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

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

10.1101/2021.01.23.21249902 ◽

2021 ◽

Author(s):

Julja Burchard ◽

Ashoka D. Polpitiya ◽

Angela C. Fox ◽

Todd Randolph ◽

Tracey C. Fleischer ◽

...

Keyword(s):

Preterm Birth ◽

Observational Study ◽

Preterm Births ◽

The United States ◽

Elevated Risk ◽

Clinical Validation ◽

Spontaneous Preterm Birth ◽

Effective Interventions ◽

Increased Risk ◽

Risk Predictor

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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Enrichment of Clinically Relevant Organisms in Spontaneous Preterm-Delivered Placentas and Reagent Contamination across All Clinical Groups in a Large Pregnancy Cohort in the United Kingdom

Applied and Environmental Microbiology ◽

10.1128/aem.00483-18 ◽

2018 ◽

Vol 84 (14) ◽

Cited By ~ 27

Author(s):

Lydia J. Leon ◽

Ronan Doyle ◽

Ernest Diez-Benavente ◽

Taane G. Clark ◽

Nigel Klein ◽

...

Keyword(s):

United Kingdom ◽

Preterm Birth ◽

Preterm Births ◽

Convincing Evidence ◽

Rrna Gene ◽

Spontaneous Preterm Birth ◽

Content Type ◽

Pregnancy Cohort ◽

The United Kingdom ◽

Adverse Pregnancy

ABSTRACT In this study, differences in the placental microbiota from term and preterm deliveries in a large pregnancy cohort in the United Kingdom were studied by using 16S-targeted amplicon sequencing. The impacts of contamination from DNA extraction, PCR reagents, and the delivery itself were also examined. A total of 400 placental samples from 256 singleton pregnancies were analyzed, and differences between spontaneous preterm-, nonspontaneous preterm-, and term-delivered placentas were investigated. DNA from recently delivered placentas was extracted, and screening for bacterial DNA was carried out by using targeted sequencing of the 16S rRNA gene on the Illumina MiSeq platform. Sequenced reads were analyzed for the presence of contaminating operational taxonomic units (OTUs) identified via sequencing of negative extraction and PCR-blank samples. Differential abundances and between-sample (beta) diversity metrics were then compared. A large proportion of the reads sequenced from the extracted placental samples mapped to OTUs that were also found for negative extractions. Striking differences in the compositions of samples were also observed, according to whether the placenta was delivered abdominally or vaginally, providing strong circumstantial evidence for delivery contamination as an important contributor to observed microbial profiles. When OTU- and genus-level abundances were compared between the groups of interest, a number of organisms were enriched in the spontaneous preterm-delivery cohort, including organisms that have been associated previously with adverse pregnancy outcomes, specifically Mycoplasma spp. and Ureaplasma spp. However, analyses of the overall community structure did not reveal convincing evidence for the existence of a reproducible “preterm placental microbiome.” IMPORTANCE Preterm birth is associated with both psychological and physical disabilities and is the leading cause of infant morbidity and mortality worldwide. Infection is known to be an important cause of spontaneous preterm birth, and recent research has implicated variation in the “placental microbiome” in the risk of preterm birth. Consistent with data from previous studies, the abundances of certain clinically relevant species differed between spontaneous preterm- and nonspontaneous preterm- or term-delivered placentas. These results support the view that a proportion of spontaneous preterm births have an intrauterine-infection component. However, an additional observation from this study was that a substantial proportion of sequenced reads were contaminating reads rather than DNA from endogenous, clinically relevant species. This observation warrants caution in the interpretation of sequencing outputs from low-biomass samples such as the placenta.

