Identification of biochemical biomarkers associated with premature cervical shortening in high-risk, asymptomatic pregnant women: a retrospective data analysis

Figures & data

Figure 1. Study design and analysis. Flow chart depicting the inclusion and exclusion criteria of participants for this study, refined from the PPeTaL database (Leow et al. 2020). *Quality control – five samples were excluded from the analysis as they were low volume samples and unable to have the biochemical analysis completed.

Table 1. Participants’ demographic details categorised in the three-tiered model – normal (CL >25 mm), Short (CL 16–25 mm), Very Short (CL ≤15 mm).

	Normal CL (>25 mm)	Short CL (16–25 mm)	Very short CL (≤15 mm)	p-Value
Women (n)	88	25	18
Maternal age, years (x̅ ± sd)	34.1 ± 4.0	33.0 ± 4.8	34.9 ± 5.1	0.82
Maternal BMI, kg/m^2 (x̅ ± sd)	25.2 ± 5.3	25.0 ± 6.4	27.8 ± 5.4	0.49
Parity, n (%)
Nulliparous	36 (41.0%)	5 (20.0%)	4 (22.2%)	0.08
1	36 (41.0%)	13 (52.0%)	9 (50%)	0.54
2 or 3	15 (17.0%)	7 (28.0%)	3 (16.7%)	0.45
≥ 4	1 (1.1%)	0 (0%)	2 (11.1%)	0.03*
Preterm birth cases, n (%)	17 (19.3%)	7 (28.0%)	11 (61.1%)	0.001*
Extreme PTB <28 weeks	1 (1.1%)	0 (0%)	5 (27.8%)	<0.001*
Very PTB 28–<32 weeks	0 (0%)	2 (8.0%)	1 (5.6%)	0.04*
Late PTB 32–<37 weeks	16 (18.2%)	5 (20.0%)	5 (27.8%)	0.65
Current smoker, n (%)	7 (8.0%)	3 (12.0%)	1 (5.6%)	0.73
Fertility assisted pregnancy, n (%)	10 (11.4%)	2 (8.0%)	4 (2.2%)	0.34
Uterine malformation, n (%)	20 (22.7%)	3 (12%)	1 (5.6%)	0.15
History of cervical surgery, n (%)	23 (26.1%)	8 (32%)	6 (33.3%)	0.74
History of miscarriage, n (%)
0	47 (53.4%)	17 (68.0%)	5 (27.8%)	0.03*
1	23 (26.1%)	5 (20.0%)	9 (50.0%)	0.07
2–3	14 (15.9%)	0 (0%)	2 (11.1%)	0.09
≥ 4	4 (4.5%)	3 (12.0%)	2 (11.1%)	0.32

Continuous variables displayed as a mean (x̅) and standard deviation (sd). Categorical variables displayed as gross quantities (n) and proportions (%).

CL: cervical length; BMI: body mass index.

*Indicates a statistically significant result i.e., p-value <0.05.

Table 2. Odds ratios and p-values for the two-tiered model using standard logistic regression to explore the relationship between IL-1RA or ECM1 and CL.

	Odds ratio	p-Value	95% Confidence interval
IL-1RA	1.001	0.046*	[1.000, 1.001]
ECM1	1.004	0.025*	[1.001, 1.008]

CL: Short (≤25 mm) relative to Normal (>25 mm).

IL-1RA: interleukin-1 receptor antagonist; ECM1: extracellular matrix protein-1.

CL: cervical length; *Indicates a statistically significant result i.e., p-value <0.05.

Table 3. Relative risk ratios and p-values for the multinominal logistic regression analysis between the panel of seven biochemical biomarkers and CL.

	Relative risk ratio	p-Value	95% confidence interval
(a) CERVIX LENGTH – SHORT (16–25 mm) relative to Normal
GGH	1.004	0.597	[0.989, 1.020]
VDBP	1.000	0.489	[1.000, 1.001]
IL-1RA	1.001	0.003*	[1.000, 1.002]
TIMP-1	1.007	0.902	[0.896, 1.132]
PEDF	1.041	0.164	[0.984, 1.101]
LAMC2	1.015	0.151	[0.994, 1.037]
ECM1	1.006	0.007*	[1.002, 1.011]
(b) CERVIX LENGTH – VERY SHORT (≤15 mm) relative to Normal
GGH	0.997	0.764	[0.979, 1.016]
VDBP	1.000	0.420	[0.999, 1.000]
IL-1RA	1.000	0.647	[0.999, 1.001]
TIMP-1	0.929	0.306	[0.807, 1.070]
PEDF	0.959	0.358	[0.877, 1.049]
LAMC2	1.001	0.526	[0.981, 1.037]
ECM1	1.002	0.580	[1.996, 1.007]

CL: Short (16–25 mm) relative to Normal (>25 mm), and Very Short (≤15 mm) relative to Normal.

GGH: γ-glutamyl hydrolase; VDBP: Vitamin D binding protein; IL-1RA: Interleukin-1 receptor antagonist; TIMP-1: Metalloproteinase inhibitor-1; PEDF: Pigment epithelium-derived factor; LAMC2: Laminin subunit gamma-2; ECM1: Extracellular matrix protein-1; CL: cervical length.

*Indicates a statistically significant result i.e., p-value <0.05.

Figure 2. The seven candidate biochemical biomarkers and the underlying biological processes with which are associated, modified from Leow et al. (2020). Inflammation, stress, hormonal regulation, matrix remodelling, and vascular modification are key to cervical change, and each of the candidate biochemical biomarkers have been linked with these processes (Leow et al., 2020).

Leow, S. M., et al., 2020. Preterm birth prediction in asymptomatic women at mid-gestation using a panel of novel protein biomarkers: the Prediction of PreTerm Labor (PPeTaL) study. American Journal of Obstetrics & Gynecology MFM, 2 (2), 100084.

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Data availability statement

The data that support the findings of this study are available from the corresponding author, Di Salvo, L., upon reasonable request.