Chemerin is present in human cord blood and is positively correlated with birthweight

Research

www. AJOG.org

OBSTETRICS

Chemerin is present in human cord blood and is positively correlated with birthweight Shali Mazaki-Tovi, MD; Michal Kasher-Meron, MD; Rina Hemi, PhD; Jigal Haas, MD; Itai Gat, MD; Daniel Lantsberg, MD; Israel Hendler, MD; Hannah Kanety, PhD OBJECTIVE: Chemerin, a novel adipokine, has been implicated in adipogene-

sis,inflammation,andmetabolism.Theaimsofthisstudyweretodeterminethe presence of chemerin in cord blood and its association with birthweight. STUDY DESIGN: This cross-sectional study included the following: (1)

twins with (n ⫽ 24) or without (n ⫽ 28) birthweight discordancy; and (2) singletons subclassified into small-for-gestational-age (SGA; n ⫽ 18); appropriate for gestational age (AGA; n ⫽ 33); and large-for-gestationalage (LGA; n ⫽ 8). Cord blood chemerin was determined. Parametric and nonparametric statistics were used for analysis. RESULTS: The results of the study included the following: (1) within the

discordant twins group, the median chemerin concentration was signif-

icantly lower in the SGA group than in their cotwins; (2) within singletons, the median chemerin concentration was significantly higher in the LGA than the AGA newborns; and (3) the regression model revealed that chemerin was independently associated with birthweight. CONCLUSION: Cord blood chemerin is present in cord blood and its

concentrations are positively correlated with birthweight. These novel findings support a role of adipokines in fetal growth. Key words: chemerin, discordant twins, fetal growth, large for gestational age, small for gestational age

Cite this article as: Mazaki-Tovi S, Kasher-Meron M, Hemi R, et al. Chemerin is present in human cord blood and is positively correlated with birthweight. Am J Obstet Gynecol 2012;207:412.e1-10.

F

etal growth is determined by a complex interaction between environmental, genetic, and hormonal factors.1-8 The implicit paradigm that has governed many studies concerning fetal growth is that the fetal insulin–insulin growth factor system is the most imporFrom the Department of Obstetrics and Gynecology (Drs Mazaki-Tovi, Haas, Gat, Lantsberg, and Hendler) and the Institute of Endocrinology (Drs Kasher-Meron, Hemi, and Kanety), Sheba Medical Center, TelHashomer, and the Sackler School of Medicine, Tel Aviv University, Tel Aviv (Dr Kanety), Israel. Received June 6, 2012; revised July 24, 2012; accepted Aug. 2, 2012. This study was supported by grants from the Mintz-Law Foundation of Tel-Aviv University and the Talpiot Medical Leadership Program, Sheba Medical Center, Tel Hashmer, Israel (all to S.M.-T.). The authors report no conflict of interest. The first 2 authors contributed equally to the study and article. Reprints: Hannah Kanety, PhD, Sheba Medical Center, Tel-Hashomer, Israel 52621. [email protected]. 0002-9378/$36.00 © 2012 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2012.08.008

412.e1

tant among the hormonal factors.9 Although there is ample empirical and epidemiological evidence to support this view,10,11 independent studies have recently revealed an association between adipokines and fetal growth and development.12-17 Adipose tissue has emerged as a powerful and potent endocrine organ that can exert a systemic effect via the production of adipokines.18-20 Several adipokines play an important role in the regulation of insulin sensitivity, lipid metabolism, and energy homeostasis as well as inflammation.21-23 The physiological importance of adipokines in adults has led to the hypothesis that alterations in circulating maternal concentrations of adipokines are associated with normal gestation24-34 as well as in complications of pregnancy including preeclampsia,35-52 gestational diabetes mellitus,53-67 preterm birth,68-70 delivery of large-for-gestational-age (LGA) newborns,71 small-for-gestational-age (SGA)72-75 neonates, and others.76-87 Similarly, circulating fetal adipokines have been implicated in the development of human fetus. The following findings suggest an association between

American Journal of Obstetrics & Gynecology NOVEMBER 2012

adipokines and fetal growth: (1) several adipokines have been detected in cord blood including leptin,88-91 adiponectin,25,88-92 visfatin,70,75,93-96 resis17,28,72,84,97-101 tin, omentin-1,13 vaspin,13 apelin,102,103 retinol-binding protein 4 (RBP4),14-16,104 and others12; (2) circulating fetal concentrations of some adipokines are higher than in their mothers,25,84,89-92,102,105,106 suggesting fetal production of these active molecules; (3) a positive correlation has been reported between cord blood adiponectin,25,84,89,91,92,105-110 leptin,90,91,111,112 visfatin,93,95 resistin,100,101 RBP4,14,15and birth weight; (4) human placenta expresses leptin113, resistin,114 visfatin115 and other adipokines; and (5) receptors of adiponectin,116 leptin117,118, and retinol-binding protein119 transcripts were localized in trophoblast cells. Taken together, these data suggest that adipokines play a role in fetal growth. Chemerin, a novel adipokine, was originally identified as a retinoid-responsive gene in psoriatic skin lesions.120 Chemerin is a natural ligand of chemerin receptor (CMKLR1)121 and serves as a ligand for additional receptors.122 Chemerin has

Obstetrics

www.AJOG.org

TABLE 1

Demographic and clinical characteristics of twins Demographic

Discordant twins (n ⴝ 24)

Concordant twins (n ⴝ 28)

P value

Gestational age at delivery, wks

37.0 (34.5–38.0)

37.0 (35.0–38.0)

.86

Maternal age, y

31.5 (28.0–33.7)

29.0 (24.0–33.2)

.30

Maternal BMI, kg/m

28.1 (26.6–28.1)

28.7 (27.2–30.5)

.98

.............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. 2 ..............................................................................................................................................................................................................................................

Gravidity

2.5 (1.0–4.7)

2.5 (1–3.2)

.77

Parity

1 (1.0–3.7)

2 (1–3)

.62

.............................................................................................................................................................................................................................................. ..............................................................................................................................................................................................................................................

Larger twin birthweight, g

2642 (2266–2881)

2492 (2066–2800)

.31

Smaller twin birthweight, g

1780 (1483–2086)

2265 (1996–2561)

.01

.............................................................................................................................................................................................................................................. ..............................................................................................................................................................................................................................................

Larger twin birth length, cm

47 (45.2–48.7)

47.0 (43.4–48.6)

.98

Smaller twin birth length, cm

41.7 (38.6–44.5)

46.0 (43.2–48.0)

.02

Larger twin percentile

37.5 (25–50)

25 (20–47.5)

.10

15 (15–30)

.001

.............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. ..............................................................................................................................................................................................................................................

Smaller twin percentile

3 (3–5)

..............................................................................................................................................................................................................................................

Discordancy, %

32.2 (26.7–40.9)

6.9 (3.4–10.7)

.001

..............................................................................................................................................................................................................................................

Data are presented as median and interquartile range. BMI, body mass index. Mazaki-Tovi. Cord blood chemerin is associated with birthweight. Am J Obstet Gynecol 2012.

been suggested to play a regulatory role in both inflammation and metabolism. The evidence supporting a role for this protein in energy homeostasis includes the following: (1) white adipose tissue expresses high levels of chemerin and its receptor123-128; (2) maturation of 3T3-L1 cells into adipocytes is associated with increased expression and secretion of bioactive chemerin123,125,126; (3) knockdown of chemerin or its receptor in adipocyte culture resulted in reduced perilipin, glucose transporter 4, adiponectin, and leptin expression123; (4) adipose tissue explants from obese patients secretes more chemerin than lean subjects,129 and chemerin messenger ribonucleic acid (mRNA) expression is significantly higher in adipose tissue of patients with type 2 diabetes mellitus; and (5) studies in humans have found an association between chemerin and components of metabolic syndrome,124,130-136 diabetes,137-139 and alterations in body mass index (BMI).135,140 This unique set of properties in addition to a mounting body of evidence regarding the role of adipokines in fetal growth prompted us to investigate the association between cord blood adiponectin and birthweight. To the best of our knowledge, the association between cord blood chemerin and birthweight has not been reported.

