Objective:To determine the inter‐relationships between five first‐trimester biomarkers (pregnancy associated plasma protein A [PAPP‐A], alpha‐fetoprotein [AFP], beta human chorionic gonadotrophin [beta‐hCG], placenta growth factor [PlGF] and soluble fms‐like tyrosine kinase receptor‐1 [sFlt‐1]) and a range of adverse pregnancy outcomes (APOs).
Design:Prospective cohort study of nulliparous singleton pregnancy.
Population or Sample:4056 pregnancy outcome prediction study participants.
Methods:The biomarker concentrations were measured in maternal serum at ~12 weeks of gestation. Univariable analysis of APOs was performed using logistic regression. Multivariable analysis used best subsets logistic regression with cross‐validation.
Main outcome measures:Pre‐eclampsia (PE), small for gestational age (SGA), including severe SGA (birthweight <3rd), fetal growth restriction (FGR), preterm birth (PTB, both induced and spontaneous [iPTB and sPTB, respectively]), pre‐viable loss and stillbirth, plus combinations of outcomes.
Results:Lower values of PAPP‐A, PlGF and sFlt‐1 and higher values of AFP were associated with FGR (OR for 1 SD higher value 0.59 [95% CI 0.48–0.74], OR 0.56 [95% CI 0.44–0.70], OR 0.68 [95% CI 0.54–0.87] and OR 1.53 [95% CI 1.25–1.88]), severe SGA (OR 0.59 [95% CI 0.49–0.72], OR 0.71 [95% CI 0.57–0.87], OR 0.74 [95% CI 0.60–0.91] and OR 1.41 [95% CI 1.17–1.71]), sPTB (OR 0.61 [95% CI 0.50–0.73], OR 0.79 [95% CI 0.66–0.96], OR 0.57 [95% CI 0.47–0.70] and OR 1.41 [95% CI 1.18–1.67]) and iPTB (OR 0.72 [95% CI 0.57–0.91], OR 0.62 [95% CI 0.49–0.78], OR 0.71 [95% CI 0.56–0.90] and OR 1.44 [95% CI 1.16–1.78]), respectively. When combinations of biomarkers were assessed, PAPP‐A and AFP were independently associated with severe SGA; PAPP‐A alone with PE + PTB; PlGF alone with severe PE; PlGF, beta‐hCG, AFP and PAPP‐A with the combination of PE and SGA; AFP and sFlt‐1 with sPTB; and AFP and PlGF with iPTB.
Conclusions:Combinations of first‐trimester placental biomarkers are associated with APOs. However, the patterns vary for different types of APO, indicating heterogeneity in the underlying pathophysiological pathways.