Perinatal immunoproteins predict the risk of cerebral palsy in preterm children

Figures & data

Table I. The cytokine groups analyzed from umbilical cord blood obtained at the time of birth.

1. Chemokines (n = 32)	2. Growth factors (n = 28)	3. TNF family (n = 12)	4. Hematopoietin family (n = 20)	5. IL-1 family (n = 5)	6. Others (n = 12)
CCL1-5	AR	CD27	FLT3lig	IL-1ra	ALCAM
CCL7,8	ANG	CD30	GM-CSF^a	IL-1α, -1β^a	FST
CCL11^a	βNGF	DR-6	IL-2	IL-1sr2	ICAM-1,-3
CCL13-20	BDNF	FAS	IL-2sRα	ST2/IL-1r4	IL-10rβ
CCL23,24	BTC	FASL	IL-2rβ, γ		IL-17
CCL26-28	EGF	HVEM	IL-3^a,-4^a,-5		L-selectin
CXCL2,3,5	FGF1,2,4	RANK	IL-5Rα		MMP-7,-9
CXCL6,8^a,9	FGF7,9	TNF-R1	IL-6^a,-7,-9		PECAM-1
CXCL11-13	GDNF	TNF-α^a, -β	IL-13,-15		TIMP-1,-2
CX3CL1	HGF	TRAIL-R1,4	Leptin
XCL1	IGF-1R		OSM
	IGF-2		SCF, -R
	IGFBP1- 4		spg130
	M-CSF
	M-CSF-R
	NT3,4
	PLGF
	PDGF-Rα
	TGF-α
	VEGF
	VEGF-R2

^aThe indicated cytokines, as well as IL-10, IL-12p70, and G-CSF, were additionally analyzed from cord blood and peripheral blood collected 1 day and 7 days after birth using an independent immunoassay.

Table II. Characteristics of children with and without CP who were born at <32 weeks of gestation.

Variable	CP children (n = 19)	Non-CP children (n = 150)	P
Gestational age at birth (wks)	28 + 0 (23 + 2 – 31 + 4)	29 + 4 (24 + 1 – 31 + 6)	0.090
ELGAN	9	41	0.071
Male	13	77	0.160
Birth weight (g)	1110 (540–1970)	1211 (370–2295)	0.289
Primigravida	3	48	0.189
Maternal fever^a	10	48	0.603
Pre-eclampsia	5	52	0.457
Spontaneous premature birth^b	14	95	0.393
Antenatal steroid	16	124	1.0
Histologic chorioamnionitis	10	53	0.226
Small for gestational age infant	4	40	0.783
5-minute Apgar score	7 (3–8)	7 (0–10)	0.784
CRIB I score^c	5 (0–15)	2 (0–15)	0.047
Lowest mean arterial pressure (24 h)	22 (10–36)	26 (10–55)	0.270
Duration of mechanical ventilation (d)	7.5 (0–79)	2.9 (0–96)	0.043
Additional O2 at 36 wks of gestation	9	32	0.013
Neonatal sepsis	6	41	0.779
IVH gr2-4	9	15	<0.001
cPVL	7	3	<0.001

^aMaternal fever was defined as a value above median.

^bThe birth type was missing in one labor.

^cCRIB = Clinical Risk Index for Babies (16).

cPVL = cystic periventricular leukomalacia; ELGAN = extremely low gestational age newborn; IVH = intraventricular hemorrhage.

Table III. Summary of factor analysis.

Factor 1 (27.7%)	Factor 2 (12.1%)	Factor 3 (9.1%)	Factor 4 (6.7%)	Factor 5 (5.1%)
Eot3/CCL26	IL-5Rα	NT3	IL-3	IL-1β
TRAIL-R1	IL-9	SGP130	GDNF	MIP-3α/CCL19
IGF-1R	IL-2rγ	SCF	Eot/CCL11	IL-1α
IL-2rβ	BTC	NT4	MCP-3/CCL7	MIP-1β/CCL4
FGF2	FASL	TNF-α	IL-7	GCP-2/CXCL6
CD30	ST2/IL-1r4	M-CSF	IL-13	IL-6
Lymphotactin/XCL1	VEGF-R2	TNF-β	IL-4	ENA78/CXCL5
TGF-α	CCL28	IL-17	PLGF	IL-8/CXCL8
FGF4	HCC1/CCL14	I-309/CCL1	GM-CSF	MCP-1/CCL2
PDGF-Rα	Fractalkine/CX3CL1	FLT3lig	IL-5	MCP-2/CCL8
SDF-1β/CXCL12	SCF-R	RANTES/CCL5	FGF7
βNGF	MCP-4/CCL13	IL-2	FAS
IGF-2	HVEM	VEGF
IL-10rβ	RANK	MIP-1δ/CCL15
CTACK/CCL27	TRAIL-R4	IGFBP3
IL-1sr2		TNF-R1
IGFBP4
CD27