Moreover, only a handful of studies have determined its concentrations in pregnant women. Pfau et al141 reported that circulating chemerin in pregnant women with and without gestational diabetes were positively correlated with homeostasis model assessment of insulin resistance. Consistent with the aforementioned report, Stepan et al50 found higher chemerin concentrations in patients with preeclampsia than in normal controls. In addition, these authors reported a positive correlation between chemerin and blood pressure, free fatty acids, cholesterol, triglycerides, leptin, adiponectin, and C-reactive protein. Subsequently, Duan et al142 have corroborated the association between high maternal serum concentrations and preeclampsia. Thus, the aims of this study were to determine the presence of chemerin in cord blood and to evaluate its association with birthweight (specifically, birthweight categories) in singletons and twins with and without growth restriction.

M ATERIALS AND M ETHODS Subjects This cross-sectional study included 2 groups: (1) twins (n ⫽ 52) and (2) singletons (n ⫽ 59). The twins group in-

Research

cluded 26 pairs of dichorionic twins, which were further divided according to the presence (n ⫽ 12) or absence (n ⫽ 14) of birthweight discordancy. The inclusion criteria for the discordant twins group were as follows: (1) dichorionic twins gestation with discordant growth according to the estimated fetal weight by an ultrasound scan; (2) the estimated fetal weight of the smaller twin was below the 10th percentile,143 and the birthweight percentile below the 10th percentile was confirmed at birth; (3) the estimated fetal weight of the larger cotwin was between the 10th and the 90th percentiles, and the birthweight percentile between the 10th and the 90th percentiles144 was confirmed at birth; and (4) the absence of the end diastolic flow or reverse flow in the umbilical artery in Doppler studies of the smaller twin. The inclusion criteria for the concordant twins group were dichorionic twin gestation with concordance growth according to the estimated fetal weight by an ultrasound scan and the estimated fetal weight of both twins was between the 10th and 90th percentiles. The birthweight percentile between the 10th and 90th percentiles was confirmed at birth. The inclusion criteria for the singletons group were a normal pregnancy; a single gestation; and a gestational age 42 weeks or less of gestation. Newborns in the singleton group were further divided by birthweight percentile into the following 3 groups: (1) SGA, defined as a birthweight percentile in the 10th percentile or less (n ⫽ 18); (2) appropriate for gestational age (AGA) defined as a birthweight between the 10th and 90th percentile (n ⫽ 33); and (3) LGA defined as a birthweight above the 90th percentile and greater than 4000 g (n ⫽ 8). Birthweight percentiles were calculated according to population-based birthweight standards.144 Exclusion criteria for both twins and singletons neonates included the following: (1) prior abnormal maternal metabolic or medical conditions; (2) pregnancies complicated with congenital anomalies or chromosomal abnormalities; (3) abnormal 50 g glucose challenge test, performed between 24 and 28 weeks

NOVEMBER 2012 American Journal of Obstetrics & Gynecology

412.e2

Research

Obstetrics

of gestation145; (4) preeclampsia, eclampsia, and HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome or the fetal demise of 1 twin; (5) preterm prelabor rupture of membranes; and (6) clinical signs or symptoms of chorioamnionitis.

Definitions Gestational age at delivery was determined by ultrasound examination during the first trimester. Chorionicity was established by ultrasound examination in the first trimester in which 2 separated gestational sacs were documented and confirmed after birth by a different sex or by placental histology. Growth discordance was defined as the difference of 25% or less in birthweight expressed as a proportion of the birthweight of the larger twin.146 Oligohydramnious was defined as a single vertical pocket of less than 2 cm. Upon enrollment, pulsed-wave and color Doppler ultrasound examination of the umbilical arteries was performed with a real-time scanner equipped with a 3.5 MHz or a 5 MHz curvilinear probe. Umbilical artery Doppler velocimetry was defined as abnormal in the presence of abnormal waveforms (absent or reversed end-diastolic velocities). Maternal BMI was calculated upon enrollment according to the following formula: weight (kilograms)/ height (meters)2. Birthweight was obtained immediately after the delivery using a standard electrical scale. Recumbent length was measured on the second day of life with an infantometer containing a stationary headboard, a movable footboard, and a built-in centimeter scale. Methods Arterial cord blood was obtained from the newborns at the time of delivery and before the separation of the placenta, and chemerin concentration was determined in all newborns. Serum obtained by centrifugation of blood was immediately frozen and stored at –70°C until further analysis. Chemerin concentration was determined using an enzymelinked immunosorbent assay kit (Mediagnost, Tubingen, Germany). The 412.e3

www.AJOG.org

FIGURE 1

Comparison between cord blood chemerin concentrations in dichorionic twin gestations with and without growth discordance

In twins, median chemerin cord blood concentration was significantly lower in SGA than in AGA neonates in the presence of discordant growth. There was no significant difference in median chemerin cord blood concentration between the larger (heavier) neonates and smaller (lighter) neonates in pregnancy without growth discordance. AGA, appropriate for gestational age; SGA, small-for-gestational-age. Mazaki-Tovi. Cord blood chemerin is associated with birthweight. Am J Obstet Gynecol 2012.

sensitivity of the chemerin assay was 5 pg/mL. Inter- and intraassay coefficients of variability were below 6%. The protocol was approved by the institutional review board at the Sheba Medical Center, and all patients provided a written informed consent.

Statistical analysis Normality of the data was tested using the Shapiro-Wilk or Kolmogorov-Smirnov tests. Data are presented as median and interquartile range (IQR). Comparison between 2 paired samples was con-

American Journal of Obstetrics & Gynecology NOVEMBER 2012

ducted with a paired Student t test or a Wilcoxon signed ranks test, and comparison between unrelated variables was conducted with a Student t test or a Mann-Whitney U test, as appropriate. Comparison between more than 2 groups was conducted by 1 way analysis of variance or a Kruskal Wallis test. Correlation between variables was assessed in a pooled analysis of all the neonates using either a Pearson or a Spearman’s rank correlation as appropriate. Linear regression analysis was used to determine which factors were signifi-

Obstetrics

www.AJOG.org

Research

TABLE 2

Demographic and clinical characteristics of singletons Demographic

SGA (n ⴝ 18)

AGA (n ⴝ 33)

LGA (n ⴝ 8)

P value

Gestational age at delivery, wks

39.0 (38.0–40.0)

39.3 (37.4–40.1)

40.0 (39.2–41.7)

.06

Maternal age, y

29.0 (26.0–33.0)

32.0 (28.0–35.2)

32.0 (27.7–35.0)

.30

Maternal BMI, kg/m

24.7 (23.0–29.0)

27.5 (24.7–28.8)

25.8 (24.8–28.1)

.18

................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ 2 ................................................................................................................................................................................................................................................................................................................................................................................

Gravidity

3 (1–4)

2 (1–3)

3.5 (2–5.5)

.17

Parity

2 (1–3)

2 (1–3)

2 (2–4.5)

.32

................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................

Birthweight, g

2425 (2250–2630)

3115 (2913–3442)

4235 (4133–4291)

.001

................................................................................................................................................................................................................................................................................................................................................................................

Percentile

5 (3–5)

35 (25–55)

95 (90–97)

.001

................................................................................................................................................................................................................................................................................................................................................................................

