardants such as polybrominated diphenyl ethers (PBDEs) in their plasma. These molecules have structural homology to thyroid hormones and may function as endocrine disruptors. Thyroid dysfunction has previously been associated with increased risk for preterm birth. Therefore, we conducted a multi-center, case-cohort study to evaluate if high plasma concentrations of a common PBDE congener in the first trimester increases the risk of preterm birth and its subtypes. Methods Pregnant women were recruited at the onset of initiation of prenatal care at Kaiser-Permanente Southern California (KPSC)-West Los Angeles and KPSC-San Diego medical centers. Plasma samples from women whose pregnancies ended preterm and random subset of those delivering at term were assayed for PBDE-47 and thyroid-stimulating hormone (TSH) by immunoassay. Quartile cutoffs were calculated for the patients at term and used to determine if women with exposures in the 4th quartile are at increased risk for preterm birth using logistic regression. Results We found that high concentrations of PBDE-47 in the first trimester significantly increased the odds of both indicated (adjusted odds ratio, adjOR=2.35, 95% confidence interval [CI]: 1.31, 4.21) and spontaneous (adjOR=1.76, 95% CI: 1.02, 3.03) preterm birth. Regardless of pregnancy outcome, TSH concentrations did not differ between women with high and low concentrations of PBDE-47. Conclusions These results suggest that high plasma concentrations of PBDE-47 in the first trimester, increases the risk of indicated and spontaneous preterm birth.

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Time to First Cigarette and Self-Reported Health Among US Adult Smokers

Tobacco Use Insights ◽

10.1177/1179173x18825262 ◽

2019 ◽

Vol 12 ◽

pp. 1179173X1882526 ◽

Cited By ~ 1

Author(s):

Baksun Sung

Keyword(s):

United States ◽

Propensity Score ◽

Odds Ratio ◽

Adjusted Odds Ratio ◽

Smoking Behavior ◽

The United States ◽

Elevated Risk ◽

Poor Health ◽

Increased Risk ◽

Reported Health

Background: Numerous studies have reported that shorter time to first cigarette (TTFC) is linked to elevated risk for smoking-related morbidity. However, little is known about the influence of early TTFC on self-reported health among current smokers. Hence, the objective of this study was to examine the association between TTFC and self-reported health among US adult smokers. Methods: Data came from the 2012-2013 National Adult Tobacco Survey (NATS). Current smokers aged 18 years and older (N = 3323) were categorized into 2 groups based on TTFC: ≤ 5 minutes (n = 1066) and >5 minutes (n = 2257). Propensity score matching (PSM) was used to control selection bias. Results: After adjusting for sociodemographic and smoking behavior factors, current smokers with early TTFC had higher odds for poor health in comparison with current smokers with late TTFC in the prematching (adjusted odds ratio [AOR] = 1.65; 95% confidence interval [CI] = 1.31-2.08) and postmatching (AOR = 1.60; 95% CI = 1.22-2.09) samples. Conclusions: In conclusion, smokers with early TTFC were associated with increased risk of poor health in the United States. To reduce early TTFC, elaborate efforts are needed to educate people about harms of early TTFC and benefits of stopping early TTFC.

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Condensation: Cerclage is associated with a longer time interval to delivery and fewer late preterm births in asymptomatic singletons with a short cervix and no history of spontaneous preterm birth.

American Journal of Obstetrics & Gynecology MFM ◽

10.1016/j.ajogmf.2021.100430 ◽

2021 ◽

pp. 100430

Author(s):

Moti Gulersen ◽

Eran Bornstein ◽

Alixandra Domney ◽

Matthew J. Blitz ◽

Timothy J. Rafael ◽

...

Keyword(s):

Preterm Birth ◽

Preterm Births ◽

Late Preterm ◽

Time Interval ◽

Spontaneous Preterm Birth ◽

Short Cervix ◽

History Of

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Real-world safety of palbociclib in breast cancer patients in the United States: a new user cohort study

BMC Cancer ◽

10.1186/s12885-021-07790-z ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Daniel C. Beachler ◽

Cynthia de Luise ◽

Aziza Jamal-Allial ◽

Ruihua Yin ◽

Devon H. Taylor ◽

...

Keyword(s):

Breast Cancer ◽

United States ◽

Pulmonary Embolism ◽

Cohort Study ◽

Real World ◽

The United States ◽

Elevated Risk ◽

Breast Cancer Patients ◽

Increased Risk ◽

Serious Infections

Abstract Background There is limited real-world safety information on palbociclib for treatment of advanced stage HR+/HER2- breast cancer. Methods We conducted a cohort study of breast cancer patients initiating palbociclib and fulvestrant from February 2015 to September 2017 using the HealthCore Integrated Research Database (HIRD), a longitudinal claims database of commercial health plan members in the United States. The historical comparator cohort comprised patients initiating fulvestrant monotherapy from January 2011 to January 2015. Propensity score matching and Cox regression were used to estimate hazard ratios for various safety events. For acute liver injury (ALI), additional analyses and medical record validation were conducted. Results There were 2445 patients who initiated palbociclib including 566 new users of palbociclib-fulvestrant, and 2316 historical new users of fulvestrant monotherapy. Compared to these historical new users of fulvestrant monotherapy, new users of palbociclib-fulvestrant had a greater than 2-fold elevated risk for neutropenia, leukopenia, thrombocytopenia, stomatitis and mucositis, and ALI. Incidence of anemia and QT prolongation were more weakly associated, and incidences of serious infections and pulmonary embolism were similar between groups after propensity score matching. After adjustment for additional ALI risk factors, the elevated risk of ALI in new users of palbociclib-fulvestrant persisted (e.g. primary ALI algorithm hazard ratio (HR) = 3.0, 95% confidence interval (CI) = 1.1–8.4). Conclusions This real-world study found increased risks of several adverse events identified in clinical trials, including neutropenia, leukopenia, and thrombocytopenia, but no increased risk of serious infections or pulmonary embolism when comparing new users of palbociclib-fulvestrant to fulvestrant monotherapy. We observed an increased risk of ALI, extending clinical trial findings of significant imbalances in grade 3/4 elevations of alanine aminotransferase (ALT).

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