The role of fetal growth restriction in the association between Down syndrome and perinatal mortality

Objective: Down syndrome (DS) is associated with significant risk of perinatal mortality. We hypothesize that this association is primarily mediated through the effects of fetal growth restriction (FGR). Methods: This was a retrospective cohort analysis using the US Natality Database from 2011 to 2013. Analysis was limited to singleton nonanomalous pregnancies or confirmed DS pregnancies without severe structural anomalies between 24 and 42 w in gestation. The risk of stillbirth (SB) associated with DS was estimated using both Cox proportional Hazard (HR) regression and accelerated failure time (AFT) methods. The risk of neonatal mortality was estimated using logistic regression analyses. Mediation analysis was then performed to estimate the effect of small for gestational age (SGA), defined as birthweight ≤10th percentile for gestational age, on perinatal mortality associated with DS. All regression models were selected using backward stepwise elimination method. The final regression models included adjustment for maternal age, hypertension, and diabetes. Results: The final cohort included 2446 DS cases among 9,804,718 births. The overall SB rate was 223.6/1000 births in DS group and 4.7/1000 births without DS (p <.001, adjusted hazard ratio (aHR): 58.25; 95% CI [53.44,63.49]). Based on the AFT model, DS survival-to-delivery rate is 4.3 times lower (TR: 0.23; 95% CI [0.22,0.24]). Thirty-five percentage of the effect of DS on stillbirth was mediated through SGA (% mediation:35.1%; 95% CI [33.7,36.4]). The rate of neonatal mortality among DS was 69.0/1000 births compared with 2.8/1000 births without DS (p <.001, adjusted odds ratio (aOR): 27.16; 95% CI: [22.63,32.60]). Only 11.6% of the effect of DS on neonatal deaths was mediated through SGA (%mediation:11.6%; 95% CI [8.4,10.6]). Conclusion: Over one-third of overall stillbirths were mediated through SGA. Routine surveillance of fetal growth and standard SGA surveillance protocols may reduce the risk of perinatal mortality in DS pregnancies. Conversely, it is important to point out that these surveillance strategies may not be effective two-third of the cases not affected by growth restriction.