Data are presented as median and interquartile range. AGA, appropriate for gestational age; BMI, body mass index; LGA, of large-for-gestational-age; SGA, small-for-gestational-age. Mazaki-Tovi. Cord blood chemerin is associated with birthweight. Am J Obstet Gynecol 2012.

cantly and independently correlated with cord blood chemerin variations. The following parameters were included in the model: maternal age, maternal BMI, gestational age at blood collection, and birthweight. Significance was accepted at P ⬍ .05. Statistical analyses were conducted using the IBM Statistical Package for the Social Sciences (IBM SPSS version 19; IBM Corp Inc, Armonk, NY).

Results Table 1 displays the demographic and clinical characteristics of the twins study population. Of the 26 enrolled pregnant women, 12 had severe growth-discordant twins (median birthweight discordancy: 32.5%; IQR, 26.7– 40.9%); in all cases the smaller twin was SGA (median: third percentile; IQR, third to fifth percentile), and the cotwin was AGA (median: 37.5th percentile; IQR, 25th to 50th percentile) (Table 1). Among the 12 SGA neonates, 10 had oligohydramnious. The control group included 14 pairs of concordant twins (median birthweight discordancy: 6.9%; IQR, 3.4 –10.7%), and both twins were AGA (Table 1). Cord blood chemerin within the discordant twins group Within the discordant twins pairs, median cord blood chemerin concentration was significantly lower in SGA newborns than in their AGA cotwin (median: 78.9 ng/mL; IQR, 56.4 – 83.0 ng/mL vs median: 106.8 ng/mL; IQR, 83.5–133.3 ng/ mL; P ⫽ .01; Figure 1).

Cord blood chemerin within the concordant group Within the concordant twins group, there were no significant differences in median cord blood chemerin concentrations between the AGA neonates (smaller AGA, 112.8 ng/mL; IQR, 80.9 –125.3 ng/mL vs larger AGA, 104.5 ng/mL; IQR, 89.2–134.3 ng/mL; P ⫽ .9; Figure 1). Correlations Bivariate analysis in the 52 twin newborns revealed significant positive correlation between cord blood chemerin and birthweight (r ⫽ 0.36, P ⫽ .008) and birth length (r ⫽ 0.31, P ⫽ .02). Cord blood chemerin in SGA, AGA, and LGA singleton newborns Table 2 displays the demographic and clinical characteristics of the singleton study population. Median chemerin cord blood concentrations were significantly higher in the LGA than in the AGA neonates (LGA, 149.4 ng/mL; IQR, 125.3–169.8 ng/mL vs AGA, 119.9 ng/ mL; IQR, 95.5–135.7 ng/mL; P ⫽ .04; Figure 2). The median chemerin cord blood concentrations were comparable between SGA (133.8 ng/mL; IQR, 110.9 –162.8 ng/mL) and both LGA (P ⫽ .5) and AGA neonates (P ⫽ .1, Figure 2). The association between cord blood chemerin concentration and possible confounding factors was further studied by regression analysis in a pooled data of all participants in the study. Gestational age at delivery (P ⬍ .001) and birthweight (P ⫽ .005) were independently

associated with cord blood chemerin concentrations after adjustment for maternal age and maternal BMI.

Comment The present study provides evidence, for the first time, that chemerin is present in the cord blood. Moreover, we were able to report that higher concentrations of cord blood chemerin were detected in AGA compared with SGA cotwins as well as in LGA compared with AGA singletons. The source(s) of chemerin in cord blood is currently unknown; however, several potential sources can be hypothesized, including placenta, the maternal compartment, and fetal tissues. Goralski et al123 have reported that chemerin mRNA is expressed in human placenta, supporting the possibility that the placenta is a source of fetal chemerin. This finding was subsequently corroborated in a recent study by Garces et al147 in which, using immunohistochemistry, chemerin was localized to the cytotrophoblast and Hofbauer’s cells in term human placenta. Additional information is needed to determine whether chemerin is secreted by the placenta and what is the relative contribution of the placenta to fetal circulation. An additional putative source of circulating fetal chemerin is the maternal compartment. Detection of chemerin in maternal circulation has been reported by Pfau et al,141 Stepan et al,50 and Duan et al.148 Importantly, chemerin is translated as a 163 amino acid preproprotein,

NOVEMBER 2012 American Journal of Obstetrics & Gynecology

412.e4

Research

Obstetrics

secreted as an 18 kDa inactive proprotein and undergoes extracellular serine protease cleavage of the C-terminal portion of the protein to generate the 16 kDa active chemerin.121,123,149-152 The relatively high molecular weight of this protein suggests that simple transport of chemerin across the placenta is not plausible. Thus far, specific placental transport for chemerin has not been identified. In conclusion, although conceivable, it is unlikely that either the placental or the maternal compartments are a major source of fetal circulating chemerin. High concentrations in LGA newborns as well as positive correlation between cord blood chemerin and birthweight point to fetal tissues as the main source of fetal circulating chemerin. There is a paucity of scientific data regarding expression and secretion of chemerin by fetal tissues. In adults, expression of chemerin has been identified in various tissues including pancreas, lung, pituitary, and ovary; however, the most abundant expression is in adipose tissue and liver.121,123,153,154 Indeed, the term hepatoadipokine has been coined by the group including Stumvoll and Blüher to describe this protein.135 The liver is one of the largest organs in term newborns, and neonatal fat mass constitutes up to 14% of total birthweight.155 Fetal contribution to cord blood chemerin is further supported by the finding that along with the liver and white adipose tissue, the highest levels of chemerin expression have been detected in brown adipose tissue,125 which is abundant in human term neonates. Thus, it is conceivable that these organs are responsible for the presence of chemerin in fetal circulation. Noteworthy is the finding that epithelial cells in the fetal intestine produce chemerin,156 suggesting that in fetal life additional tissues are capable of producing this protein. In contrast to twin gestation, we did not find a significant difference in cord blood chemerin between SGA and AGA singleton newborns. The discrepancy of these findings is unclear but may be related to differences in the clinical characteristic between the 2 groups. Singleton SGA newborns were 412.e5

www.AJOG.org

FIGURE 2

Comparison between cord blood chemerin concentrations in SGA, AGA, and LGA neonates

Median chemerin cord blood concentration was significantly higher in LGA than in AGA neonates. There were no significant differences in the median chemerin cord blood concentration between SGA and either LGA or AGA neonates. AGA, appropriate for gestational age; BMI, body mass index; LGA, of large-for-gestational-age; SGA, small-for-gestational-age. Mazaki-Tovi. Cord blood chemerin is associated with birthweight. Am J Obstet Gynecol 2012.

included in the study strictly on the ground of birthweight percentile, whereas the SGA included in the twin group also had abnormal blood flow in the umbilical artery, and most of them had oligohydramnios. In addition, the median birthweight percentile for the twin SGA group was lower compared with the SGA singletons. Finally, comparison between SGA and AGA singleton gestation does not allow us to completely eliminate maternal known and unknown confounding fac-

American Journal of Obstetrics & Gynecology NOVEMBER 2012

tors that may affect chemerin concentration. Such a confounding factor may be a maternal proinflammatory state previously reported in mothers of SGA neonates.41,157-165 Clearly this limitation does not exist in twin gestation. Hence, twin gestation can be considered a more reliable model for evaluating differences in cord blood chemerin concentration. An additional novel finding in this study is the positive association between cord blood chemerin and birthweight. Higher chemerin concentrations in AGA

