First-trimester ADAM12 and PAPP-A as markers for intrauterine fetal growth restriction through their roles in the insulin-like growth factor system.
BACKGROUND
PAPP-A is a marker used as part of the most effective method of screening for chromosomal anomalies in the first trimester. ADAM12 is a recently discovered pregnancy associated member of the ADAM (a multidomain glycoprotein metalloprotease) family. Recently, ADAM12 has been shown as a potential marker for early screening for chromosomal anomalies. Both PAPP-A and ADAM12 have been identified as proteases to insulin-like growth factor binding proteins. In this role, they may have a regulatory function in controlling the amount of free bioactive insulin-like growth factor (IGF). We therefore wish to examine if the levels of either of these proteases are related to various growth related adverse pregnancy outcomes.


METHODS
PAPP-A and ADAM12 were measured in a subset of samples collected at 11 to 14 weeks as part of an OSCAR clinic screening for chromosomal anomalies. Follow-up of pregnancies screened between September 1999 and August 2003 identified 1705 pregnancies with an outcome of intrauterine fetal demise on or after 24 weeks, preterm delivery at 24-34 weeks or 35-36 weeks, very low birthweight (<1.5 kg), low birthweight (<2.5 kg), large birthweight (>4.5 kg), and birth weight below the 3rd or 5th or 10th centile for gestation. A series of 414 normal outcome pregnancies constituted the control group. Marker levels were adjusted for gestation and maternal weight and the log MoM of the markers were compared using t-test of unequal variance between the control group and the various adverse outcome groups.


RESULTS
ADAM12 and PAPP-A concentrations were reduced in low for gestational age birth weights and in all births with weights below 2.5 kg. There was a linear relationship between the severity of the IUGR and the decrease in PAPP-A and ADAM12. In the larger babies, only ADAM12 was found to be significantly increased in babies above the 90th centile of weight for gestation.


CONCLUSIONS
The results of our study are compatible with the proposed role of ADAM12 and PAPP-A in promoting growth and development by breaking down IGF binding proteins and causing the release of free IGF for uptake into cells to promote growth. In those cases that eventually result in poor fetal growth, levels of PAPP-A and ADAM12 at 11-14 weeks are significantly lower than normal-in this instance, lowered PAPP-A and ADAM12 would result in less free IGF being available for cell uptake and growth stimulation. Further studies may elucidate if screening using such modalities can lead to new potential treatments for poorly growing fetuses.
Cowans
Nicholas J
NJ
Prenatal Screening Unit, Clinical Biochemistry Department, Harold Wood Hospital, Romford, RM3 0BE, UK.
Spencer
Kevin
K
D051722:ADAM Proteins / Q000097:blood*; D000072199:ADAM12 Protein; D015415:Biomarkers / Q000097:blood; D001835:Body Weight; D005260:Female; D005317:Fetal Growth Retardation / Q000097:blood* / Q000175:diagnosis / Q000209:etiology; D005865:Gestational Age; D006801:Humans; D008423:Maternal Age; D008565:Membrane Proteins / Q000097:blood*; D011247:Pregnancy; D011256:Pregnancy Outcome; D011261:Pregnancy Trimester, First / Q000097:blood*; D011266:Pregnancy-Associated Plasma Protein-A / Q000032:analysis*; D012907:Smoking / Q000009:adverse effects
D015415:Biomarkers; D008565:Membrane Proteins; D051722:ADAM Proteins; D000072199:ADAM12 Protein; C000606480:ADAM12 protein, human; D011266:Pregnancy-Associated Plasma Protein-A