Association of fetal fraction with hypertensive disorders of pregnancy incidence and disease severity

BACKGROUND: Hypertensive disorders of pregnancy contribute to maternal and offspring morbidity and mortality. Studies suggest that a lower early pregnancy fetal fraction is associated with an increased risk of hypertensive disorders of pregnancy. However, maternal obesity significantly affects fetal fraction and is a risk factor for hypertensive disorders of pregnancy. OBJECTIVE: We determined the association between fetal fraction (using a standardized single-institution platform, including male and female fetuses) and hypertensive disorders of pregnancy, stratified by obesity status. Second, we evaluated differences in total cell-free DNA concentration and correlation of fetal fraction with clinical markers of hypertensive disorders of pregnancy severity. STUDY DESIGN: This was a retrospective, single-institution study of a previously validated cell-free DNA-based noninvasive prenatal screening assay of 1058 samples. Maternal body mass index at the time of noninvasive prenatal screening was assessed, and hypertensive disorders of pregnancy were confirmed by a detailed medical record review. Differences in fetal fraction and total cell-free DNA concentration between the groups were assessed with univariate analyses. Multivariable regression was used to evaluate the association between fetal fraction and hypertensive disorders of pregnancy, adjusted for body mass index, maternal age, gestational age at noninvasive prenatal screening, and fetal sex. The association between fetal fraction and hypertensive disorders of pregnancy among individuals with obesity (body mass index, >= 30 kg/m(2)) and individuals without obesity (body mass index, <30 kg/m(2)) was investigated while controlling for the aforementioned covariates. Lastly, multivariable linear regression was used to evaluate the association between fetal fraction and clinical markers of hypertensive disorders of pregnancy severity. RESULTS: We identified individuals with (n=117) and without (n=941) hypertensive disorders of pregnancy with noninvasive prenatal screening drawn before 20 weeks of gestation and with fetal fraction and body mass index data available. Those with hypertensive disorders of pregnancy had a lower fetal fraction (10.2%+/- 4.2% vs 11.6%+/- 4.7%; P<.01), without differences in total cell-free DNA concentration (P=.14). When groups were stratified by obesity status, this relationship was only valid for individuals without obesity (P=.02). Only when logistic regression analysis was restricted to individuals without obesity did the likelihood of hypertensive disorders of pregnancy rise with decreasing fetal fraction (odds ratio, 0.93; 95% confidence interval, 0.88-0.99; P=.02). In addition, fetal fraction was inversely associated with maximum systolic blood pressure at the time of hypertensive disorders of pregnancy only in the population without obesity (beta, -0.08; 95% confidence interval, -0.147 to -0.01; P=.02). CONCLUSION: Although a lower fetal fraction is associated with the development of hypertensive disorders of pregnancy, the use of this parameter for the prediction may be problematic in individuals with obesity, as obesity has such a profound effect on fetal fraction. However, we uniquely noted that among individuals without obesity, fetal fraction is lower for those that develop hypertensive disorders of pregnancy and lower fetal fraction increases the odds of hypertensive disorders of pregnancy development. Lastly, low fetal fraction in the population without obesity that developed hypertensive disorders of pregnancy was associated with higher systolic blood pressure at the time of hypertensive disorders of pregnancy, an important clinical marker of hypertensive disorders of pregnancy severity. As analytical approaches of cell-free DNA interrogation advance, the prediction of placental-mediated disorders with first-trimester sampling is likely to improve, although this may remain challenging in gravidas with obesity, a cohort at high risk of developing hypertensive disorders of pregnancy.