Obstetrics

www.AJOG.org versus SGA cotwins, as well as in LGA versus AGA singletons, are consistent with this finding. A plausible explanation for the positive correlation between cord blood chemerin and birthweight is the production by the liver and adipose tissue. Of note, both liver size and fat deposit are positively correlated with birthweight. The latter may be especially pertinent in this context because although neonatal fat mass constitutes up to 14% of total birthweight, it explains almost half of its variance.155 Moreover, chemerin has been implicated in adipogenesis 123,125,126 and adipose tissue obtained from obese patients secretes more chemerin than those taken from lean adults.129 Collectively these data suggest that the production of chemerin by fetal liver and especially by adipose tissue may explain the association between birthweight and cord blood concentrations of this adipokine. Interestingly, a recent study by the group including Goralski166 demonstrated that the chemerin receptor (CMKLR1) deficiency in mice is associated with reduced embryonic musculature and a lower embryo mass compared with wild-type controls. Indeed, the wet weight of the CMKLR1⫹/– and CMKLR1–/– embryos was approximately 10% lower at midand late gestation compared with wildtype controls. Furthermore, embryo mass appeared to persist into adulthood, resulting in a lower total body mass and bone-free lean body mass at adulthood in CMKLR1-deficient mice. Collectively these finding suggest that a putative mechanism by which chemerin is associated with birthweight involves reduced activation of CMKLR1 and consequently diminished skeletal muscle mass. Several strengths and limitations of our study should be acknowledged. The cross-sectional design of the present study precludes comment on causality in the association between cord blood chemerin and fetal growth. The elucidation of molecular or cellular mechanisms to account for the association between chemerin and fetal growth was beyond the scope of this work. An additional limitation is the relatively small number of neonates in the LGA groups. Nevertheless, despite the

modest sample size, we were able to report a statistically significant difference between LGA and AGA newborns. Furthermore, inclusion criteria for this group included both birthweight above the 90th percentile and absolute weight of more than 4000 g, suggesting that neonates included in this group genuinely represent aberrant fetal growth. Among the strengths of our study is the use of the discordant and concordant twin gestation; comparison between SGA, AGA, and LGA newborns; well-defined inclusion criteria for the study group; and meticulous statistical methods. In conclusion, several features about chemerin suggest that this molecule might be important for understanding fetal growth. The biological importance of this protein resides in the fact that it is a mediator of adipogenesis, myogenesis, and energy balance. Our study provides the first observation that chemerin is present in human cord blood and is correlated with birthweight. The results of this study lend support to the concept that adipokines, and particularly chemerin, may play a role in the complex and intriguing process of fetal growth. Further exploration of the mechanism(s) governing the production and secretion of chemerin and the biological function of this protein in fetal life is merited. f REFERENCES 1. Pereira G, Cook A, Haggar F, Bower C, Nassar N. Seasonal variation in fetal growth: accounting for sociodemographic, biological, and environmental exposures. Am J Obstet Gynecol 2012;206:74-7. 2. Desai M, Ross MG. Fetal programming of adipose tissue: effects of intrauterine growth restriction and maternal obesity/high-fat diet. Semin Reprod Med 2011;29:237-45. 3. Haimovich Y, Scher-Landsberg J, Azem F, Mandel D, Mimouni FB, Many A. Neonatal outcome of preterm discordant twins. J Perinatal Med 2011;39:317-22. 4. Zhang J, Merialdi M, Platt LD, Kramer MS. Defining normal and abnormal fetal growth: promises and challenges. Am J Obstet Gynecol 2010;202:522-8. 5. Bryant AS, Worjoloh A, Caughey AB, Washington AE. Racial/ethnic disparities in obstetric outcomes and care: prevalence and determinants. Am J Obstet Gynecol 2010;202:33543.

Research

6. Piedrahita JA. The role of imprinted genes in fetal growth abnormalities. Birth Defects Res A Clin Mol Teratol 2011;91:682-92. 7. Rodriguez G, Collado MP, Samper MP, et al. Subcutaneous fat distribution in small for gestational age newborns. J Perinat Med 2011; 39:355-7. 8. Varvarigou AA, Fouzas S, Beratis NG. Effect of prenatal tobacco smoke exposure on fetal growth potential. J Perinat Med 2010;38: 683-7. 9. Gicquel C, Le BY. Hormonal regulation of fetal growth. Horm Res 2006;65(Suppl 3):28-33. 10. Giudice LC. Multifaceted roles for IGFBP-1 in human endometrium during implantation and pregnancy. Ann N Y Acad Sci 1997;828: 146-56. 11. Clapp JF III, Schmidt S, Paranjape A, Lopez B. Maternal insulin-like growth factor-I levels (IGF-I) reflect placental mass and neonatal fat mass. Am J Obstet Gynecol 2004;190:730-6. 12. Briana DD, Malamitsi-Puchner A. The role of adipocytokines in fetal growth. Ann N Y Acad Sci 2010;1205:82-7. 13. Briana DD, Boutsikou M, Baka S, et al. Omentin-1 and vaspin are present in the fetus and neonate, and perinatal concentrations are similar in normal and growth-restricted pregnancies. Metabolism 2011;60:486-90. 14. Chan TF, Tsai YC, Wu CH, Lee CH, Wang SH, Su JH. The positive correlation between cord serum retinol-binding protein 4 concentrations and fetal growth. Gynecol Obstet Invest 2011;72:98-102. 15. Giacomozzi C, Ghirri P, Lapolla R, et al. Retinol-binding protein 4 in neonates born small for gestational age. J Endocrinol Invest 2010;33: 218-21. 16. Ortega-Senovilla H, Schaefer-Graf U, Meitzner K, et al. Gestational diabetes mellitus causes changes in the concentrations of adipocyte fatty acid-binding protein and other adipocytokines in cord blood. Diabetes Care 2011;34:2061-6. 17. Vitoratos N, Dimitrakaki A, Vlahos NF, et al. Maternal and umbilical resistin levels do not correlate with infant birth weight either in normal pregnancies and or in pregnancies complicated with gestational diabetes. J Matern Fetal Neonatal Med 2010;23:1019-23. 18. Kahn BB, Flier JS. Obesity and insulin resistance. J Clin Invest 2000;106:473-81. 19. Matsuzawa Y, Funahashi T, Nakamura T. Molecular mechanism of metabolic syndrome X: contribution of adipocytokines adipocyte-derived bioactive substances. Ann N Y Acad Sci 1999;892:146-54. 20. Spiegelman BM, Flier JS. Obesity and the regulation of energy balance. Cell 2001;104: 531-43. 21. Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 1993;259:87-91. 22. Tilg H, Moschen AR. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 2006;6:772-83.

