Study on the Relationship and Predictive Value of First-Trimester Pregnancy-Associated Plasma Protein-A, Maternal Factors, and Biochemical Parameters in Gestational Diabetes Mellitus: A Large Case-Control Study in Southern China Mothers

Figures & data

Figure 1 Flow chart showing the subjects selected for the study.

Abbreviations: FPG, fasting plasma glucose; OGTT, oral glucose tolerance test.

Table 1 Baseline Characteristics of the Subjects

	GDM	Normoglycemic Control	Z/χ^2	P
Subjects, n	750	4122
Age, y^†	31.97 (29.09–35.34)	30.28 (28.01–33.11)	9.519	<0.001*
Pre-gestational BMI, kg/m^2†	21.04 (19.42–23.11)	20.20 (18.75–21.97)	7.946	<0.001*
GWG before GDM diagnosis, kg	7.00 (5.50–9.00)	7.00 (5.40–8.50)	3.395	0.001*
Parity, n (%)			40.920	<0.001*
Nullipara	328 (43.73%)	2325 (56.40%)
Multipara	422 (56.27%)	1797 (43.60%)
Assisted reproductive technology, n (%)	33 (4.40%)	127 (3.08%)	3.210	0.074
Family history of diabetes, n (%)	93 (12.40%)	171 (4.15%)	67.286	<0.001*
Previous history of GDM, n (%)	13 (1.73%)	12 (0.29%)	18.179	<0.001*

Notes: *P < 0.05 compared with normoglycemic control. ^†Values are expressed as the median (interquartile range).

Abbreviations: GDM, gestational diabetes mellitus; BMI, body mass index; GWG, gestational weight gain.

Table 2 Biochemical Markers, PAPP-A, and Free β-HCG of the Study Participants in the First Trimester

	GDM	Normoglycemic Control	Z	P
Subjects, n	750	4122
FPG, mmol/L	4.67 (4.44–4.97)	4.59 (4.37–4.83)	7.104	<0.001*
TC, mmol/L	4.69 (4.11–5.25)	4.55 (4.05–5.15)	2.860	0.004*
TG, mmol/L	1.23 (0.94–1.64)	1.11 (0.87–1.41)	6.888	<0.001*
HDL, mmol/L	1.62 (1.40–1.84)	1.66 (1.46–1.89)	−3.430	0.001*
LDL, mmol/L	2.45 (1.99–2.88)	2.30 (1.94–2.71)	4.283	<0.001*
PAPP-A, MoM	0.86 (0.59–1.20)	0.97 (0.68–1.27)	−4.947	<0.001*
Free β-HCG, MoM	1.11 (0.76–1.67)	1.17 (0.81–1.73)	−2.944	0.019*

Note: *P < 0.05 compared with normoglycemic control.

Abbreviations: GDM, gestational diabetes mellitus; FPG, fasting plasma glucose; TC, total cholesterol; TG, triglyceride; HDL, high-density lipoproteins; LDL, low-density lipoproteins; PAPP-A, pregnancy-associated plasma protein A; β-HCG, beta-subunit of human chorionic gonadotropin.

Table 3 Stepwise Logistic Regression Analysis of Risk Factors for GDM

	β	SE	OR (95% CI)	P
Age	0.077	0.010	1.08 (1.06–1.10)	<0.001
Pre-gestational BMI	0.083	0.016	1.09 (1.05–1.12)	<0.001
GWG before GDM diagnosis	0.081	0.015	1.08 (1.05–1.12)	<0.001
Family history of diabetes	1.169	0.144	3.22 (2.43–4.27)	<0.001
Previous history of GDM	1.378	0.438	3.97 (1.68–9.37)	0.002
FPG	0.858	0.102	2.36 (1.93–2.88)	<0.001
TG	−0.245	0.093	1.61 (1.39–1.87)	<0.001
TC	0.477	0.076	0.78 (0.65–0.94)	0.008
LDL	0.428	0.115	1.53 (1.22–1.92)	0.001
PAPP-A	−0.311	0.097	0.73 (0.61–0.89)	0.001
Constant	−10.747	0.730	−	−

Abbreviations: OR, odds ratio; GDM, gestational diabetes mellitus; BMI, body mass index; GWG, gestational weight gain; FPG, fasting plasma glucose; TG, triglyceride; TC, total cholesterol; LDL, low-density lipoproteins; PAPP-A, pregnancy-associated plasma protein A.

