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Significance of IGFBP-4 in the development of fetal growth restriction

Qing Qiu¹, Mike Bell, Xiaoyin Lu

¹Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.

The Journal of Clinical Endocrinology and Metabolism

|June 13, 2012

Insights

Elevated Insulin-like Growth Factor Binding Protein-4 (IGFBP-4) in early pregnancy is linked to fetal growth restriction (FGR). This finding suggests IGFBP-4 may serve as an early biomarker for FGR, aiding in prevention and treatment strategies.

Area of Science:

Reproductive Endocrinology
Maternal-Fetal Medicine
Biomarker Discovery

Background:

Fetal growth restriction (FGR) significantly contributes to perinatal mortality and morbidity.
Animal studies indicate IGFBP-4 dysregulation in FGR, but human data are limited.
IGFBP-4 is hypothesized to regulate IGF bioavailability at the maternal-fetal interface.

Purpose of the Study:

To investigate the association between maternal serum IGFBP-4 levels and FGR.
To explore the expression of IGFBP-4 and its protease, PAPP-A, at the maternal-fetal interface.
To determine if IGFBP-4 can serve as an early predictive biomarker for FGR.

Main Methods:

A nested case-control study within the Ottawa and Kingston (OaK) Birth Cohort.
Measurement of circulating IGFBP-4, PAPP-A, IGF-I, and IGF-II via Western blot in early gestation.
Immunohistochemical analysis of IGFBP-4 and PAPP-A expression in placental villi and decidua.

Main Results:

Maternal serum IGFBP-4 levels were significantly elevated in early pregnancy in women who later developed FGR compared to controls.
IGFBP-4 was highly expressed in extravillous trophoblasts and decidual cells.
No significant differences in circulating PAPP-A, IGF-I, or IGF-II were observed between FGR and control groups.

Conclusions:

Maternal circulating IGFBP-4 in early pregnancy is associated with the development of FGR.
IGFBP-4 plays a role in regulating IGF bioavailability and may be a crucial factor in placental development.
IGFBP-4 shows potential as an early clinical biomarker for identifying pregnancies at risk of FGR.

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Abstract

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.

Conclusion:

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.

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