Stillbirth, Inflammatory Markers, and Obesity: Results from the Stillbirth Collaborative Research Network

Margo S Harrison, Vanessa R Thorsten, Donald J Dudley, Corette B Parker, Matthew A Koch, Carol J R Hogue, Barbara J Stoll, Robert M Silver, Michael W Varner, M Halit Pinar, Donald R Coustan, George R Saade, Radek K Bukowski, Deborah L Conway, Marian Willinger, Uma M Reddy, Robert L Goldenberg

 Obesity is associated with increased risk of stillbirth, although the mechanisms are unknown. Obesity is also associated with inflammation. Serum ferritin, C-reactive protein, white blood cell count, and histologic chorioamnionitis are all markers of inflammation.  This article determines if inflammatory markers are associated with stillbirth and body mass index (BMI). Additionally, we determined whether inflammatory markers help to explain the known relationship between obesity and stillbirth.  White blood cell count was assessed at admission to labor and delivery, maternal serum for assessment of various biomarkers was collected after study enrollment, and histologic chorioamnionitis was based on placental histology. These markers were compared for stillbirths and live births overall and within categories of BMI using analysis of variance on logarithmic-transformed markers and logistic regression for dichotomous variables. The impact of inflammatory markers on the association of BMI categories with stillbirth status was assessed using crude and adjusted odds ratios (COR and AOR, respectively) from logistic regression models. The interaction of inflammatory markers and BMI categories on stillbirth status was also assessed through logistic regression. Additional logistic regression models were used to determine if the association of maternal serum ferritin with stillbirth is different for preterm versus term births. Analyses were weighted for the overall population from which this sample was derived.  A total of 497 women with singleton stillbirths and 1,414 women with live births were studied with prepregnancy BMI (kg/m2) categorized as normal (18.5-24.9), overweight (25.0-29.9), or obese (30.0 + ). Overweight (COR, 1.48; 95% confidence interval [CI]: 1.14-1.94) and obese women (COR, 1.60; 95% CI: 1.23-2.08) were more likely than normal weight women to experience stillbirth. Serum ferritin levels were higher (geometric mean: 37.4 ng/mL vs. 23.3,p < 0.0001) and C-reactive protein levels lower (geometric mean: 2.9 mg/dL vs. 3.3,p = 0.0279), among women with stillbirth compared with live birth. Elevated white blood cell count (15.0 uL × 103or greater) was associated with stillbirth (21.2% SB vs. 10.0% live birth,p < 0.0001). Histologic chorioamnionitis was more common (33.2% vs. 15.7%,p < 0.0001) among women with stillbirth compared with those with live birth. Serum ferritin, C-reactive protein, and chorioamnionitis had little impact on the ORs associating stillbirth with overweight or obesity. Adjustment for elevated white blood cell count did not meaningfully change the OR for stillbirth in overweight versus normal weight women. However, the stillbirth OR for obese versus normal BMI changed by more than 10% when adjusting for histologic chorioamnionitis (AOR, 1.38; 95% CI: 1.02-1.88), indicating confounding. BMI by inflammatory marker interaction terms were not significant. The association of serum ferritin levels with stillbirth was stronger among preterm births (p = 0.0066).  Maternal serum ferritin levels, elevated white blood cell count, and histologic chorioamnionitis were positively and C-reactive protein levels negatively associated with stillbirth. Elevated BMIs, both overweight and obese, were associated with stillbirth when compared with women with normal BMI. None of the inflammatory markers fully accounted for the relationship between obesity and stillbirth. The association of maternal serum ferritin with stillbirth was stronger in preterm than term stillbirths.