Table 4 ROC Curve Analysis of the Efficacies of Parameters in Predicting GDM

	AUC	95% CI	P
PAPP-A	0.56	0.53–0.58	<0.001
Maternal factors	0.66	0.64–0.68	<0.001
Biochemical markers	0.62	0.60–0.64	<0.001
FPG	0.58	0.56–0.60	<0.001
TG	0.58	0.56–0.60	<0.001
TC	0.53	0.51–0.56	0.002
LDL	0.55	0.53–0.57	<0.001
PAPP-A +Maternal factors + Biochemical markers	0.70	0.68–0.72	<0.001

Notes: Maternal factors: age, pre-gestational body mass index, gestational weight gain before GDM diagnosis, family history of diabetes, and previous history of GDM. Biochemical markers: fasting plasma glucose, total cholesterol, triglycerides, low-density lipoprotein.

Abbreviations: AUC, areas under the ROC curves; CI, confidence interval; PAPP-A, pregnancy-associated plasma protein A; FPG, fasting plasma glucose; TG, triglyceride; TC, total cholesterol; LDL, low-density lipoproteins.

Figure 2 Receiver operating characteristic (ROC) curves for maternal factors, biochemical markers, PAPP-A, and a combination of maternal factors, biochemical markers, and PAPP-A for predicting GDM in the first trimester. The difference between PAPP-A and a combination of maternal factors, and biochemical markers was statistically significant (Z= 9.983, P<0.001).

Table 5 PAPP-A Performance as a Predictor for GDM

Cut-off Point, MOM	Sensitivity,% (95% CI)	Specificity,% (95% CI)	PLR (95% CI)	NLR (95% CI)	PPV,% (95% CI)	NPV,% (95% CI)
0.37	94.7 (93.1~96.3)	3.4 (2.9~4.0)	0.98 (0.96~1.00)	1.55 (1.10~2.18)	15.1 (14.1~16.2)	78.0 (72.0~84.0)
0.62	73.1 (69.9~76.2)	19.7 (18.5~20.9)	0.91 (0.87~0.95)	1.37 (1.20~1.56)	14.2 (13.1~15.3)	80.1 (77.6~82.6)
0.83*	52.7 (49.1 ~56.2)	37.1 (35.6~ 38.5)	0.84 (0.78~0.90)	1.28 (1.17~1.39)	13.2 (12.0~14.4)	81.1 (79.4~82.9)
0.88	48.9 (45.4~52.5)	41.6 (40.1~43.1)	0.84 (0.78~0.91)	1.23 (1.14~1.23)	13.2 (12.0~14.5)	81.7 (80.1~83.4)
1.13	30.8 (27.5~34.1)	64.5 (63.0 ~ 65.9)	0.87 (0.77~0.97)	1.07 (1.02~1.13)	13.6 (12.0~15.3)	83.7 (82.4~84.9)
1.38	15.1 (12.5~17.6)	81.1 (80.0~82.3)	0.80 (0.67~0.96)	1.05 (1.01~1.08)	12.7 (10.5~14.9)	84.0 (82.9~85.1)
1.64	7.9 (5.9~9.8)	90.8 (89.9~91.7)	0.85 (0.66~1.11)	1.02 (0.99~1.04)	13.4 (10.2~16.6)	84.4 (83.3~85.5)
1.89	3.2 (1.9~4.5)	96.0 (95.4~ 96.6)	0.81 (0.53~1.23)	1.01 (0.99~1.02)	12.8 (8.0~ 17.5)	84.5 (83.5~85.5)
2.15	1.6 (0.7~2.5)	98.4 (98.0~98.8)	0.99 (0.54~1.84)	1.00 (0.99~1.01)	15.4 (7.4~ 23.4)	84.6 (83.68~85.6)
2.41	0.3 (0.0~0.6)	99.3 (99.1~ 99.6)	0.41 (0.10~1.71)	1.00 (1.00~1.01)	6.9 (−2.3~16.1)	84.6 (0.83.5~85.6)

Notes: *Optimal cut-off point, which showed the highest combination of Sensitivity and Specificity.