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The impact of interpregnancy interval on occurance of preterm births in the present pregnancy

International Journal of Reproduction Contraception Obstetrics and Gynecology ◽

10.18203/2320-1770.ijrcog20211531 ◽

2021 ◽

Vol 10 (5) ◽

pp. 2020

Author(s):

Balaji Thanjavur Elumalai ◽

Vaishnavi Govindarajan

Keyword(s):

Preterm Birth ◽

Preterm Births ◽

Neonatal Morbidity ◽

P Value ◽

Interpregnancy Interval ◽

Maternal Characteristics ◽

Increased Risk ◽

Pregnancy Intervals ◽

The Impact ◽

Present Pregnancy

Background: The pregnancy outcomes are influenced by the inter pregnancy intervals. Both short and long inter pregnancy intervals are known to adversely affect the mother and the baby. The main aim of birth spacing was to achieve ideal inter pregnancy intervals and thus to decrease maternal, neonatal morbidity and mortality.Methods: It is a prospective observational study. In this study, about 500 gravida 2 women who has delivered vaginally in the index pregnancy, with gestational age more than 28 weeks of gestation and with known interpregnancy interval were included in the study. They followed up to to delivery and occurance of preterm births in relation to maternal characteristics and interpregnancy interval were analysed.Results: Our study showed that Inter pregnancy intervals of 18-24 months were found to have the least number of preterm births when compared to intervals <18 months and >24 months. This association was found to be statistically significant (p value, Pearson chi square 0.0008). This relationship between inter pregnancy intervals and preterm births persisted when stratified according to maternal age, education, residence and BMI.A previous preterm birth was associated with increased risk of recurrent preterm birth (p value -0.034) and was statistically significant. The history of PROM in present pregnancy associated with preterm birth (p value -0.001) and association was statistically significant.Conclusions: From this study it was found that the 18-24 months birth to pregnancy interval is associated with the least incidence of preterm births.

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Integrated Review of Cytokines in Maternal, Cord, and Newborn Blood: Part I—Associations With Preterm Birth

Biological Research For Nursing ◽

10.1177/1099800409344620 ◽

2009 ◽

Vol 11 (4) ◽

pp. 371-376 ◽

Cited By ~ 46

Author(s):

Debra Lyon ◽

Ching-Yu Cheng ◽

Lois Howland ◽

Debra Rattican ◽

Nancy Jallo ◽

...

Keyword(s):

Preterm Birth ◽

Proinflammatory Cytokines ◽

Preterm Labor ◽

Neonatal Morbidity ◽

The United States ◽

Fetal Outcome ◽

Fetal Outcomes ◽

Consistent Finding ◽

Mediators Of Inflammation ◽

Adverse Pregnancy

Preterm birth (PTB; spontaneous delivery prior to 37 weeks gestation) affects one out of eight infants born in the United States and is the most common cause of neonatal morbidity and mortality. Although the pathogenesis of PTB is multifactorial, a growing body of literature supports the hypothesis that one cause of PTB is inflammation in pregnancy. Investigators have implicated mediators of inflammation, most notably proinflammatory cytokines, as being associated with and perhaps a playing a causal role in the pathogenesis of preterm labor and adverse early fetal outcomes. Though researchers have pursued the association of cytokines with preterm labor and subsequent early adverse fetal outcomes as a line of research, there has been little integration of diverse findings across studies. This systematic review appraises the empirical evidence from human studies for the association of levels of cytokines in blood with preterm labor and adverse early fetal outcome to examine the current state of the science in this important area of biobehavioral research. The most consistent finding is that increased levels of proinflammatory cytokines, particularly interleukin (IL) 6, IL-β1, and tumor necrosis factor α (TNF-α), are associated with PTB as compared to levels found at term birth. However, there have been relatively few studies and results have not been consistent. Therefore, further research is needed to elucidate the association of these inflammatory mediators with adverse pregnancy outcomes.

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Obstetrical, maternal and neonatal outcomes in pregnancies affected by muscular dystrophy

Journal of Perinatal Medicine ◽

10.1515/jpm-2017-0299 ◽

2018 ◽

Vol 46 (7) ◽

pp. 791-796 ◽

Cited By ~ 2

Author(s):

Adriano Petrangelo ◽

Eman Alshehri ◽

Nicholas Czuzoj-Shulman ◽

Haim A. Abenhaim

Keyword(s):

