Biochemical predictors of preterm birth in twin pregnancies: A systematic review involving 6077 twin pregnancies

In women with twin pregnancies biomarkers are not used to predict preterm birth in clinical practice. This systematic review assessed the risk of both spontaneous and iatrogenic preterm birth in twin pregnancies based on biochemical predictors. We searched the electronic databases from January 1990 to June 2019 without language restrictions. All studies on twin pregnancies where biochemical predictors and preterm birth were evaluated were included. We reported our findings as odds ratio (OR) with 95 % confidence intervals (CI) and pooled the estimates using random-effects meta-analysis for various predictor thresholds. From 12,623 citations, we included 33 studies involving 6077 pregnancies. The odds of preterm birth <28 weeks (OR 12.06, 95 % CI 4.90-29.70, I2 = 0%), <32 weeks (OR 10.03, 95 % CI 6.11-16.47, I2 = 0%), <34 weeks (OR 6.26, 95 % CI 3.85-10.17, I2 = 30 %), <37 weeks (OR 5.34, 95 % CI 3.68-7.76, I2 = 15 %) and delivery within 14 days of testing (OR 13.95, 95 % CI 4.33-44.98, I2 = 0%) was increased among women with a positive fetal Fibronectin (fFN) test who were either symptomatic or asymptomatic for preterm birth. Similarly, higher odds of preterm birth was also seen among twin pregnancies asymptomatic for preterm birth with a positive fFN test at gestations <32 weeks (OR 10.54, 95 % CI 5.66-19.64, I2 = 19 %), < 34 weeks (OR 8.07, 95 % CI 5.28-12.33, I2 = 0%) and < 37 weeks (OR 6.21, 95 % CI 4.34-8.87, I2 = 0%). As for other biomarkers, a significantly higher odds of preterm birth <37 weeks was seen among women with elevated maternal serum human Chorionic Gonadotrophin (mshCG) (OR 1.51, 95 % CI 1.07-2.13, I2 = 0%), 25 Hydroxy Vitamin D level <75 nmol/l (OR 2.59, 95 % CI 1.35-4.95, I2=NA), positive phosphorylated Insulin-like Growth Factor Binding Protein-1 (phIGFBP-1) (OR 4.23, 95 % CI 1.97-9.09, I2 = 0%) and in those with elevated Interleukin 8 (IL-8) (OR 3.13, 95 % CI 1.18-8.34, I2=NA). A higher odds of preterm birth at <34 weeks gestation was seen among women with maternal serum Alpha fetoprotein (AFP)>3.5 MoM (OR 2.35, 95 % CI 1.12-4.96, I2=NA) while higher odds of preterm birth at <32 weeks was seen among women with 25 Hydroxy Vitamin D level <75 nmol/l (OR 3.01, 95 % CI 1.26-7.19, I2=NA). Delivery within seven days of testing was significantly increased in women with a positive Matrix Metallo Protein-8 (MMP-8) test (OR 10.59, 95 % CI 3.70-30.29, I2=NA). Fetal Fibronectin is strongly associated with predicting preterm birth among women with twin pregnancies who are either asymptomatic or symptomatic for preterm birth as well as in those asymptomatic for preterm birth. Other biomarkers have shown a positive association in the prediction of preterm birth among women with twin pregnancies. Further studies are recommended to evaluate their role.