All cytokines had a factor loading above 0.500 and are presented in descending order. The total variance of cytokines explained in each factor is presented in parentheses. Factor loading describes the correlation between a variable and a factor.

Table IV. Differences in cord blood cytokines comprising factor 1 or factor 2 between children with and without CP.

Factor	Cytokine group	Cytokine	CP children	Children without CP	P
Factor 1	1	Eot3/CCL26	1333 (304–2679)	684 (164–3338)	0.002
	1	Lymphotactin/XCL1	1503 (429–3645)	810 (202–2999)	0.003
	1	SDF-1β/CXCL12	1349 (317–2830)	772 (211–3171)	0.002
	1	CTACK/CCL27	1811 (839–3637)	1273 (351–3643)	0.004
	2	IGF-1R	1463 (401–3244)	741 (187–2605)	0.001
	2	FGF2	1482 (427–3188)	772 (191–3246)	0.001
	2	TGF-α	1360 (453–2805)	733 (192–2981)	0.001
	2	FGF4	1622 (743–3311)	955 (204–3200)	0.001
	2	PDGF-Rα	1163 (327–2290)	650 (179–1980)	0.002
	2	βNGF	1381 (444–3249)	787 (232–2600)	0.003
	2	IGF-2	1392 (342–3463)	680 (168–2596)	0.001
	2	IGFBP4	7266 (4930–12617)	4859 (2119–10819)	<0.001
	3	TRAIL-R1	1307 (362–2892)	682 (155–2687)	0.002
	3	CD30	1703 (540–3347)	929 (276–3359)	0.002
	3	CD27	3940 (2199–8157)	2622 (916–8110)	0.003
	4	IL-2rβ	1594 (473–3635)	831 (223–2976)	0.002
	5	IL-1sr2	1789 (558–4296)	1086 (251–2768)	0.001
	6	IL-10rβ	2245 (1023–4935)	1241 (364–4312)	0.001
Factor 2	1	CCL28	162 (106–284)	130 (85–325)	0.075
	1	HCC1/CCL14	961 (710–1260)	646 (247–1420)	<0.001
	1	Fractalkine/CX3CL1	219 (141–580)	169 (105–314)	<0.001
	1	MCP-4/CCL13	263 (157–400)	192 (87–786)	0.003
	2	BTC	170 (106–248)	129 (68–298)	0.10
	2	VEGF-R2	295 (197–516)	229 (140–539)	0.003
	3	FASL	188 (132–267)	133 (70–452)	<0.001
	3	HVEM	6393 (4588–11803)	4521 (1282–12033)	0.001
	3	RANK	656 (367–1920)	422 (198–1487)	0.027
	3	TRAIL-R4	369 (255–671)	294 (157–752)	0.014
	4	IL-5Rα	163 (104–260)	127 (77–288)	0.006
	4	IL-9	182 (109–285)	144 (77–288)	0.009
	4	IL-2rγ	194 (110–285)	146 (77–356)	0.007
	4	SCF-R	1283 (1047–1924)	1028 (584–2164)	0.002
	5	ST2	178 (112–395)	133 (73–329)	0.013

Numbers are presented as median (minimum–maximum). The P values are based on Mann–Whitney U test (not corrected for multiple comparisons). The factors 1 and 2 are presented in Table III and the cytokine groups in Table I.

Figure 1. IL-12 at birth, on day 1, and on day 7 in children with CP compared to children without CP. *P = 0.023.

The CRIB (clinical risk index for babies) score: a tool for assessing initial neonatal risk and comparing performance of neonatal intensive care units. The international neonatal network. Lancet. 1993;342:193–8.

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