Cohort Study ◽

Muscular Dystrophy ◽

Large Population ◽

The United States ◽

Population Based ◽

Adverse Outcomes ◽

Neonatal Outcomes ◽

Increased Risk ◽

Maternal And Neonatal Outcomes ◽

Adverse Pregnancy

Abstract Objective: Pregnancies in women affected by a muscular dystrophy are at an increased risk of adverse maternal and neonatal outcomes due to the effect of the disease on the muscular, cardiac and respiratory systems. We sought to evaluate the risk of adverse outcomes within a large population-based cohort study. Methods: We used the data extracted from the Nationwide Inpatient Sample (NIS) to conduct a retrospective population-based cohort study consisting of over 12 million births that occurred in the United States between 1999 and 2013. Births to mothers with muscular dystrophy were identified using the International Classification of Diseases, Ninth Revision (ICD-9) codes and were compared with births to mothers with no maternal muscular dystrophy. Unconditional logistic regression analysis was used to evaluate the adjusted effect of muscular dystrophy on maternal and neonatal outcomes. Results: During the 14-year study period, there was an increasing trend in the incidence of muscular dystrophy, with a cumulative incidence of 7.26 in 100,000 births. Women with muscular dystrophy and their neonates were at a significantly increased risk of adverse pregnancy outcomes: specifically, an increased risk of preeclampsia, preterm premature rupture of membranes, preterm labor, venous thromboembolism, cardiac dysrhythmia, requiring a blood transfusion and giving birth by cesarean section. Neonates born to affected mothers were at a significantly higher risk of being born preterm, with a congenital malformation and suffering intrauterine growth restriction. Conclusion: The risk of several adverse maternal and neonatal outcomes is increased in pregnant women with muscular dystrophy. As such, additional surveillance in order to mitigate the risk of adverse outcomes is warranted in these pregnancies.

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Neonatal morbidity pattern in early term births

International Journal of Contemporary Pediatrics ◽

10.18203/2349-3291.ijcp20185153 ◽

2018 ◽

Vol 6 (1) ◽

pp. 93

Author(s):

Maya Menon ◽

Sreejyothi G. ◽

Raveendranath K.

Keyword(s):

Continuous Process ◽

Preterm Births ◽

Neonatal Morbidity ◽

Adverse Outcomes ◽

Full Term ◽

Neonatal Outcomes ◽

Feeding Problems ◽

Early Term ◽

Increased Risk ◽

Term Births

Background: Late preterm births are defined as birth between 34 and 36 completed weeks gestation and term births as born after 37 weeks of gestation. Maturation is a continuous process till term and the severity of adverse outcomes with birth increases with decreasing gestational age. Recent studies showed increased risk of morbidities for babies at 37 weeks than its term counterpart babies at 39 weeks. Considering the risk for adverse neonatal outcomes in early term births, various studies recommended that the label “term” be redefined as early term, full term and late term designations to more accurately acknowledge deliveries occurring at or beyond 37 weeks of gestation. This designation will help precise identification and targeting these early term babies for early intervention and for better neonatal outcomes.Methods: This is a prospective study which included all term births delivered during the 12-month study between January 2017 and December 2017. Babies born between 37 and 38 6/7 weeks were designated as early term and those born after 39 weeks as full-term babies. Neonatal outcomes of these babies were recorded and monitored till discharge.Results: There were 660 term live births during the study period. The incidence of early term births account for 19.7%, as compared with full term births representing 80.3 %. Compared with term babies, early term births were at risk for transitional problems such as respiratory distress (61.5% vs 38.5%), hypoglycemia (76.2% vs 23.8%), hyperbilirubinemia requiring phototherapy (53.7% vs 46.7%) and feeding problems (59.1% vs 40.9%).Conclusions: Early term births are associated with increased risk of neonatal morbidities as compared with full term births. This indicates need for more attention towards preventing early term births.

