Early Pregnancy Levels of Pregnancy-Associated Plasma Protein A and the Risk of Intrauterine Growth Restriction, Premature Birth, Preeclampsia, and Stillbirth

Smith, Gordon C. S.; Stenhouse, Emily; Crossley, Jennifer A.; Aitken, David A.; Cameron, Alan; Connor, J. M.

doi:10.1210/jcem.87.4.8430

Cited by 370 publications

(121 citation statements)

References 14 publications

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“…The clinical investigations of the complex relationship among PAPP-A levels during pregnancy, gestational diabetes (GDM) and cardiovascular disease risk are evolving [36–39]. Low levels of PAPP-A during the first trimester are associated with fetal Down’s syndrome [40] and other adverse events [37, 41–43]. A recent study [39] among Chinese women showed that PAPP-A levels in the first trimester were not predictive of development of GDM which is highly prevalent (approximately 19%) in China [44].…”

Section: Discussionmentioning

confidence: 99%

Pregnancy-associated plasma protein-A is a stronger predictor for adverse cardiovascular outcomes after acute coronary syndrome in type-2 diabetes mellitus

Neradilek

et al. 2017

Cardiovasc Diabetol

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BackgroundThe risk prediction of pregnancy-associated plasma protein-A (PAPP-A) for future cardiovascular (CV) events post acute coronary syndrome (ACS) in patients with type-2 diabetes mellitus (T2DM) was investigated in comparison to other risk factors.MethodsPAPP-A was measured at hospital admission in 320 consecutive ACS patients (136 with T2DM and 184 without). All patients were followed for 2 years for occurrence of CV death, non-fatal MI or stroke. Effect of PAPP-A on the CV event risk was estimated using Cox regression models. Receiver operating characteristics (ROC) curves were generated to demonstrate the sensitivity and specificity of PAPP-A in predicting CV events.ResultsACS patients with T2DM had higher PAPP-A (19.29 ± 16.36 vs. 13.29 ± 13.90 ng/ml, p < 0.001) and higher rate of CV events 2 years post ACS (27.2 vs. 13.6%, p = 0.002) than those without. Higher levels of PAPP-A were significantly associated with increased risk of CV events during 2-year follow-up [HR = 2.97 for 1 SD increase in log10(PAPP-A), 95% CI 2.11–4.18, p < 0.001] in T2DM and (HR = 3.16, 95% CI 2.27–4.39, p < 0.001) in non-T2DM. Among patients with T2DM, PAPP-A showed a larger area under the curve (AUC 0.79) that was significantly more predictive than hsCRP (AUC 0.64), eGFR (AUC 0.66) and LVEF < 50% (AUC 0.52); predictive ability did not improve significantly by including those factors into the model.ConclusionsPatients with T2DM had higher levels of PAPP-A and increased risk of CV events. Elevated PAPP-A compared to other risk factors was a stronger predictor for future CV events 2 years post ACS in patients with T2DM. Trial registration ISRCTN10805074. Registered on 20 January 2017, retrospectively registered.

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Section: Discussionmentioning

confidence: 99%

Pregnancy-associated plasma protein-A is a stronger predictor for adverse cardiovascular outcomes after acute coronary syndrome in type-2 diabetes mellitus

Neradilek

et al. 2017

Cardiovasc Diabetol

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“…PAPP-A is closely related to pregnancy because it plays an important role in trophoblast invasion by modulating the activity of insulin-like growth factor (IGF) through the cleavage of binding proteins [19-20]. Previous studies have shown that PAPP-A alters placental trophoblast differentiation and invasion by mediating IGF in the first trimester of pregnancy, which is associated with PE, miscarriage, preterm delivery, fetal growth restriction, and fetal death [21-24]. …”

Section: Introductionmentioning

confidence: 99%

CircRNA-0004904, CircRNA-0001855, and PAPP-A: Potential Novel Biomarkers for the Prediction of Preeclampsia