NOVEMBER 2012 American Journal of Obstetrics & Gynecology

412.e6

Research

Obstetrics

23. Trayhurn P, Wood IS. Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr 2004;92:347-55. 24. Catalano PM, Hoegh M, Minium J, et al. Adiponectin in human pregnancy: implications for regulation of glucose and lipid metabolism. Diabetologia 2006;49:1677-85. 25. Mazaki-Tovi S, Kanety H, Sivan E. Adiponectin and human pregnancy. Curr Diab Rep 2005;5:278-81. 26. Kajantie E, Hytinantti T, Hovi P, Andersson S. Cord plasma adiponectin: a 20-fold rise between 24 weeks gestation and term. J Clin Endocrinol Metab 2004;89:4031-6. 27. Mazaki-Tovi S, Kanety H, Pariente C, et al. Maternal serum adiponectin levels during human pregnancy. J Perinatol 2007;27:77-81. 28. Cortelazzi D, Corbetta S, Ronzoni S, et al. Maternal and foetal resistin and adiponectin concentrations in normal and complicated pregnancies. Clin Endocrinol (Oxf) 2007;66: 447-53. 29. Mazaki-Tovi S, Romero R, Kusanovic JP, et al. Adiponectin multimers in maternal plasma. J Matern Fetal Neonatal Med 2008;21:796-815. 30. Nien JK, Mazaki-Tovi S, Romero R, et al. Plasma adiponectin concentrations in nonpregnant, normal and overweight pregnant women. J Perinat Med 2007;35:522-31. 31. Mazaki-Tovi S, Romero R, Kusanovic JP, et al. Maternal visfatin concentration in normal pregnancy. J Perinat Med 2009;37:206-17. 32. Haugen F, Drevon CA. Activation of nuclear factor-kappaB by high molecular weight and globular adiponectin. Endocrinology 2007;148: 5478-86. 33. Mazaki-Tovi S, Kanety H, Pariente C, et al. Insulin sensitivity in late gestation and early postpartum period: the role of circulating maternal adipokines. Gynecol Endocrinol 2011; 27:725-31. 34. Nien JK, Mazaki-Tovi S, Romero R, et al. Resistin: a hormone which induces insulin resistance is increased in normal pregnancy. J Perinat Med 2007;35:513-21. 35. D’Anna R, Baviera G, Corrado F, Giordano D, Di Benedetto A, Jasonni VM. Plasma adiponectin concentration in early pregnancy and subsequent risk of hypertensive disorders. Obstet Gynecol 2005;106:340-4. 36. D’Anna R, Baviera G, Corrado F, et al. Adiponectin and insulin resistance in early- and late-onset pre-eclampsia. BJOG 2006;113: 1264-9. 37. Mazaki-Tovi S, Romero R, Vaisbuch E, et al. Maternal serum adiponectin multimers in preeclampsia. J Perinat Med 2009;37:349-63. 38. Haugen F, Ranheim T, Harsem NK, Lips E, Staff AC, Drevon CA. Increased plasma levels of adipokines in preeclampsia: relationship to placenta and adipose tissue gene expression. Am J Physiol Endocrinol Metab 2006;290: E326-33. 39. Kajantie E, Kaaja R, Ylikorkala O, Andersson S, Laivuori H. Adiponectin concentrations in maternal serum: elevated in preeclampsia but

412.e7

www.AJOG.org unrelated to insulin sensitivity. J Soc Gynecol Investig 2005;12:433-9. 40. Lu D, Yang X, Wu Y, Wang H, Huang H, Dong M. Serum adiponectin, leptin and soluble leptin receptor in pre-eclampsia. Int J Gynaecol Obstet 2006;95:121-6. 41. Mazaki-Tovi S, Romero R, Kim SK, et al. Could alterations in maternal plasma visfatin concentration participate in the phenotype definition of preeclampsia and SGA? J Matern Fetal Neonatal Med 2010;23:857-68. 42. Naruse K, Yamasaki M, Umekage H, Sado T, Sakamoto Y, Morikawa H. Peripheral blood concentrations of adiponectin, an adipocytespecific plasma protein, in normal pregnancy and preeclampsia. J Reprod Immunol 2005; 65:65-75. 43. Nien JK, Mazaki-Tovi S, Romero R, et al. Adiponectin in severe preeclampsia. J Perinat Med 2007;35:503-12. 44. Ramsay JE, Jamieson N, Greer IA, Sattar N. Paradoxical elevation in adiponectin concentrations in women with preeclampsia. Hypertension 2003;42:891-4. 45. Vaisbuch E, Romero R, Mazaki-Tovi S, et al. Retinol binding protein 4 —a novel association with early-onset preeclampsia. J Perinat Med 2010;38:129-39. 46. Chen D, Dong M, Fang Q, He J, Wang Z, Yang X. Alterations of serum resistin in normal pregnancy and pre-eclampsia. Clin Sci (Lond) 2005;108:81-4. 47. Fasshauer M, Waldeyer T, Seeger J, et al. Circulating high-molecular-weight adiponectin is upregulated in preeclampsia and is related to insulin sensitivity and renal function. Eur J Endocrinol 2008;158:197-201. 48. Fasshauer M, Waldeyer T, Seeger J, et al. Serum levels of the adipokine visfatin are increased in pre-eclampsia. Clin Endocrinol (Oxf) 2008;69:69-73. 49. Seol HJ, Kim JW, Kim HJ. Retinol-binding protein-4 is decreased in patients with preeclampsia in comparison with normal pregnant women. J Perinat Med 2011;39:287-9. 50. Stepan H, Philipp A, Roth I, et al. Serum levels of the adipokine chemerin are increased in preeclampsia during and 6 months after pregnancy. Regul Pept 2011;168:69-72. 51. Suwaki N, Masuyama H, Nakatsukasa H, et al. Hypoadiponectinemia and circulating angiogenic factors in overweight patients complicated with pre-eclampsia. Am J Obstet Gynecol 2006;195:1687-92. 52. Hendler I, Blackwell SC, Mehta SH, et al. The levels of leptin, adiponectin, and resistin in normal weight, overweight, and obese pregnant women with and without preeclampsia. Am J Obstet Gynecol 2005;193:979-83. 53. Kinalski M, Telejko B, Kuzmicki M, Kretowski A, Kinalska I. Tumor necrosis factor alpha system and plasma adiponectin concentration in women with gestational diabetes. Horm Metab Res 2005;37:450-4. 54. Ranheim T, Haugen F, Staff AC, Braekke K, Harsem NK, Drevon CA. Adiponectin is reduced in gestational diabetes mellitus in normal

American Journal of Obstetrics & Gynecology NOVEMBER 2012

weight women. Acta Obstet Gynecol Scand 2004;83:341-7. 55. Worda C, Leipold H, Gruber C, KautzkyWiller A, Knofler M, Bancher-Todesca D. Decreased plasma adiponectin concentrations in women with gestational diabetes mellitus. Am J Obstet Gynecol 2004;191:2120-4. 56. Chan TF, Chen YL, Lee CH, et al. Decreased plasma visfatin concentrations in women with gestational diabetes mellitus. J Soc Gynecol Investig 2006;13:364-7. 57. Chan TF, Chen HS, Chen YC, et al. Increased serum retinol-binding protein 4 concentrations in women with gestational diabetes mellitus. Reprod Sci 2007;14:169-74. 58. Chen D, Fang Q, Chai Y, Wang H, Huang H, Dong M. Serum resistin in gestational diabetes mellitus and early postpartum. Clin Endocrinol (Oxf) 2007;67:208-11. 59. Mazaki-Tovi S, Romero R, Kusanovic JP, et al. Visfatin in human pregnancy: maternal gestational diabetes vis-a-vis neonatal birthweight. J Perinat Med 2009;37:218-31. 60. Haider DG, Handisurya A, Storka A, et al. Visfatin response to glucose is reduced in women with gestational diabetes mellitus. Diabetes Care 2007;30:1889-91. 61. Krzyzanowska K, Krugluger W, Mittermayer F, et al. Increased visfatin concentrations in women with gestational diabetes mellitus. Clin Sci (Lond) 2006;110:605-9. 62. Krzyzanowska K, Zemany L, Krugluger W, et al. Serum concentrations of retinol-binding protein 4 in women with and without gestational diabetes. Diabetologia 2008;51:1115-22. 63. Kuzmicki M, Telejko B, Szamatowicz J, et al. High resistin and interleukin-6 levels are associated with gestational diabetes mellitus. Gynecol Endocrinol 2009;25:258-63. 64. Lewandowski KC, Stojanovic N, Press M, et al. Elevated serum levels of visfatin in gestational diabetes: a comparative study across various degrees of glucose tolerance. Diabetologia 2007;50:1033-7. 65. Lewandowski KC, Stojanovic N, Bienkiewicz M, et al. Elevated concentrations of retinolbinding protein-4 (RBP-4) in gestational diabetes mellitus: negative correlation with soluble vascular cell adhesion molecule-1 (sVCAM-1). Gynecol Endocrinol 2008;24:300-5. 66. Szamatowicz J, Kuzmicki M, Telejko B, et al. Serum visfatin concentration is elevated in pregnant women irrespectively of the presence of gestational diabetes. Ginekol Pol 2009;80: 14-8. 67. Mazaki-Tovi S, Romero R, Vaisbuch E, et al. Maternal serum adiponectin multimers in gestational diabetes. J Perinat Med 2009;37: 637-50. 68. Mazaki-Tovi S, Romero R., Vaisbuch E, et al. Dysregulation of maternal serum adiponectin in preterm labor. J Matern Fetal Neonatal Med 2009;22:887-904. 69. Mazaki-Tovi S, Romero R., Vaisbuch E, et al. Maternal plasma visfatin in preterm labor. J Matern Fetal Neonatal Med 2009;22:693-704.