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Pregnancy outcomes among women with thyrotoxicosis a retrospective cohort study

10.21203/rs.3.rs-162247/v1 ◽

2021 ◽

Author(s):

Panwad Harn-a-morn ◽

Prapai Dejkhamron ◽

Theera Tongsong ◽

Suchaya Luewan

Keyword(s):

Preterm Birth ◽

Pregnant Women ◽

Pregnancy Outcomes ◽

Adverse Outcomes ◽

Low Risk ◽

Obstetric Outcomes ◽

Study Group ◽

Increased Risk ◽

Adverse Pregnancy ◽

Singleton Pregnancies

Abstract Objective: To compare adverse outcomes between: 1) pregnant women with thyrotoxicosis and low risk pregnancies, 2) pregnant women with thyrotoxicosis requiring no anti-thyroid drug (ATD) and low risk pregnancies, and 3) those treated with methimazole (MMI) and propylthiouracil (PTU)Methods: The medical records of singleton pregnancies with thyrotoxicosis were comprehensively reviewed. Low-risk pregnancies matched for age and parity were randomly recruited as controls. The obstetric outcomes were compared between both groups, and the outcomes of various subgroups of the study group were also compared.Results: A total of 408 pregnant women with thyrotoxicosis were recruited. Compared with the controls, the women of the study group had significantly higher rates of low birth weight (LBW) (23.7% vs 17.7%; p:0.036), preterm birth (19.3% vs 12.3%; p:0.007), preeclampsia (8.5% vs 4.4%; p: 0.019) and cesarean section (21.5% vs 16.0%; p:0.046). In the study group (thyrotoxicosis), 67, 127, and 158 patients were treated with MMI, PTU and no anti-thyroid drug (ATD), respectively. All obstetric outcomes were comparable between the women treated with PTU and those with MMI, and between the controlled and uncontrolled groups. However, women who needed ATD had significantly higher rates of LBW and preterm birth than those without medications.Conclusions: Thyrotoxicosis, whether treated or not needing ATDs, was significantly associated with an increased risk of adverse pregnancy outcomes. Also, active disease, indicated by the need for ATD significantly increased the risk of such adverse outcomes, whereas the patients treated with MMI or PTU had comparable adverse outcomes.

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A Multisite Examination of Everyday Discrimination and the Prevalence of Spontaneous Preterm Birth in African American and Latina Women in the United States

American Journal of Perinatology ◽

10.1055/s-0039-1693696 ◽

2019 ◽

Vol 37 (13) ◽

pp. 1340-1350

Author(s):

Kimberly E. Fryer ◽

Anissa I. Vines ◽

Alison M. Stuebe

Keyword(s):

African American ◽

Preterm Birth ◽

African American Women ◽

The United States ◽

Research Network ◽

Latina Women ◽

Spontaneous Preterm Birth ◽

Cross Sectional ◽

American Women ◽

Adverse Pregnancy

Abstract Objective African American women have a higher risk of spontaneous preterm birth than White and Latina women. Although Latina women are exposed to similar social determinants of health, they have lower rates of spontaneous preterm birth. One theory for this difference is the maternal stress biological pathway, whereby lifetime stressors, such as racial discrimination, lead to a premature activation of parturition. We investigated the prevalence of self-reported discrimination and its association with the prevalence of spontaneous preterm birth. Study Design Using data from the Community Child Health Research Network Study, a multisite cohort study from 2008 to 2012, we conducted a cross-sectional analysis of 1,154 African American women and 578 Latina women. Results Adjusting for multiple risk factors, African American and Latina women who experienced the highest tertile of discrimination had a higher prevalence of preterm birth compared with those who experienced discrimination less than once per year, adjusted hazard ratio (aHR) = 1.5 (0.7–3.1) and 3.6 (0.9–14.4), respectively. Conclusion In our cohort, we found a statistically significant association only in the medium discrimination group in Latina women, but we did not find a statistically significant association in African American women. Reduction in experienced discrimination may be an important intervention for reducing adverse pregnancy outcomes.