Abbreviations: MOM, multiple of the median; CI, confidence interval; PLR, positive likelihood ratio; NLR, negative likelihood ratio; PPV, positive predictive value; NPV, negative predictive value.

Table 6 FPG Performance as a Predictor for GDM

Cut-off Point, mmol/l	Sensitivity,%(95% CI)	Specificity,% (95% CI)	PLR (95% CI)	NLR (95% CI)	PPV,% (95% CI)	NPV,% (95% CI)
3.81	99.1 (98.4~99.8)	0.9 (0.6~1.2)	1.00 (0.99~1.01)	1.04 (0.47~2.32)	15.4 (14.4~16.4)	84.1 (73.3~94.9)
4.07	96.8 (95.5~98.1)	5.0 (4.3~5.7)	1.02 (1.00~1.03)	0.64 (0.42~0.97)	15.6 (14.6~16.7)	89.6 (85.6~93.5)
4.32	85.6 (83.1~88.1)	20.2 (19.0~21.5)	1.07 (1.04~1.11)	0.71 (0.59~0.86)	16.3 (15.2~17.5)	88.5 (86.5~90.6)
4.58	61.5 (58.0~64.9)	48.8 (47.3~50.3)	1.20 (1.13~1.28)	0.79 (0.72~0.87)	17.9 (16.4~19.4)	87.4 (86.1~88.8)
4.83	35.6 (32.2~39.0)	74.9 (73.6~76.3)	1.42 (1.27~1.59)	0.86 (0.81~0.91)	20.5 (18.3~22.7)	86.5 (85.4~87.6)
5.07*	19.9 (17.0~22.7)	91.4 (90.5~92.2)	2.30 (1.93~2.74)	0.88 (0.85~0.91)	29.5 (25.5~33.5)	86.2 (85.2~87.3)
5.08	19.1 (16.3~21.9)	91.7 (90.9~92.5)	2.30 (1.92~2.75)	0.88 (0.85~0.92)	29.5 (25.4~33.5)	86.2 (85.1~87.2)
5.34	9.2 (7.1~11.3)	97.8 (97.3~98.2)	4.17 (3.08~5.64)	0.93 (0.91~0.95)	43.1 (35.5~50.8)	85.5 (84.5~86.6)
5.60	5.3 (3.7~6.9)	99.4 (99.2~99.7)	9.16 (5.56~15.10)	0.95 (0.94~0.97)	62.5 (50.6~74.4)	85.2 (84.2~86.2)
5.98	2.9 (1.7~4.1)	99.7 (99.6~99.9)	10.99 (5.35~22.57)	0.97 (0.96~0.97)	66.7 (50.6~82.8)	85.0 (83.9~86.0)

Notes: *Optimal cut-off point, which showed the highest combination of Sensitivity and Specificity.

Abbreviations: MOM, multiple of the median; CI, confidence interval; PLR, positive likelihood ratio; NLR, negative likelihood ratio; PPV, positive predictive value; NPV, negative predictive value.

