First-trimester placentation and the risk of antepartum stillbirth

JAMA. 2004 Nov 10;292(18):2249-54. doi: 10.1001/jama.292.18.2249.


Context: Preterm birth and low birth weight are determined, at least in part, during the first trimester of pregnancy. However, it is unknown whether the risk of stillbirth is also determined during the first trimester.

Objective: To determine whether the risk of antepartum stillbirth varies in relation to circulating markers of placental function measured during the first trimester of pregnancy.

Design, setting, and participants: Multicenter, prospective cohort study (conducted in Scotland from 1998 through 2000) of 7934 women who had singleton births at or after 24 weeks' gestation, who had blood taken during the first 10 weeks after conception, and who were entered into national registries of births and perinatal deaths.

Main outcome measures: Antepartum stillbirths and stillbirths due to specific causes.

Results: There were 8 stillbirths among the 400 women with levels of pregnancy-associated plasma protein A (PAPP-A) in the lowest fifth percentile compared with 17 among the remaining 7534 women (incidence rate per 10,000 women per week of gestation: 13.4 vs 1.4, respectively; hazard ratio [HR], 9.2 [95% confidence interval [CI], 4.0-21.4]; P<.001). When analyzed by cause of stillbirth, low level of PAPP-A was strongly associated with stillbirth due to placental dysfunction, defined as abruption or unexplained stillbirth associated with growth restriction (incidence rate: 11.7 vs 0.3, respectively; HR, 46.0 [95% CI, 11.9-178.0]; P<.001), but was not associated with other causes of stillbirth (incidence rate: 1.7 vs 1.1, respectively; HR, 1.4 [95% CI, 0.2-10.6]; P = .75). There was no relationship between having a low level of PAPP-A and maternal age, ethnicity, parity, height, body mass index, race, or marital status. Adjustment for maternal factors did not attenuate the strength of associations observed. There was no association between maternal circulating levels of the free beta subunit of human chorionic gonadotropin and stillbirth risk.

Conclusion: The risk of stillbirth in late pregnancy may be determined by placental function in the first 10 weeks after conception.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chorionic Gonadotropin, beta Subunit, Human / blood*
  • Cohort Studies
  • Female
  • Fetal Death / epidemiology*
  • Humans
  • Pregnancy
  • Pregnancy Outcome*
  • Pregnancy Trimester, First / blood*
  • Pregnancy Trimester, Second
  • Pregnancy Trimester, Third
  • Pregnancy-Associated Plasma Protein-A / metabolism*
  • Proportional Hazards Models
  • Risk


  • Chorionic Gonadotropin, beta Subunit, Human
  • Pregnancy-Associated Plasma Protein-A