Validating the ratio of insulin like growth factor binding protein 4 to sex hormone binding globulin as a prognostic predictor of preterm birth in Viet Nam: a case-cohort study

Abstract

Objective

To validate a serum biomarker developed in the USA for preterm birth (PTB) risk stratification in Viet Nam.

Methods

Women with singleton pregnancies (n = 5000) were recruited between 19⁺⁰-23⁺⁶ weeks’ gestation at Tu Du Hospital, Ho Chi Minh City. Maternal serum was collected from 19⁺⁰-22⁺⁶ weeks’ gestation and participants followed to neonatal discharge. Relative insulin-like growth factor binding protein 4 (IGFBP4) and sex hormone binding globulin (SHBG) abundances were measured by mass spectrometry and their ratio compared between PTB cases and term controls. Discrimination (area under the receiver operating characteristic curve, AUC) and calibration for PTB <37 and <34 weeks’ gestation were tested, with model tuning using clinical factors. Measured outcomes included all PTBs (any birth ≤37 weeks’ gestation) and spontaneous PTBs (birth ≤37 weeks’ gestation with clinical signs of initiation of parturition).

Results

Complete data were available for 4984 (99.7%) individuals. The cohort PTB rate was 6.7% (n = 335). We observed an inverse association between the IGFBP4/SHBG ratio and gestational age at birth (p = 0.017; AUC 0.60 [95% CI, 0.53-0.68]). Including previous PTB (for multiparous women) or prior miscarriage (for primiparous women) improved performance (AUC 0.65 and 0.70, respectively, for PTB <37 and <34 weeks’ gestation). Optimal performance (AUC 0.74) was seen within 19-20 weeks’ gestation, for BMI >21 kg/m2 and age 20-35 years.

Conclusion

We have validated a novel serum biomarker for PTB risk stratification in a very different setting to the original study. Further research is required to determine appropriate ratio thresholds based on the prevalence of risk factors and the availability of resources and preventative therapies.

Keywords:

• Preterm birth
• pregnancy
• protein biomarker
• risk prediction
• viet nam
• validation

Acknowledgments

We wish to acknowledge the study participants, the research site personnel at Tu Du Hospital and OUCRU Clinical Trials Unit, and the Sera Prognostics, Inc. clinical laboratory and clinical operations teams. Babak Shahbaba, PhD, Mike Walker, PhD, and Jing Shi, PhD provided statistical analysis support. Jennifer Logan, PhD, an employee of Sera Prognostics, Inc., contributed to the writing of this article.

Ethics approval

The study was approved by the University of Oxford Tropical Research Ethics Committee (OXTREC reference number 28-16) and the Tu Du Hospital ethics committee. Written informed consent was obtained from all participants.

Disclosure statement

JJB, ADP, ACF, TCF, DEH, and PEK were employees, consultants and stockholders of Sera Prognostics, Inc., at the time of this work. JJB, ADP, TCF, and PEK are named on issued and pending patents on potential protein biomarkers of preterm birth. All other authors report no conflicts relevant to this work.

Contribution to authorship

Study conceptualization was by JEH, JJB, DEH, SK, LQT. Data curation was performed by LPD, VKTT, TTD, BTHN, EK. Formal analysis was performed by JJB, AP, TCF. Funding acquisition was attained by SK. Investigations were performed by JEH JJB, LPD, TCF. Methodology was developed by JEH, JJB, LPD, AP, VKTT, TTD, SK, LQT. Project administration was performed by LPD, VKTT, TTD, BTHN, GT, EK. Project supervision was the responsibility of GT, EK, LQT and JEH. Validation of data was performed by JJB and AP. AP also performed the visualizations of data. Writing of the original draft was by JEH, JJB, AP, ACF, TCF. Writing - reviewing and editing of subsequent drafts was by all authors.

Data sharing

Data supporting the findings of this study are present in the paper and/or the Supplemental Materials. Additional data related to this paper may be requested from the authors.

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

Funding for this study was provided by the Bill and Melinda Gates Foundation. The funding source had no role or influence regarding the study design, data collection, data analysis, interpretation of results or decision to publish.