Table 7 TG Performance as a Predictor for GDM

Cut-off Point, mmol/l	Sensitivity,% (95% CI)	Specificity,% (95% CI)	PLR (95% CI)	NLR (95% CI)	PPV,% (95% CI)	NPV,% (95% CI)
0.67	95.6 (94.1~97.1)	7.4 (6.6~8.2)	1.03 (1.01~1.05)	0.60 (0.42~0.85)	15.8 (14.7~16.9)	90.2 (87.0~93.4)
0.97	73.5 (70.3~76.6)	34.9 (33.4~36.3)	1.13 (1.08~1.18)	0.76 (0.67~0.86)	17.0 (15.7~18.3)	87.8 (86.3~89.4)
1.25*	49.1 (45.5~52.6)	62.7 (61.2~64.1)	1.31 (1.21~1.43)	0.81 (0.76~0.88)	19.3 (17.5~21.1)	87.1 (85.9~88.3)
1.27	46.8 (43.2~50.4)	64.3 (62.9~65.8)	1.31 (1.20~1.43)	0.83 (0.77~0.89)	19.3 (17.5~21.1)	86.9 (85.7~88.1)
1.58	27.5 (24.3~30.7)	82.7 (81.5~83.9)	1.59 (1.39~1.82)	0.88 (0.84~0.92)	22.4 (19.7~25.1)	86.2 (85.2~87.3)
1.88	15.3 (12.8~17.9)	91.0 (90.1~91.8)	1.70 (1.40~2.06)	0.93 (0.90~0.96)	23.6 (19.8~27.4)	85.5 (84.5~86.6)
2.18	10.0 (7.9~12.1)	94.7 (94.1~95.4)	1.90 (1.48~2.44)	0.95 (0.93~0.97)	25.7 (20.7~30.7)	85.3 (84.2~86.0)
2.49	5.2 (3.6~6.8)	97.2 (96.7~97.7)	1.88 (1.32~2.68)	0.98 (0.96~0.99)	25.5 (18.6~32.4)	84.9 (83.9~86.0)
2.81	3.1 (1.8~4.3)	98.7 (98.4~99.1)	2.39 (1.47~3.87)	0.98 (0.97~1.00)	30.3 (19.9~40.6)	84.8 (83.8~85.9)
3.43	1.3 (0.5~2.2)	99.4 (99.1~99.6)	2.11 (1.02~4.37)	0.99 (0.98~1.00)	27.8 (13.1~42.4)	84.7 (83.7~85.7)

Notes: *Optimal cut-off point, which showed the highest combination of Sensitivity and Specificity.

Abbreviations: MOM, multiple of the median; CI, confidence interval; PLR, positive likelihood ratio; NLR, negative likelihood ratio; PPV, positive predictive value; NPV, negative predictive value.

Table 8 TC Performance as a Predictor for GDM

Cut-off Point, mmol/l	Sensitivity,%(95% CI)	Specificity,% (95% CI)	PLR (95% CI)	NLR (95% CI)	PPV,% (95% CI)	NPV,% (95% CI)
3.29	98.3 (97.3~99.2)	2.2 (1.7~2.6)	1.00 (0.99~1.02)	0.79 (0.45~1.41)	15.5 (14.4~16.5)	87.4 (81.0~93.8)
3.66	90.0 (87.9~92.1)	10.4 (9.5~11.4)	1.00 (0.98~1.03)	0.96 (0.76~1.21)	15.5 (14.4~16.5)	85.1 (82.0~88.3)
4.13	74.1 (71.0~77.3)	28.0 (26.7~29.4)	1.03 (0.98~1.08)	0.92 (0.81~1.05)	15.8 (14.6~17.0)	85.6 (83.8~87.5)
4.60	53.1 (49.5~56.6)	52.4 (50.9~53.9)	1.12 (1.04~1.20)	0.90 (0.83~0.97)	16.9 (15.4~18.4)	86.0 (84.6~87.3)
4.71*	49.6 (46.0~53.2)	58.2 (56.7~59.7)	1.19 (1.09~1.29)	0.87 (0.80~0.93)	17.7 (16.1~19.4)	86.4 (85.1~87.7)
5.07	34.5 (31.1~37.9)	72.0 (70.6~73.4)	1.23 (1.10~1.38)	0.91 (0.86~0.96)	18.3 (16.3~20.3)	85.8 (84.6~87.0)
5.54	15.9 (13.3~18.5)	85.5 (84.4~86.5)	1.09 (0.91~1.31)	0.98 (0.95~1.02)	16.6 (13.9~19.3)	84.8 (83.7~85.9)
6.01	8.5 (6.5~10.5)	93.1 (92.3~93.8)	1.23 (0.95~1.59)	0.98 (0.96~1.01)	18.3 (14.2~22.3)	84.8 (83.8~85.9)
6.49	3.5 (2.2~4.8)	96.9 (96.4~97.4)	1.13 (0.74~1.70)	1.00 (0.98~1.01)	17.0 (11.0~22.9)	84.7 (83.6~85.7)
7.12	1.3 (0.5~2.2)	98.9 (98.6~99.2)	1.20 (0.61~2.36)	1.00 (0.99~1.01)	17.9 (27.9~84.6)	84.6 (83.6~85.7)