Obstetrics

www.AJOG.org 70. Mazaki-Tovi S, Romero R, Vaisbuch E, et al. Evidence for differential regulation of the adipokine visfatin in the maternal and fetal compartments in normal spontaneous labor at term. J Perinat Med 2010;38:281-8. 71. Mazaki-Tovi S, Romero R, Vaisbuch E, et al. Retinol-binding protein 4: a novel adipokine implicated in the genesis of LGA in the absence of gestational diabetes mellitus. J Perinat Med 2010;38:147-55. 72. Briana DD, Boutsikou M, Baka S, et al. Perinatal changes of plasma resistin concentrations in pregnancies with normal and restricted fetal growth. Neonatology 2008;93:153-7. 73. Mazaki-Tovi S, Romero R., Vaisbuch E, et al. Maternal serum adiponectin multimers in patients with a small-for-gestational-age newborn. J Perinat Med 2009;37:623-35. 74. Catov JM, Patrick TE, Powers RW, Ness RB, Harger G, Roberts JM. Maternal leptin across pregnancy in women with small-for-gestational-age infants. Am J Obstet Gynecol 2007;196:558. 75. Mazaki-Tovi S, Vaisbuch E, Romero R, et al. Maternal and neonatal circulating visfatin concentrations in patients with pre-eclampsia and a small-for-gestational age neonate. J Matern Fetal Neonatal Med 2010;23:1119-28. 76. Mazaki-Tovi S, Romero R., Vaisbuch E, et al. Adiponectin in amniotic fluid in normal pregnancy, spontaneous labor at term, and preterm labor: a novel association with subclinical intrauterine infection/inflammation. J Matern Fetal Neonatal Med 2009;23:120-30. 77. McLachlan KA, O’Neal D, Jenkins A, Alford FP. Do adiponectin, TNF alpha, leptin and CRP relate to insulin resistance in pregnancy? Studies in women with and without gestational diabetes, during and after pregnancy. Diabetes Metab Res Rev 2006;22:131-8. 78. Mazaki-Tovi S, Romero R., Vaisbuch E, et al. Low circulating maternal adiponectin in patients with pyelonephritis: adiponectin at the crossroads of pregnancy and infection. J Perinat Med 2009;38:9-17. 79. Mazaki-Tovi S, Romero R, Kusanovic JP, et al. Visfatin/pre-B cell colony-enhancing factor in amniotic fluid in normal pregnancy, spontaneous labor at term, preterm labor and prelabor rupture of membranes: an association with subclinical intrauterine infection in preterm parturition. J Perinat Med 2008;36:485-96. 80. Vaisbuch E, Romero R, Mazaki-Tovi S, et al. Maternal plasma retinol binding protein 4 in acute pyelonephritis during pregnancy. J Perinat Med 2010;38:359-66. 81. Mazaki-Tovi S, Vaisbuch E, Romero R, et al. Hyperresistinemia—a novel feature in systemic infection during human pregnancy. Am J Reprod Immunol 2010;63:358-69. 82. Mazaki-Tovi S, Vaisbuch E, Romero R, et al. Maternal plasma concentration of the pro-inflammatory adipokine pre-B-cell-enhancing factor (PBEF)/visfatin is elevated in pregnant patients with acute pyelonephritis. Am J Reprod Immunol 2010;63:252-62.

83. Briana DD, Malamitsi-Puchner A. Adipocytokines in normal and complicated pregnancies. Reprod Sci 2009;16:921-37. 84. Chan TF, Yuan SS, Chen HS, et al. Correlations between umbilical and maternal serum adiponectin levels and neonatal birthweights. Acta Obstet Gynecol Scand 2004;83:165-9. 85. Fasshauer M, Bluher M, Stumvoll M, Tonessen P, Faber R, Stepan H. Differential regulation of visfatin and adiponectin in pregnancies with normal and abnormal placental function. Clin Endocrinol (Oxf) 2007;66:434-9. 86. Lappas M, Permezel M, Rice GE. Leptin and adiponectin stimulate the release of proinflammatory cytokines and prostaglandins from human placenta and maternal adipose tissue via nuclear factor-kappaB, peroxisomal proliferator-activated receptor-gamma and extracellularly regulated kinase 1/2. Endocrinology 2005;146:3334-42. 87. Vaisbuch E, Mazaki-Tovi S, Kusanovic JP, et al. Retinol binding protein 4: an adipokine associated with intra-amniotic infection/inflammation. J Matern Fetal Neonatal Med 2010; 23:111-9. 88. Marinoni E, Letizia C, Ciardo F, Corona G, Moscarini M, Di IR. Effects of prenatal betamethasone administration on leptin and adiponectin concentrations in maternal and fetal circulation. Am J Obstet Gynecol 2008;199: 141-6. 89. Mazaki-Tovi S, Kanety H, Pariente C, et al. Determining the source of fetal adiponectin. J Reprod Med 2007;52:774-8. 90. Sivan E, Mazaki-Tovi S, Pariente C, et al. Adiponectin in human cord blood: relation to fetal birth weight and gender. J Clin Endocrinol Metab 2003;88:5656-60. 91. Mazaki-Tovi S, Kanety H, Pariente C, Hemi R, Schiff E, Sivan E. Cord blood adiponectin in large-for-gestational age newborns. Am J Obstet Gynecol 2005;193:1238-42. 92. Corbetta S, Bulfamante G, Cortelazzi D, et al. Adiponectin expression in human fetal tissues during mid- and late gestation. J Clin Endocrinol Metab 2005;90:2397-402. 93. Malamitsi-Puchner A, Briana DD, Gourgiotis D, Boutsikou M, Baka S, Hassiakos D. Blood visfatin concentrations in normal full-term pregnancies. Acta Paediatr 2007;96:526-9. 94. Malamitsi-Puchner A, Briana DD, Boutsikou M, Kouskouni E, Hassiakos D, Gourgiotis D. Perinatal circulating visfatin levels in intrauterine growth restriction. Pediatrics 2007;119: e1314-8. 95. Briana DD, Boutsikou M, Gourgiotis D, et al. Role of visfatin, insulin-like growth factor-I and insulin in fetal growth. J Perinat Med 2007; 35:326-9. 96. Ibanez L, Sebastiani G, Lopez-Bermejo A, Diaz M, Gomez-Roig MD, de ZF. Gender specificity of body adiposity and circulating adiponectin, visfatin, insulin, and insulin growth factor-I at term birth: relation to prenatal growth. J Clin Endocrinol Metab 2008;93:2774-8. 97. Ng PC, Lee CH, Lam CW, Wong E, Chan IH, Fok TF. Plasma ghrelin and resistin concen-