Jiang

Lash

Zhao

et al. 2018

Cell Physiol Biochem

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Background/Aims: Circular RNAs (circRNAs) are transcribed prevalently in the genome; however, their potential roles in multiple cardiovascular diseases, particularly preeclampsia (PE), are not yet well understood. This study investigated the expression profiles of circRNAs and explored circRNA-mediated pregnancy-associated plasma protein A (PAPP-A) expression as a potential biomarker for PE before 20 weeks of pregnancy. Methods: A nested case-control two-phase screening/validation study was performed in pregnant women before 20 weeks of gestation (before clinical diagnosis) at Guangzhou Women and Children’s Medical Center from 2012 to 2015. In the screening phase, circRNA expression profiles of blood cells were assessed using a human circRNA microarray, which was designed to detect simultaneously 5396 circRNAs, in 5 patients with PE and 5 age- and gestational week-matched controls. In the validation phase, 18 circRNAs in blood cells predicted by bioinformatics tools were validated by quantitative reverse transcription PCR in a cohort of 60 patients (PE and age-, gestational week-, and sample storage time-matched controls). Then, we examined the involvement of circRNAs in PE-related pathways via interactions with miRNAs by multiple bioinformatics approaches. Bioinformatics analysis predicted that hsa_circ_0004904 and hsa_circ_0001855 miRNA sponges directly target PAPP-A. PAPP-A was verified in the serum of the same cohort of patients using an enzyme-linked immunosorbent assay. Finally, we combined PAPP-A with circRNAs to create a novel preclinical diagnostic model for PE with logistic regression and evaluated the efficiency of this model with receiver operating curve analysis. Results: Volcano plot analysis using various parameters showed that circRNAs were differentially expressed among both groups (P < 0.01, fold change > 2). In the screening phase, we found that 2178 circRNAs were differentially expressed between the control and PE groups, in which 884 circRNAs were downregulated and 1294 circRNAs were upregulated in the PE group compared with the control group. In the validation phase, two circRNAs, hsa_circ_0004904 and hsa_circ_0001855, were significantly upregulated in PE patients compared with healthy pregnant women (P < 0.05). PAPP-A expression levels, related to the two circRNAs based on bioinformatics prediction, were increased in the PE group compared with the control group. The area under the curve of the combined model was 0.94 in the predicted PE subjects. Conclusions: This is the first study to report circRNA profiling in patients with PE prior to the onset of symptoms. Our data suggested that hsa_circ_0004904 and hsa_circ_0001855 combined with PAPP-A might be promising biomarkers for the detection of PE. Moreover, circRNAs may provide new insights into the potential mechanisms underlying the pathophysiology of PE.

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“…Preeclampsia and FGR share a number of associations with biomarkers of placental function, including low first trimester of pregnancy-associated plasma protein A (PAPP-A), high second trimester α-fetoprotein (AFP) in maternal serum (23), and high resistance patterns of uterine artery Doppler flow velocimetry (24, 25). However, DiAcSpm is the first circulating maternal factor to our knowledge to demonstrate opposite associations with the 2 conditions.…”

Section: Discussionmentioning

confidence: 99%

Placental polyamine metabolism differs by fetal sex, fetal growth restriction, and preeclampsia

Gong¹,

Sovio²,

Aye³

et al. 2018

JCI Insight

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Preeclampsia and fetal growth restriction (FGR) are major causes of the more than 5 million perinatal and infant deaths occurring globally each year, and both are associated with placental dysfunction. The risk of perinatal and infant death is greater in males, but the mechanisms are unclear. We studied data and biological samples from the Pregnancy Outcome Prediction (POP) study, a prospective cohort study that followed 4,212 women having first pregnancies from their dating ultrasound scan through delivery. We tested the hypothesis that fetal sex would be associated with altered placental function using multiomic and targeted analyses. We found that spermine synthase (SMS) escapes X-chromosome inactivation (XCI) in the placenta and is expressed at lower levels in male primary trophoblast cells, and male cells were more sensitive to polyamine depletion. The spermine metabolite N1,N12-diacetylspermine (DiAcSpm) was higher in the female placenta and in the serum of women pregnant with a female fetus. Higher maternal serum levels of DiAcSpm increased the risk of preeclampsia but decreased the risk of FGR. To our knowledge, DiAcSpm is the first maternal biomarker to demonstrate opposite associations with preeclampsia and FGR, and this is the first evidence to implicate polyamine metabolism in sex-related differences in placentally related complications of human pregnancy.

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Early Pregnancy Levels of Pregnancy-Associated Plasma Protein A and the Risk of Intrauterine Growth Restriction, Premature Birth, Preeclampsia, and Stillbirth

Cited by 370 publications

References 14 publications

Pregnancy-associated plasma protein-A is a stronger predictor for adverse cardiovascular outcomes after acute coronary syndrome in type-2 diabetes mellitus

Pregnancy-associated plasma protein-A is a stronger predictor for adverse cardiovascular outcomes after acute coronary syndrome in type-2 diabetes mellitus

CircRNA-0004904, CircRNA-0001855, and PAPP-A: Potential Novel Biomarkers for the Prediction of Preeclampsia

Placental polyamine metabolism differs by fetal sex, fetal growth restriction, and preeclampsia

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