Documente Academic
Documente Profesional
Documente Cultură
Department of Obstetrics and Gynecology, IRCCS Foundation Policlinico San Matteo and University of Pavia, 27100 Pavia, Italy
Department of Pediatrics, University of Pavia, IRCCS Foundation Policlinico San Matteo and University of Pavia, 27100 Pavia, Italy
c
Immunogenetics Laboratory, Immunohematology and Transfusion Center, IRCCS Foundation Policlinico San Matteo and University of Pavia, 27100 Pavia,
Italy
b
a r t i c l e
i n f o
Article history:
Received 21 January 2016
Received in revised form 3 May 2016
Accepted 11 May 2016
Keywords:
Vaginal and serum sHLA-G
IL-6
Preterm premature rupture of membranes
a b s t r a c t
Objective: To evaluate soluble HLA-G (sHLA-G) concentrations in maternal blood serum and cervical vaginal uid in pregnancies complicated by preterm premature rupture of membranes (PPROM) compared
to controls.
Study design: Case-control study of 24 women with PPROM and 40 controls.
Main outcome measures: Vaginal and serum sHLA-G and IL-6 concentrations.
Findings: Women with PPROM had signicantly higher serum and vaginal sHLA-G concentrations compared to controls (respectively median 31.48 U\ml versus 13.9 U\ml p < 0.001 and 1.7 U\ml versus
0.1 U\ml p < 0.001). Vaginal expression of IL-6 was higher in PPROM cases compared to controls
(respectively, median 31.19 pg\ml versus 6.67 pg\ml; p < 0.001). Higher serum and vaginal sHLA-G were
associated with both a shorter length of pregnancy and histological chorioamnionitis in the PPROM group.
Conclusions: Higher vaginal and serum sHLA-G in PPROM cases may be a sign of local and systemic
inammation.
2016 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
Preterm premature rupture of membranes (PPROM) and
preterm birth (PTB), dened as a delivery before 37 weeks of
gestation (Liu et al., 2012), are the leading causes of perinatal morbidity and mortality (Holst and Garnier, 2008). Multiple etiologies
can activate the common terminal pathway of parturition, and
intrauterine infection is one of the most important mechanisms
of diseases causally linked to PTB (Kusanovic et al., 2009). Investigators have hypothesized that understanding markers of infection
may alter clinical care and thus lead to better neonatal outcomes
(Galazios et al., 2011; Tosun et al., 2010).
Among pro-inammatory cytokines, interleukin-6 (IL-6) is the
most studied for a higher predictive value of chorioamnionitis
Corresponding author at: Department of Obstetrics and Gynecology, IRCCS Foundation Policlinico San Matteo, Viale Golgi 19, 27100 Pavia, Italy.
E-mail address: elena.loc@libero.it (E. Locatelli).
http://dx.doi.org/10.1016/j.jri.2016.05.004
0165-0378/ 2016 Elsevier Ireland Ltd. All rights reserved.
(Wei et al., 2010; Young et al., 2002; Kacerovsky et al., 2015) and
of neonatal infection (Kurt et al., 2007); nevertheless, its clinical
usefulness is limited by the large variability in threshold used in
different studies and the lack of routine measure (Taylor et al.,
2013).
Inammation at the maternal-foetal interface may play a critic
role in the etiology of spontaneous PTB (Wei et al., 2010). Pregnancy
represents a unique immune status wherein the maternal immune
system has to accept allogenic foetus by appropriate modulation of
the inammatory responses at the maternal-foetal interface.
Human leukocyte antigen-G (HLA-G), a member of non classic
HLA class I molecules characterized by low allelic polymorphism
and restricted tissue expression, and its soluble form, (sHLA-G),
has a crucial role in immune-tolerant mechanism of pregnancy by
inhibiting natural killer (NK) cell function (Hunt and Langat, 2009;
Rizzo et al., 2009). Altered serum levels of sHLA-G in maternal blood
are associated with recurrent spontaneous abortion, preeclampsia,
intrauterine growth restriction, PTB, and PPROM (Rizzo et al., 2015;
Biyik, 2014; Cecati et al., 2011; Steinborn et al., 2007). Increased
77
78
Table 1
Demographic and clinical characteristics of controls and women with preterm premature rupture of membranes.