Research

trations are suppressed in infants of insulin-dependent diabetic mothers. J Clin Endocrinol Metab 2004;89:5563-68. 98. Mami C, Marseglia L, Manganaro R, et al. Serum levels of resistin and its correlation with adiponectin and insulin in healthy full term neonates. Early Hum Dev 2009;85:37-40. 99. Martos-Moreno GA, Barrios V, Saenz de PM, et al. Influence of prematurity and growth restriction on the adipokine profile, IGF1, and ghrelin levels in cord blood: relationship with glucose metabolism. Eur J Endocrinol 2009; 161:381-9. 100. Gohlke BC, Bartmann P, Fimmers R, Huber A, Hecher K, Roth CL. Fetal adiponectin and resistin in correlation with birth weight difference in monozygotic twins with discordant growth. Horm Res 2008;69:37-44. 101. Cho GJ, Yoo SW, Hong SC, et al. Correlations between umbilical and maternal serum resistin levels and neonatal birth weight. Acta Obstet Gynecol Scand 2006;85:1051-6. 102. Malamitsi-Puchner A, Gourgiotis D, Boutsikou M, Baka S, Hassiakos D, Briana DD. Circulating apelin concentrations in mother/infant pairs at term. Acta Paediatr 2007;96:1751-4. 103. Aslan M, Celik O, Celik N, et al. Cord blood nesfatin-1 and apelin-36 levels in gestational diabetes mellitus. Endocrine 2012;41:424-9. 104. Laudes M, Oberhauser F, Bilkovski R, et al. Human fetal adiponectin and retinol-binding protein (RBP)-4 levels in relation to birth weight and maternal obesity. Exp Clin Endocrinol Diabetes 2009;117:146-9. 105. Lopez-Bermejo A, Fernandez-Real JM, Garrido E, et al. Maternal soluble tumour necrosis factor receptor type 2 (sTNFR2) and adiponectin are both related to blood pressure during gestation and infant’s birthweight. Clin Endocrinol (Oxf) 2004;61:544-52. 106. Kotani Y, Yokota I, Kitamura S, Matsuda J, Naito E, Kuroda Y. Plasma adiponectin levels in newborns are higher than those in adults and positively correlated with birth weight. Clin Endocrinol (Oxf) 2004;61:418-23. 107. Inami I, Okada T, Makimoto M, et al. Impact of serum adiponectin concentration on birth size and early postnatal growth. Pediatr Res 2007;61:604-6. 108. Kajantie E, Hytinantti T, Hovi P, Andersson S. Cord plasma adiponectin: a 20-fold rise between 24 weeks gestation and term. J Clin Endocrinol Metab 2004;89:4031-6. 109. Pardo IM, Geloneze B, Tambascia MA, Barros-Filho AA. Hyperadiponectinemia in newborns: relationship with leptin levels and birth weight. Obes Res 2004;12:521-4. 110. Tsai PJ, Yu CH, Hsu SP, et al. Cord plasma concentrations of adiponectin and leptin in healthy term neonates: positive correlation with birthweight and neonatal adiposity. Clin Endocrinol (Oxf) 2004;61:88-93. 111. Ong KK, Ahmed ML, Sherriff A, et al. Cord blood leptin is associated with size at birth and predicts infancy weight gain in humans. ALSPAC Study Team. Avon Longitudinal Study

NOVEMBER 2012 American Journal of Obstetrics & Gynecology

412.e8

Research

Obstetrics

of Pregnancy and Childhood. J Clin Endocrinol Metab 1999;84:1145-8. 112. Sivan E, Whittaker PG, Sinha D, et al. Leptin in human pregnancy: the relationship with gestational hormones. Am J Obstet Gynecol 1998;179:1128-32. 113. Masuzaki H, Ogawa Y, Sagawa N, et al. Nonadipose tissue production of leptin: leptin as a novel placenta-derived hormone in humans. Nat Med 1997;3:1029-33. 114. Yura S, Sagawa N, Itoh H, et al. Resistin is expressed in the human placenta. J Clin Endocrinol Metab 2003;88:1394-7. 115. Ognjanovic S, Bryant-Greenwood GD. Pre-B-cell colony-enhancing factor, a novel cytokine of human fetal membranes. Am J Obstet Gynecol 2002;187:1051-8. 116. Caminos JE, Nogueiras R, Gallego R, et al. Expression and regulation of adiponectin and receptor in human and rat placenta. J Clin Endocrinol Metab 2005;90:4276-86. 117. Hoggard N, Hunter L, Duncan JS, Williams LM, Trayhurn P, Mercer JG. Leptin and leptin receptor mRNA and protein expression in the murine fetus and placenta. Proc Natl Acad Sci USA 1997;94:11073-8. 118. Henson MC, Swan KF, O’Neil JS. Expression of placental leptin and leptin receptor transcripts in early pregnancy and at term. Obstet Gynecol 1998;92:1020-8. 119. Smeland S, Bjerknes T, Malaba L, Eskild W, Norum KR, Blomhoff R. Tissue distribution of the receptor for plasma retinol-binding protein. Biochem J 1995;305( Pt 2):419-24. 120. Nagpal S, Patel S, Jacobe H, et al. Tazarotene-induced gene 2 (TIG2), a novel retinoidresponsive gene in skin. J Invest Dermatol 1997;109:91-5. 121. Wittamer V, Franssen JD, Vulcano M, et al. Specific recruitment of antigen-presenting cells by chemerin, a novel processed ligand from human inflammatory fluids. J Exp Med 2003;198: 977-85. 122. Ernst MC, Sinal CJ. Chemerin. At the crossroads of inflammation and obesity. Trends Endocrinol Metab 2010;21:660-7. 123. Goralski KB, McCarthy TC, Hanniman EA, et al. Chemerin, a novel adipokine that regulates adipogenesis and adipocyte metabolism. J Biol Chem 2007;282:28175-88. 124. Bozaoglu K, Bolton K, McMillan J, et al. Chemerin is a novel adipokine associated with obesity and metabolic syndrome. Endocrinology 2007;148:4687-94. 125. Takahashi M, Takahashi Y, Takahashi K, et al. Chemerin enhances insulin signaling and potentiates insulin-stimulated glucose uptake in 3T3-L1 adipocytes. FEBS Lett 2008;582: 573-8. 126. Roh SG, Song SH, Choi KC, et al. Chemerin—a new adipokine that modulates adipogenesis via its own receptor. Biochem Biophys Res Commun 2007;362:1013-8. 127. Parlee SD, Ernst MC, Muruganandan S, Sinal CJ, Goralski KB. Serum chemerin levels vary with time of day and are modified by obe-

