Diagnostic accuracy of maternal serum macrophage inhibitory cytokine-1 and pregnancy-associated plasma protein-A at 6-10 weeks of gestation to predict miscarriage.

OBJECTIVE: To determine whether serum macrophage inhibitory cytokine-1, pregnancy-associated plasma protein-A (PAPP-A), anandamide, or ß-human chorionic gonadotropin (hCG) measured in an asymptomatic population in the middle of the first trimester with a viable fetus predicts subsequent miscarriage. METHODS: We undertook a prospective cohort study at Mercy Hospital for Women between 2004 and 2008. Participants (N=782) were recruited from prenatal clinics, where samples were taken from asymptomatic women at 6 0/7 to 10 6/7 weeks of gestation. We collected samples from only those women for whom we were able to obtain ultrasound evidence of a singleton with fetal cardiac activity. Serum macrophage inhibitory cytokine-1, PAPP-A, anandamide, and ß-hCG concentrations were assayed. RESULTS: Twenty-one (2.7%) miscarried and 761 did not. Among those who miscarried, macrophage inhibitory cytokine-1 and PAPP-A were significantly decreased at 63% (multiples of the median (MOM) 0.63, 25th-75th percentiles 0.33-0.88) and 23% (MOM 0.23, 25th-75th percentiles 0.12-0.48) of levels seen among those with ongoing pregnancies (P<.001 for both comparisons). In contrast, neither serum ß-hCG (MOM 0.99, 25th-75th percentiles 0.46-1.86) nor anandamide (MOM 1.07, 25th-75th percentiles 0.87-1.19) was elevated or decreased among those who miscarried compared with those with ongoing pregnancies. At a fixed 10% false-positive rate (90% specificity), a test combining macrophage inhibitory cytokine-1 and PAPP-A yielded 63% sensitivity and a 6.6 positive likelihood ratio in predicting miscarriage. CONCLUSION: Low serum levels of macrophage inhibitory cytokine-1 and PAPP-A measured from asymptomatic women at 6-10 weeks of gestation with viable pregnancies can predict subsequent miscarriage. These analytes are likely to have an important biological role in early pregnancy and are likely to be useful clinical biomarkers for miscarriage and other early pregnancy complications. LEVEL OF EVIDENCE: II.

Serum concentrations of soluble Flt-1 are decreased among women with a viable fetus and no symptoms of miscarriage destined for pregnancy loss.

Miscarriage is the most common complication of pregnancy. Pre-clinical miscarriage has an estimated incidence of 30%, whilst clinical miscarriage has an incidence of 12-15%. Two thirds of pregnancies lost to miscarriage are believed to be attributable to defective placentation, thus a number of studies have sought to identify markers of defective placentation that could be used as clinical biomarkers of miscarriage. Decreased soluble FMS-like tyrosine kinase-1 (sFlt1), placental growth factor (PlGF), and soluble endoglin (sEng) in the maternal circulation during the first trimester have recently been proposed as potential markers of pregnancy loss. However, in these studies clinical samples were only obtained once women had presented with symptoms of miscarriage. In this study we prospectively screened serum samples collected from asymptomatic women with a viable fetus. We assessed maternal serum levels of sFlt1, PlGF and sEng across the first trimester of normal pregnancy and compared levels between women who continued to a live birth, to those who subsequently miscarried. Both sFlt1 and PlGF significantly (p≤0.05) increased across gestation in normal pregnancy with serum levels rising from 0.65±0.12 ng/ml at 6 weeks to 1.85±0.24 ng/ml at 12 weeks for sFlt1, and 57.2±19.2 pg/ml to 106±22.7 pg/ml for PlGF. sEng remained unchanged throughout the the first trimester. Importantly we detected a significant (35%, p≤0.05) decrease in sFlt1 levels between our control and miscarriage cohort, however there was significant overlap between cases and controls, suggesting serum sFlt1 is unlikely to be useful as a clinical biomarker in asymptomatic women. Nevertheless, our data suggests a dysregulation of angiogenic factors may be involved in the pathophysiology of miscarriage.