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High Fetal Fraction in First Trimester May Be Useful Marker of Fetal Growth Restriction

Key findings

  • This retrospective study examined data from over 2,000 patients who underwent first trimester cell-free DNA aneuploidy screening and received normal results
  • A fetal fraction value at or above the 95th percentile (in this study, =16.5%) was associated with delivery of an infant with birth weight less than the fifth percentile for gestational age
  • High fetal fraction was not associated with preterm birth or hypertensive disorders of pregnancy in this cohort

Higher levels of cell-free DNA (cfDNA) have been observed in the serum of women with preeclampsia, fetal growth restriction and preterm birth at the time these conditions are diagnosed. Although cfDNA is released into the maternal circulation by apoptotic placental cells throughout pregnancy, elevated levels may be a marker of poor placental function or, in the case of preterm labor, placental senescence.

Many women choose to have cfDNA screening in the first trimester to assess their risk for common trisomies. The fetal fraction (FF)—the amount of fetal cfDNA divided by the total amount of fetal and maternal cfDNA in the circulation—is reported on most cell-free DNA aneuploidy screening tests, however the clinical utility of this value has not been established.

Ilona Goldfarb, MD, a specialist in the Maternal-Fetal Medicine (MFM) Program at Massachusetts General Hospital, MFM fellow Lydia Shook, MD, and colleagues have demonstrated that women with a high FF in the first trimester are at an increased risk of delivering an infant with birth weight less than the fifth percentile. The study was published in the American Journal of Perinatology.

Study Design

The researchers examined data on 2,033 women who had cfDNA aneuploidy screening performed at Mass General between 11 and 13 weeks of gestation, with normal aneuploidy results and delivered viable singleton infants between July 2016 and June 2018 after more than 24 weeks of gestation.

High FF was defined as the 95th percentile or higher, and normal FF as being between the fifth and 95th percentiles. The 102 women with low FF, less than the fifth percentile, were excluded from further analysis because such women are known to be at increased risk of aneuploidy and adverse pregnancy outcomes.

Neonatal Outcomes

  • Women with high FF had a greater chance of delivering an infant with birth weight less than the fifth percentile for gestational age (OR, 2.4; 95% CI, 1.1–4.8; P = .04)
  • High FF was also associated with a twofold greater chance of delivering an infant with birth weight less than the 10th percentile. However, this association did not persist after adjustment for confounding factors

Pregnancy Outcomes

  • Women with normal FF and those with high FF (≥16.5%) had similar rates of preterm birth (<37 weeks)
  • There was no significant association between high FF and hypertensive disorders of pregnancy

Enhanced Utility of the cfDNA Screening Test

Severe fetal growth restriction (estimated fetal weight of less than 5th percentile) is associated with an increased risk of stillbirth. Women with a high FF result on first-trimester aneuploidy screening may benefit from ultrasonographic evaluation of fetal growth in the third trimester.

2.4x
greater risk of very low birth weight for women who have a high fetal fraction on otherwise normal first-trimester aneuploidy screening

16%
95th percentile for fetal fraction in this study

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