Early- or mid-trimester amniocentesis biomarkers for predicting preterm delivery: a meta-analysis

Figures & data

Figure 1. Preferred reporting items for systematic reviews and meta-analyses (PRISMA) flow diagram.

Table 1. Characteristics of studies included in the meta-analysis.

1st author (publication year)	Study design	Study location or ethnicity	Indication for amniocentesis	Number of patients	Group	Maternal age (y)	Parity	Birth weight (g)	APGAR score	Gestational age at sampling (wk)	Gestational age at delivery (wk)	Quality assessment (NOS)
Lee (2015)	Retrospective cohort	Korea	Genetic amniocentesis at 15–20 weeks	17 (34 infants)	Early preterm (<32 weeks)	33 (27–39)*	na	705 (250–1710)*	na	na	24.7 (19.6–31.6)*	9
				79 (158 infants)	Term (37–42 weeks)	35 (28–42)*	na	2700 (1790–3510)*	na	na	37.7 (37–40.3*
Ozgu-Erdinc (2014)	Prospective cohort	Turkey	Genetic amniocentesis	16	Preterm	35 (23–40)*	1 (0–3)*	2318 ± 600	na	18.8 ± 1.5	na	8
				78	Term	35 (19–44)*	1 (0–5)*	3394 ± 413	na	18.3 ± 1.5	na
Kim (2013)	Prospective cohort	Korea	Advanced maternal age; abnormal quad/triple test; family history of chromosomal abnormalities; suspected fetal anomalies or viral infection; maternal request	36	Preterm	34.8 ± 4.3	na		na	18.3 ± 0.2	na	9
				36	Term	33.2 ± 4.3	na		na	18.0 ± 0.2	na
La Sala (2012)	Retrospective	Italy (94% Caucasian)	XXX	5050	PretermTerm	37.1 ± 3.337.6 ± 4.2	nana	2257 ± 7193316 ± 408	Apgar 1' < 7: 14% Apgar 5' < 7: 4%	16.5 ± 1.216.4 ± 1.l	nana	8
				50			na		Apgar 1' < 7: 10%; Apgar 5' <7: 2%		na
Gervasi (2012)	Prospective cohort	Italy (98.5% Caucasian)	Advanced maternal age; abnormal quad/triple test; family history of chromosomal abnormalities; suspected fetal anomalies or viral infection; maternal request	12	Early SPTD	38 (33–39)^	na	1035 (493–1341)^	na	16.5 (15.7–16.9)^	23.2 (18.1–28.9)^	8
				36	Late SPTD	36 (34–38)^	na	2577 (2300–2800)^	na	16.3 (15.9–17.1)^	36.0 (34.5–36.3)^
				18	Indicated preterm	38 (35–40)^	na	2170 (1275–2582)^	na	16.1 (15.7–16.8)^	35.5 (31.2–36.3)^
				730	Term	36 (35–38)^	na	3380 (3120–3620)^	na	16.3 (15.9–16.9)^	39.7 (38.9–40.7)^
Bamberg (2012)	Cohort	Germany	Genetic amniocentesis	4	Miscarriage	40 (37–45)*	na		na	16.5 (16–18)*	na	8
				8	Early preterm	36 (32–38)*	na		na	16 (15–17)*	na
				9	Late preterm	36 (34–41)*	na		na	16 (15–18)*	na
				4	Preeclampsia	38 (34–41)*	na		na	16.5 (16–18)*	na
				273	Term	35 (19–43)*	na		na	17 (15–20)*	na
Himaya (2011)	Nested study within a prospective cohort	Quebec	Genetic amniocentesis	2	SPTB <32 wk	na	na		na	na	na	7
				5	SPTB at 32–36 wk	na	na		na	na	na
				290	No SPTB	na	na		na	na	na
Thomakos (2010)	Case-controlled	Greece	Genetic amniocentesis	48	Preterm	38.4 ± 2.8	na	2425 (2200–2625)^	na	na	35.1 (33.7–35.9^	8
				96	Term	37.8 ± 3.5	na	3300 (3100–3600)^	na	na	38.5 (37.5–39.5)^
Tarim (2005)	Prospective cohort	Turkey	Genetic amniocentesis	20	Preterm	31.85 ± 4.33	na	na	na	17.0 ± 2.3	na	9
				196	Term	31.33 ± 6.27	na	na	na	17.2 ± 2.0	na
Biggio (2005)	Case-controlled	African-American: 32%; Caucasian: 68%African-American: 14%; Caucasian: 84%	Genetic amniocentesis	57	Preterm PROM	34.0 ± 5.9	na	na	na	16.2 ± 2.0	28.9 ± 5.6	9
				58	Term	34.9 ± 5.8	na	na	na	16.1 ± 1.8	39.0 ± 1.2
Apuzzio (2004)		United States	Genetic amniocentesis	15	Preterm	Mean: 32.7	Mean: 2.2	Mean: 1843	na	Mean: 19	Mean: 30.9	8
				81	Term	Mean: 31.3	Mean: 2.3	Mean: 3350	na	Mean: 18.7	Mean: 39
Yoon (2001)	Case-controlled	Korea	Genetic amniocentesis	19	Spontaneous preterm	32.8 ± 4.9	na	na	na	18.9 (16.1–22.3)*	28.6 (18.9–32.0)*	8
				95	Term	32.8 ± 4.3	na	na	na	19.0 (15.4–23.3	39.3 (37.4–42.3)*
Wenstrom (1998)	Case-controlled	United States (White 71%)	Genetic amniocentesis	290	Preterm	35 ± 5	na	na	na	16.3 ± 1.9	na	7
				290	Term		na	na	na		na
Ghidini (1997)	Cohort	African-America 16%	Genetic amniocentesis	13	Preterm	35.6 (22.4–42.3)*	na	na	na	16.6 (14.0–20.0)*	na	8
				166	Term	36.2 (23.7–44.6)*	na	na	na	16.7 (15.0–20.0)*	na

