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Gordon C. S. Smith, MD, PhD; Jennifer A. Crossley, PhD; David A. Aitken, PhD; Jill P. Pell, MD; Alan D. Cameron, MD; J. Michael Connor, MD, DSc; Richard Dobbie, BSc

JAMA. 2004;292:2249-2254.

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 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.

Author Affiliations: Department of Obstetrics and Gynaecology, Cambridge University and Rosie Hospital, Cambridge, England (Dr Smith); Institute of Medical Genetics, Yorkhill NHS Trust, Glasgow, Scotland (Drs Crossley, Aitken, and Connor); Department of Public Health, Greater Glasgow NHS Board, Glasgow, Scotland (Dr Pell); Department of Fetal Medicine, Queen Mother’s Hospital, Glasgow, Scotland (Dr Cameron); and Information and Statistics Division, Common Services Agency, Edinburgh, Scotland (Mr Dobbie).

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