Significance of IGFBP-4 in the development of fetal growth restriction.
BACKGROUND
Fetal growth restriction (FGR) is a leading cause of perinatal mortality and morbidity. Animal studies suggest dysregulation of IGF-binding protein (IGFBP)-4 is significant in the development of FGR, although human data are lacking. We postulated that IGFBP-4 is expressed at the maternal fetal interface and plays a role in regulating IGF bioavailability. Thus, maternal serum levels of IGFBP-4 may be associated with complications of abnormal placental growth and development including FGR.


METHODS
Circulating levels of IGFBP-4 and its protease, pregnancy-associated plasma protein-A (PAPP-A), were examined in healthy pregnancies. Their expression in villi and bed as possible sources of the circulating products were examined by immunohistochemistry. From the large Ottawa and Kingston (OaK) Birth Cohort, a nested case-control study was conducted to examine circulating levels of IGBP-4, PAPP-A, IGF-I, and IGF-II by Western blot in early gestation in 36 women who went on to develop FGR and 36 controls having normal-weight babies.


RESULTS
IGFBP-4 was elevated in early pregnancy compared with nonpregnant women and women in later pregnancy, consistent with the presence of abundant extravillous trophoblasts and decidual cells that highly expressed IGFBP-4. High expression of PAPP-A was observed in extravillous trophoblasts and decidual cells in early pregnancy but hardly detectable in the circulation at this time, suggesting maternal circulating PAPP-A originates more likely from syncytiotrophoblasts. Increased IGFBP-4 in the maternal circulation in early pregnancy was associated with the development of FGR [0.48 (0.28-0.74) in control vs. 1.22 (0.66-1.65) in FGR; odds ratio = 22 (95% confidence interval = 2.7-181)]. No difference was observed in circulating PAPP-A, IGF-I and IGF-II in the FGR vs. control group.


CONCLUSIONS
Our findings support the role of IGFBP-4 in regulating IGF bioavailability and provide new clues for the prevention and treatment of FGR, raising the possibility of clinical use of IGFBP-4 as an early biomarker for this condition.
Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
Qing
Q
Qiu
Mike
M
Bell
Xiaoyin
X
Lu
Xiaojuan
X
Yan
Marc
M
Rodger
Mark
M
Walker
Shi-Wu
SW
Wen
Shannon
S
Bainbridge
Hongmei
H
Wang
Andree
A
Gruslin
D000328:Adult; D015415:Biomarkers; D003656:Decidua / Q000737:chemistry; D005260:Female; D005317:Fetal Growth Retardation / Q000175:diagnosis / Q000209:etiology*; D006801:Humans; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000097:blood / Q000502:physiology*; D007335:Insulin-Like Growth Factor II / Q000032:analysis / Q000378:metabolism; D011247:Pregnancy / Q000097:blood*; D011266:Pregnancy-Associated Plasma Protein-A / Q000032:analysis; D014327:Trophoblasts / Q000737:chemistry
D015415:Biomarkers; D018974:Insulin-Like Growth Factor Binding Protein 4; D007335:Insulin-Like Growth Factor II; D011266:Pregnancy-Associated Plasma Protein-A