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The Effect of Treated Overt Hypothyroidism on Outcomes in Twin Pregnancies

American Journal of Perinatology ◽

10.1055/s-0037-1604289 ◽

2017 ◽

Vol 34 (14) ◽

pp. 1447-1450

Author(s):

Nathan Fox ◽

Daniel Saltzman ◽

Andrei Rebarber ◽

Simi Gupta ◽

Jonathan Rosner

Keyword(s):

Pregnancy Outcomes ◽

Adverse Pregnancy Outcomes ◽

Adverse Outcomes ◽

Overt Hypothyroidism ◽

Thyroid Function Tests ◽

Spontaneous Preterm Birth ◽

Increased Risk ◽

Adverse Pregnancy ◽

Twin Pregnancies

Objective The objective of this study was to determine if treatment of overt hypothyroidism in twin pregnancies reduces adverse outcomes associated with overt hypothyroidism in pregnancy. Methods This is a retrospective cohort study of all patients who were presented with twin gestations between 2005 and 2013 to a single obstetrical practice. Patients who were diagnosed with overt hypothyroidism were identified. Patients were followed up with serial thyroid function tests and treated appropriately. Rates of adverse pregnancy outcomes were compared between patients with and without hypothyroidism with p < 0.05 used for significance. Results In this study, 612 twin pregnancies were included; 85 patients were diagnosed with overt hypothyroidism. Patients with overt hypothyroidism were more likely to have had in vitro fertilization (78 vs. 62%; p < 0.01). After adjusting for confounding variables, patients with overt hypothyroidism had no increased risk of spontaneous preterm birth < 37 weeks' gestation (adjusted odds ratio [aOR]: 0.833; 95% confidence interval [CI]: 0.498–1.393), intrauterine growth restriction (aOR: 0.720; 95% CI: 0.446–1.163), gestational diabetes (aOR: 0.812; 95% CI: 0.353–1.871), or composite adverse outcomes (aOR: 0.659; 95% CI 0.391–1.111) compared with patients who did not have overt hypothyroidism. There was a trend toward decreased hypertensive disorders of pregnancy (aOR: 0.470; 95% CI: 0.234–0.944). Conclusion Our study shows that in twin gestations, there is no increased risk of adverse pregnancy outcomes between patients with treated overt hypothyroidism and those without overt hypothyroidism.

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Maternal lithium use and the risk of adverse pregnancy and neonatal outcomes: a Swedish population-based cohort study

BMC Medicine ◽

10.1186/s12916-021-02170-7 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Roxanne Hastie ◽

Stephen Tong ◽

Richard Hiscock ◽

Anthea Lindquist ◽

Linda Lindström ◽

...

Keyword(s):

Cohort Study ◽

Preterm Birth ◽

Gestational Age ◽

Population Based ◽

Neonatal Outcomes ◽

Large For Gestational Age ◽

Adjusted Relative Risk ◽

Spontaneous Preterm Birth ◽

Increased Risk ◽

Adverse Pregnancy

Abstract Background Lithium is prescribed during pregnancy, but there is limited information about pregnancy and neonatal outcomes following in utero exposure. Thus, this study aimed to investigate the associations between lithium use and adverse pregnancy and neonatal outcomes. Methods This population-based cohort study examined associations between maternal lithium use and major adverse pregnancy and neonatal outcomes via inverse probability weighted propensity score regression models. Results Of 854,017 women included in this study, 434 (0.05%) used lithium during pregnancy. Among pre-specified primary outcomes, lithium use during pregnancy was associated with an increased risk of spontaneous preterm birth (8.7% vs 3.0%; adjusted relative risk [aRR] 2.64 95% CI 1.82, 3.82) and birth of a large for gestational age infant (9.0% vs 3.5%; aRR 2.64 95% CI 1.91, 3.66), but not preeclampsia nor birth of a small for gestational age infant. Among secondary outcomes, lithium use was associated with an increased risk of cardiac malformations (2.1% vs 0.8%; aRR 3.17 95% CI 1.64, 6.13). In an analysis restricted to pregnant women with a diagnosed psychiatric illness (n=9552), associations remained between lithium and spontaneous preterm birth, birth of a large for gestational age infant, and cardiovascular malformations; and a positive association with neonatal hypoglycaemia was also found. These associations were also apparent in a further analysis comparing women who continued lithium treatment during pregnancy to those who discontinued prior to pregnancy. Conclusions Lithium use during pregnancy is associated with an increased risk of spontaneous preterm birth and other adverse neonatal outcomes. These potential risks must be balanced against the important benefit of treatment and should be used to guide shared decision-making.

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