WBC (103\ml)
PCR (mg\dL)
Cervix length (mm)
Gestational age at delivery (weeks)
Birth weight (gr)
Arterial cord blood pH
33 (2546)
30 (2436)
7.75 (5.3315.80)
0.0 (00.14)
34 (2741)
39.2 (3741.3)
3372.5 (28703850)
7.30 (7.107.44)
32 (2441)
30 (2333)
15.65 (8.5924.70)
0.84 (0.05.0)
17.5 (5.529)
31.5 (25.334)
1702.5 (6052760)
7.34 (7.217.47)
0.3
0.4
<0.001
<0.001
<0.001
<0.001
<0.001
0.007
0.1 (0.13.0)
13.92 (8.8255.42)
6.67 (0.1024.26)
5.94 (0.41102.3)
1.7 (0.14.1)
31.48 (3.2686.60)
31.19 (0.69345.21)
3.53 (0.2945.95)
<0.001
<0.001
<0.001
0.9
Serum sHLA-G
Vaginal sHLA-G
p value
1.03 (1.001.07)
1.02 (1.001.06)
0.030
0.033
Table 4
Median and IQR serum and vaginal sHLA-G in PPROM with and without histological chorioamnionitis (HC).
59.97 (0.71345.9)
2.8 (0.104.13)
35.65 (3.2686.60)
15.9 (0.69225.20)
1.8 (0.102.6)
25.17 (8.6936.72)
0.038
0.024
0.034
79
80
Rizzo, R., Andersen, A.S., Lassen, M.R., Sorensen, H.C., Bergholt, T., Larsen, M.H.,
Melchiorri, L., Stignani, M., Baricordi, O.R., Hviid, T.V., 2009. Soluble human
leukocyte antigen-G isoforms in maternal plasma in early and late pregnancy.
Am. J. Reprod. Immunol. 62, 320338.
Rizzo, R., Bortolotti, D., Baricordi, O.R., Fainardi, E., 2012. New insights into HLA-G
and inammatory diseases. Inamm. Allergy Drug Targets 11, 448463.
Rizzo, R., Lo Monte, G., Bortolotti, D., Graziano, A., Gentili, V., Di Luca, D., Marci, R.,
2015. Impact of soluble HLA-G levels and endometrial NK cells in uterine
ushing samples from primary and secondary unexplained infertile women.
Int. J. Mol. Sci. 16, 55105516.
Robert- Gagneux, F., Gagneux, J.P., Vu, N., Jaillard, S., Guiguen, C., Amiot, L., 2011.
High Levels od soluble HLA- G in amniotic uid is correlated with congemnital
transmission of Toxoplasma Gondii. Clin. Immunol. 138, 129134.
Souto, F.J.D., Crispim, J.C.O., Ferreira, S.C., da Silva, A.S.M., Bassi, C.L., Soares, C.P.,
Zucoloto, S., 2011. Liver HLA-G expression is associated with multiple clinical
and histopatological forms of chronic hepatitis B virus infection. J. Viral Hepat.
18, 102105.
Steinborn, A., Varkonyi, T., Scharf, A., Bahlmann, F., Klee, A., Sohn, C., 2007. Early
detection of decreased soluble HLA-G levels in the maternal circulation
predicts the occurrence of preeclampsia and intrauterine growth retardation
during further course of pregnancy. Am. J. Reprod. Immunol. 57, 277286.
Taylor, B.D., Holzman, C.B., Fichorova, R.N., Tian, Y., Jones, N.M., Fu, W., Senagore,
P.K., 2013. Inammation biomarkers in vaginal uid and preterm delivery.
Hum. Reprod. 28, 942952.
Thibodeau, V., Lajoie, J., Labbe, A.C., Zannou, M.D., Fowke, K.R., Alary, M., Poudrier,
J., Roger, M., 2011. High level of soluble HLA-G in the female genital tract of
Beninese commercial sex workers is associated with HIV-1 infection. PLoS One.
6, e25185.
Tosun, M., Celik, H., Avci, B., Yavuz, E., Alper, T., Malatyalioglu, E., 2010. Maternal
and umbilical serum levels of interleukin-6, interleukin-8, and tumor necrosis
factor-alpha in normal pregnancies and in pregnancies complicated by
preeclampsia. J. Matern. Fetal Neonatal Med. 23, 880886.
Wei, S.Q., Fraser, W., Luo, Z.C., 2010. Inammatory cytokines and spontaneous
preterm birth in asymptomatic women: a systematic review. Obstet. Gynecol.
116, 393401.
Yan, W.H., Lin, A., Chen, B.G., Chen, S.Y., 2009. Induction of both membrane-bound
and soluble HLA-G expression in active human Cytomegalovirus infection. JID
200, 820826.
Yoon, B.H., Romero, R., Moon, J.B., Shim, S.S., Kim, M., Kim, G., Jun, J.K., 2001.
Clinical signicance of intra-amniotic inammation in patients with preterm
labor and intact membranes. Am. J. Obstet. Gynecol. 185, 11301136.
Young, A., Thomson, A.J., Ledingham, M., Jordan, F., Greer, I.A., Norman, J.E., 2002.
Immunolocalization of proinammatory cytokines in myometrium, cervix, and
foetal membranes during human parturition at term. Biol. Reprod. 66,
445449.