First-trimester ultrasound and biochemical markers of aneuploidy and the prediction of impending fetal death

Objectives: To examine the clinical utility of the first-trimester markers of aneuploidy in their ability to predict future fetal loss.

Methods: We examined 54,722 singleton pregnancies with no chromosomal abnormality and with complete outcome data that had undergone screening for trisomy 21 by a combination of fetal nuchal translucency (NT) thickness, maternal serum free beta-human chorionic gonadotropin (beta-hCG) and pregnancy-associated plasma protein-A (PAPP-A) at 11 + 0 and 13 + 6 weeks' gestation. The biochemical markers were converted to multiples of the expected normal median for a pregnancy of the same gestation (MoM) and the measurements of fetal NT were expressed as the difference (delta) from the normal median NT for crown-rump length (CRL). The association between free beta-hCG, PAPP-A and delta NT and the incidence of fetal loss prior to 24 weeks, at or after 24 weeks or at any time, was assessed by comparing the relative incidence at a number of MoM or delta NT cut-offs and at various centile cut-offs. At various marker levels the likelihood ratio (LR) for fetal loss was also calculated.

Results: The rate of fetal loss increased with decreasing maternal serum free beta-hCG and PAPP-A and increasing delta NT. At the 5th centile of the normal outcome group for free beta-hCG (0.41 MoM) the odds ratio for fetal loss before 24 weeks, at or above 24 weeks and at any gestation was 3.1, 1.8 and 2.6, respectively. The respective values for the 5th centile of PAPP-A (0.415 MoM) were 3.3, 1.9 and 2.8 and for the 95th centile of delta NT they were 2.5, 1.9 and 2.2, respectively. There was almost no correlation between reduced levels (<or=0.50 MoM) of PAPP-A and reduced levels of free beta-hCG in either the normal pregnancy group (r = 0.041) or the group with fetal death (r = 0.072), indicating relatively independent prediction by either biochemical marker.

Conclusions: Low levels of maternal serum PAPP-A and free beta-hCG and increased fetal NT are associated, in the absence of an abnormal karyotype, with an increased risk of impending fetal death. The likelihood ratio profiles provided at various levels of PAPP-A or free beta-hCG may be of some help in counseling women with such results and raise awareness among health-care professionals for increased surveillance in such cases.