na: not available; NOS: Newcastle-Ottawa Scale; PROM: premature rupture of membranes; SPTB: spontaneous preterm birth.

Maternal age, parity, gestational age at sampling, and gestational age at delivery were summarized as mean ± standard deviation, median (range)* or median (interquartile range; IQR)^.

Table 2. Amniotic fluid IL-6, MMP-8, and glucose levels.

1st author (publication year)	Number of patients	Re-classify into meta-analysis	IL-6 (pg/mL)	MMP-8 (ng/mL)	Glucose (mg/dL)
Lee (2015)	17 (34 infants)	Preterm	341.1 (32.3–16,396.9)*	1821.1 (364.1–50,040.3 pg/mL)*	na
	79 (158 infants)	Term	158.5 (3.2–1494.3)*	1149.1 (92.0–8996.2 pg/mL)*	na
Ozgu-Erdinc (2014)	16	Preterm	423 (57.3–1000)*	na	39.6 ± 11.3
	78	Term	178 (3.2–1000)*	na	48.7 ± 11.9
Kim (2013)	36	Preterm	170.54 ± 55.69	5.76 ± 1.53	na
	36	Term	141.92 ± 57.21	4.89 ± 1.77	na
La Sala (2012)	50	Preterm	29.4 (12.0–122.7)^	na	na
	50	Term	13.8 (9.2–60.8)^	na	na
Gervasi (2012)	12	Preterm	2052.5 (435–3015)^	na	40 (36–46)^
	36	Preterm	414.9 (259–2348)^	na	48 (39–51)^
	18	Preterm	525.1 (283–1316)^	na	45 (41–50)^
	730	Term	414 (209–930)^	na	48 (43–52)^
Bamberg (2012)	4	Not included	242.8 (37.2–466)*	na	na
	8	Preterm	131.5 (16–332)*	na	na
	9	Preterm	225 (71.7–1856)*	na	na
	4	Preterm	201 (137–853)*	na	na
	273	Term	256.6 (36.6–2437)*	na	na
Himaya (2011)	2	Preterm	na	6460 (1988–10,932 pg/mL)*	43 (30–55)*
	5	Preterm	na	4143 (2512–6962 pg/mL)*	46 (46–68)*
	290	Term	na	2260 (1320–4117 pg/mL)*	54 (47–63)*
Thomakos (2010)	48	Preterm	176.3 (130.6–208.6)^	na	na
	96	Term	52.3 (37.2–92.3)^	na	na
Tarim (2005)	20	Preterm	na	na	30.90 ± 13.83
	196	Term	na	na	39.28 ± 10.15
Biggio (2005)	57	Preterm	na	2.39 (1.1–10.1)^	na
	58	Term	na	2.37 (1.5–4.7)^	na
Apuzzio (2004)	15	Preterm	1,031.7 ± 249.32 (SE)	na	na
	81	Term	425.4 ± 48.69 (SE)	na	na
Yoon (2001)	19	Preterm	0.32 (0.04–2.52 ng/mL)*	3.1 (0.3–1954.9)*	na
	95	Term	0.18 (0.01–1.81 ng/mL)*	1.3 (0.3–45.2)*	na
Wenstrom (1998)	290	Preterm	1.9 ± 5.2 ng/mL	na	na
	290	Term	1.0 ± 2.4 ng/mL	na	na
Ghidini (1997)	13	Preterm	570 (145–19100)*	na	na
	166	Term	330 (11–6100)*	na	na

IL-6: interleukin-6; MMP-8: matrix metalloproteinase-8; na: not available; SE: standard error.

Data were summarized as mean ± standard deviation, median (range)*, or median (interquartile range; IQR)^.

Figure 2. Meta-analysis for interleukin-6 (IL-6) (A), matrix metalloproteinase-8 (MMP-8) (B), and glucose (C) between preterm and term delivery groups. Abbreviations: SE: standard error; CI: confidence interval, lower limit and upper limit; lower limit and upper limit of 95% CI, respectively.

Figure 3. Sensitivity-analysis for IL-6 (A), MMP-8 (B), and glucose (C) between preterm and term delivery groups. Abbreviations: SE: standard error; CI: confidence interval, lower limit and upper limit; lower limit and upper limit of 95% CI, respectively.

Figure 4. Funnel plot for publication bias for interleukin-6 (IL-6). Egger’s test: t = 3.03; one-tailed p = 0.007.