412.e9

www.AJOG.org sity and tumor necrosis factor-alpha. Endocrinology 2010;151:2590-602. 128. Ernst MC, Issa M, Goralski KB, Sinal CJ. Chemerin exacerbates glucose intolerance in mouse models of obesity and diabetes. Endocrinology 2010;151:1998-2007. 129. Sell H, Laurencikiene J, Taube A, et al. Chemerin is a novel adipocyte-derived factor inducing insulin resistance in primary human skeletal muscle cells. Diabetes 2009;58: 2731-40. 130. Bozaoglu K, Segal D, Shields KA, et al. Chemerin is associated with metabolic syndrome phenotypes in a Mexican-American population. J Clin Endocrinol Metab 2009;94: 3085-8. 131. Lehrke M, Becker A, Greif M, et al. Chemerin is associated with markers of inflammation and components of the metabolic syndrome but does not predict coronary atherosclerosis. Eur J Endocrinol 2009;161:339-44. 132. Stejskal D, Karpisek M, Hanulova Z, Svestak M. Chemerin is an independent marker of the metabolic syndrome in a Caucasian population—a pilot study. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2008;152:217-21. 133. Dong B, Ji W, Zhang Y. Elevated serum chemerin levels are associated with the presence of coronary artery disease in patients with metabolic syndrome. Intern Med 2011;50: 1093-7. 134. Bluher M, Rudich A, Kloting N, et al. Two patterns of adipokine and other biomarker dynamics in a long-term weight loss intervention. Diabetes Care 2012;35:342-9. 135. Chakaroun R, Raschpichler M, Kloting N, et al. Effects of weight loss and exercise on chemerin serum concentrations and adipose tissue expression in human obesity. Metabolism 2012;61:706-14. 136. Shin HY, Lee DC, Chu SH, et al. Chemerin levels are positively correlated with abdominal visceral fat accumulation. Clin Endocrinol (Oxf) 2012;77:47-50. 137. Tonjes A, Fasshauer M, Kratzsch J, Stumvoll M, Bluher M. Adipokine pattern in subjects with impaired fasting glucose and impaired glucose tolerance in comparison to normal glucose tolerance and diabetes. PLoS One 2010;5:e13911. 138. El-Mesallamy HO, El-Derany MO, Hamdy NM. Serum omentin-1 and chemerin levels are interrelated in patients with type 2 diabetes mellitus with or without ischaemic heart disease. Diabet Med 2011;28:1194-200. 139. Yang M, Yang G, Dong J, et al. Elevated plasma levels of chemerin in newly diagnosed type 2 diabetes mellitus with hypertension. J Invest Med 2010;58:883-6. 140. Ress C, Tschoner A, Engl J, et al. Effect of bariatric surgery on circulating chemerin levels. Eur J Clin Invest 2010;40:277-80. 141. Pfau D, Stepan H, Kratzsch J, Verlohren M, et al. Circulating levels of the adipokine chemerin in gestational diabetes mellitus. Horm Res Paediatr 2010;74:56-61.

American Journal of Obstetrics & Gynecology NOVEMBER 2012

142. Duan DM, Niu JM, Lei Q, Lin XH, Chen X. Serum levels of the adipokine chemerin in preeclampsia. J Perinat Med 2011;40:121-7. 143. Cohen SB, Dulitzky M, Lipitz S, Mashiach S, Schiff E. New birth weight nomograms for twin gestation on the basis of accurate gestational age. Am J Obstet Gynecol 1997; 177:1101-4. 144. Dollberg S, Haklai Z, Mimouni FB, Gorfein I, Gordon ES. Birth weight standards in the liveborn population in Israel. Isr Med Assoc J 2005;7:311-4. 145. American College of Obstetricians and Gynecologists. ACOG practice bulletin no. 30, September 2001 (replaces technical bulletin no. 200, December 1994). Clinical management guidelines for obstetrician-gynecologists. Gestational diabetes. Obstet Gynecol 2001;98: 525-38. 146. Blickstein I, Shoham-Schwartz Z, Lancet M, Borenstein R. Characterization of the growth-discordant twin. Obstet Gynecol 1987; 70:11-5. 147. Garces MF, Sanchez E, Acosta BJ, et al. Expression and regulation of chemerin during rat pregnancy. Placenta 2012;33:373-8. 148. Duan DM, Niu JM, Lei Q, Lin XH, Chen X. Serum levels of the adipokine chemerin in preeclampsia. J Perinat Med 2011;40:121-7. 149. Meder W, Wendland M, Busmann A, et al. Characterization of human circulating TIG2 as a ligand for the orphan receptor ChemR23. FEBS Lett 2003;555:495-9. 150. Zabel BA, Allen SJ, Kulig P, et al. Chemerin activation by serine proteases of the coagulation, fibrinolytic, and inflammatory cascades. J Biol Chem 2005;280:34661-6. 151. Zabel BA, Zuniga L, Ohyama T, et al. Chemoattractants, extracellular proteases, and the integrated host defense response. Exp Hematol 2006;34:1021-32. 152. Zabel BA, Silverio AM, Butcher EC. Chemokine-like receptor 1 expression and chemerin-directed chemotaxis distinguish plasmacytoid from myeloid dendritic cells in human blood. J Immunol 2005;174:244-51. 153. Kukla M, Zwirska-Korczala K, Hartleb M, et al. Serum chemerin and vaspin in non-alcoholic fatty liver disease. Scand J Gastroenterol 2010;45:235-42. 154. Zabel BA, Ohyama T, Zuniga L, et al. Chemokine-like receptor 1 expression by macrophages in vivo: regulation by TGF-beta and TLR ligands. Exp Hematol 2006;34:1106-14. 155. Catalano PM, Tyzbir ED, Allen SR, McBean JH, McAuliffe TL. Evaluation of fetal growth by estimation of neonatal body composition. Obstet Gynecol 1992;79:46-50. 156. Maheshwari A, Kurundkar AR, Shaik SS, et al. Epithelial cells in fetal intestine produce chemerin to recruit macrophages. Am J Physiol Gastrointest Liver Physiol 2009;297:G1-10. 157. Ogge G, Romero R, Chaiworapongsa T, et al. Leukocytes of pregnant women with smallfor-gestational age neonates have a different phenotypic and metabolic activity from those of

Obstetrics

www.AJOG.org women with preeclampsia. J Matern Fetal Neonatal Med 2010;23:476-87. 158. Kanagalingam MG, Nelson SM, Freeman DJ, et al. Vascular dysfunction and alteration of novel and classic cardiovascular risk factors in mothers of growth restricted offspring. Atherosclerosis 2009;205:244-50. 159. Kusanovic JP, Romero R, Chaiworapongsa T et al. Maternal serum soluble CD30 is increased in normal pregnancy, but decreased in preeclampsia and small for gestational age pregnancies. J Matern Fetal Neonatal Med 2007;20:867-78. 160. Ness RB, Sibai BM. Shared and disparate components of the pathophysiologies of fetal growth restriction and preeclampsia. Am J Obstet Gynecol 2006;195:40-9.

161. Soto E, Romero R, Richani K, Espinoza J, et al. Preeclampsia and pregnancies with smallfor-gestational age neonates have different profiles of complement split products. J Matern Fetal Neonatal Med 2010;23:646-57. 162. Gotsch F, Romero R, Kusanovic JP, et al. Preeclampsia and small-for-gestational age are associated with decreased concentrations of a factor involved in angiogenesis: soluble Tie-2. J Matern Fetal Neonatal Med 2008;21:389-402. 163. Chaiworapongsa T, Romero R, Gotsch F, et al. Low maternal concentrations of soluble vascular endothelial growth factor receptor-2 in preeclampsia and small for gestational age. J Matern Fetal Neonatal Med 2008;21:41-52. 164. Chaiworapongsa T, Espinoza J, Gotsch F, Kim YM et al. The maternal plasma soluble vascular endothelial growth factor receptor-1 con-

Research

centration is elevated in SGA and the magnitude of the increase relates to Doppler abnormalities in the maternal and fetal circulation. J Matern Fetal Neonatal Med 2008; 21:25-40. 165. Romero R, Nien JK, Espinoza J, et al. A longitudinal study of angiogenic (placental growth factor) and anti-angiogenic (soluble endoglin and soluble vascular endothelial growth factor receptor-1) factors in normal pregnancy and patients destined to develop preeclampsia and deliver a small for gestational age neonate. J Matern Fetal Neonatal Med 2008;21:9-23. 166. Issa ME, Muruganandan S, Ernst MC, et al. Chemokine-like receptor 1 regulates skeletal muscle cell myogenesis. Am J Physiol Cell Physiol 2012;302:C1621-31.

NOVEMBER 2012 American Journal of Obstetrics & Gynecology

412.e10