The relationship of circulating proteins in early pregnancy with preterm birth

Abstract

BACKGROUND Preterm birth (PTB) (<37 completed weeks gestation) is a pathological outcome of pregnancy and a major global health problem. Babies born preterm have an elevated risk for long term adverse medical and neurodevelopmental sequelae. Substantial evidence implicates intrauterine infection and/or inflammation in PTB. However, these are often relatively late findings in the process, when PTB is inevitable. Identification of earlier markers of PTB may make successful intervention possible. Although select proteins, notably, those related to the inflammatory pathways, have been associated with PTB, there has been a lack of research into the role of other protein pathways in the development of PTB. The purpose of this study was to investigate, using a previously described biomarker discovery approach, a subset of circulating proteins and their association with PTB focusing on samples from early pregnancy. OBJECTIVES 1) To perform a large-scale biomarker discovery, utilizing an innovative platform to identify proteins associated with preterm birth in plasma taken between 10 and 15 weeks’ gestation and, 2) To determine which protein pathways are most strongly associated with preterm birth. To address these aims we measured 1129 proteins in a plasma sample from early pregnancy using a multiplexed aptamer–based proteomic technology developed in Colorado by SomaLogic. STUDY DESIGN Using a nested case-control approach, we measured proteins at a single time point in early pregnancy in 41 women who subsequently delivered preterm and 88 women who had term uncomplicated deliveries. We measured 1129 proteins using a multiplexed aptamer–based proteomic technology developed by SomaLogic. Logistic regressions and random forests were used to compare protein levels. RESULTS The complement factors B and H and the coagulation factors IX and IX ab were the highest ranking proteins distinguishing cases of preterm birth from term controls. The top 3 pathways associated with preterm birth were the complement cascade, the immune system and the clotting cascade. CONCLUSIONS Using a discovery approach, these data provide further confirmation that there is an association of immune and coagulation–related events in early pregnancy with preterm birth. Thus, plasma protein profiles at 10–15 weeks of gestation are related to the development of preterm birth later in pregnancy.

The Microbiome and Complement Activation: A Mechanistic Model for Preterm Birth

“…Specifically women in the upper quartile of C3a were three times more likely to have an adverse outcome later in pregnancy after controlling for parity and pre-pregnancy BMI compared to women in any lower quartiles. In a recent biomarker discovery study, Lynch and colleagues (Lynch, Wagner, Deterding, et al, 2016) also found that the complement factors B and H along with coagulation factors IX and IXab were the highest ranking proteins found in cases of PTB compared to term controls, suggesting that the leading pathways to PTB include the complement, immune and clotting systems. Similarly women with elevated levels of the complement factor Bb in early pregnancy were nearly four times as likely to have PTB after controlling for known PTB related risk factors (Lynch et al, 2008).…”

The maternal plasma proteome changes as a function of gestational age in normal pregnancy: a longitudinal study

“…The same applies to Pappalysin-1 (PAPP-A), one of the top nine proteins whose concentration increased more than five-fold in this study. PAPP-A is mainly produced by the placenta, and its concentration is low in the first trimester of pregnancies complicated by either chromosomal abnormalities (Trisomies 21, 18 and 13, and monosomy X) (93, 97-100, [245][246][247][248] or a subset destined to develop placenta-mediated obstetrical syndromes such as SGA and preeclampsia (119, [249][250][251][252][253][254][255][256][257][258][259][260][261] and preterm birth (262). In this study, we also report the longitudinal changes in the plasma concentrations of PAPP-A as a function of gestational age.…”

The human placental proteome secreted into the maternal and fetal circulations in normal pregnancy based on 4‐vessel sampling

“…Plasma samples were divided into aliquots and stored at 280°C in a Biorepository at the University of Colorado Hospital. Details of the cohort have been described by Lynch et al (25).…”