Notes: *Optimal cut-off point, which showed the highest combination of Sensitivity and Specificity.

Abbreviations: MOM, multiple of the median; CI, confidence interval; PLR, positive likelihood ratio; NLR, negative likelihood ratio; PPV, positive predictive value; NPV, negative predictive value.

Table 9 LDL Performance as a Predictor for GDM

Cut-off Point, mmol/l	Sensitivity,% (95% CI)	Specificity,% (95% CI)	PLR (95% CI)	NLR (95% CI)	PPV,% (95% CI)	NPV,% (95% CI)
1.21	98.7 (97.8~99.5)	1.3 (1.0~1.7)	1.00 (0.99~1.01)	1.02 (0.52~1.99)	15.4 (14.4~16.4)	84.4 (75.5~93.3)
1.58	93.2 (91.4~95.0)	7.7 (6.9~8.5)	1.01 (0.99~1.03)	0.88 (0.66~1.17)	15.5 (14.5~16.6)	86.2 (82.7~93.2)
1.95	76.3 (73.2~79.3)	25.4 (24.1~26.7)	1.02 (0.98~1.07)	0.93 (0.81~1.07)	15.7 (14.5~16.9)	85.5 (83.5~87.4)
2.32	56.5 (53.0~60.1)	50.9 (49.4~52.5)	1.15 (1.08~1.24)	0.85 (0.78~0.93)	17.3 (15.8~18.8)	86.6 (85.2~87.9)
2.45*	50.4 (46.8~54.0)	59.3 (57.8~60.8)	1.24 (1.14~1.34)	0.84 (0.78~0.90)	18.4 (16.7~20.0)	86.8 (85.5~88.0)
2.68	33.9 (30.5~37.3)	73.0 (71.6~74.4)	1.25 (1.12~1.40)	0.91 (0.86~0.96)	18.6 (16.5~20.6)	85.8 (84.7~87.0)
3.04	20.4 (17.5~23.3)	86.3 (85.3~87.4)	1.49 (1.27~1.75)	0.92 (0.89~0.96)	21.4 (18.4~24.4)	85.6 (84.6~86.7)
3.41	8.9 (6.9~11.0)	93.9 (93.2~94.6)	1.46 (1.13~1.89)	0.97 (0.95~0.99)	21.0 (16.5~25.5)	85.0 (84.0~86.0)
3.78	4.0 (2.6~5.4)	97.0 (96.5~97.6)	1.35 (0.91~2.00)	0.99 (0.97~1.00)	19.7 (13.4~26.1)	84.7 (83.7~85.8)
4.28	1.5 (0.6~2.3)	98.9 (98.6~99.2)	1.34 (0.70~2.59)	1.00 (0.99~1.00)	19.6 (9.2~30.0)	84.7 (83.6~85.7)

Notes: *Optimal cut-off point, which showed the highest combination of Sensitivity and Specificity.

Abbreviations: MOM, multiple of the median; CI, confidence interval; PLR, positive likelihood ratio; NLR, negative likelihood ratio; PPV, positive predictive value; NPV, negative predictive value.

Data Sharing Statement

The data sets used and analyzed during the current study are available from the corresponding author upon reasonable request.