OBSTETRICS Association between maternal serum cytokine proﬁles at 7-10 weeks’ gestation and birthweight in small for gestational age infants Harry M. Georgiou, PhD; Yulinda S. Thio, MD; Chris Russell, MBBS; Michael Permezel, MD; Yujing J. Heng, PhD; Stephen Lee, MBBS; Stephen Tong, MBBS, PhD OBJECTIVE: The purpose of this study was to investigate whether birth of a small-for-gestational-age (SGA) baby (birthweight, 10th percentile) is preceded by altered maternal serum cytokine proﬁles at early pregnancy, compared with control babies (birthweight, 30-80th percentile). STUDY DESIGN: A retrospective case-control study of maternal serum collected prospectively across 7-10 weeks of gestation from women at- tending their ﬁrst prenatal visit (SGA, 57 cases; control subjects, 71 cases selected retrospectively). Serum concentrations of 27 cytokines were mea- sured in each sample and analyzed by 2-way analysis of variance and non- parametric tests. Logistic regression was used for predictive modeling. RESULTS: Of 21 detectable cytokines/chemokines, 14 analytes varied signiﬁcantly (P  .030) among those women who were destined to de- liver an SGA baby, when compared with control subjects. Of the cyto- kines that varied in association with SGA, interferon- concentrations increased, and major proinﬂammatory (interleukin [IL]-2, -7, -12) and antiinﬂammatory (IL-1 receptor antagonist, -4, -10, -13) cytokine con- centrations decreased. Eotaxin and macrophage inﬂammatory pro- tein-1 were higher; monocyte chemoattractant protein-1 and IL-8 were lower. CONCLUSION: SGA births may be preceded by altered immune cyto- kine proﬁles at 7-10 weeks of gestation. Key words: cytokine proﬁle, disease prediction, inﬂammatory, immune system, small-for-gestational-age Cite this article as: Georgiou HM, Thio YS, Russell C, et al. Association between maternal serum cytokine proﬁles at 7-10 weeks’ gestation and birthweight in small for gestational age infants. Am J Obstet Gynecol 2011;204:415.e1-12. T he birth of a small-for-gestational- age (SGA) infant, 1,2 which possibly reﬂects an adverse uterine milieu, not only increases perinatal morbidity but confers a lifelong susceptibility to com- mon chronic adult diseases, such as coro- nary artery disease, diabetes mellitus, and stroke. 3 Therefore, the pathogenesis of SGA merits investigation because the de- velopment of any preventative therapies not only might improve immediate peri- natal morbidity and mortality rates but also might confer lifelong health beneﬁts. The immune system was long thought to play a limited role in pregnancy that quenched a fetal allograft response. Over the past decade, evidence has accrued that suggests that the immune system is a crucial player in the regulation of the depth of implantation, with uterine-spe- ciﬁc natural killer cells having a particu- larly critical role. 4-8 Given the role of the immune system in healthy implantation, 4-8 it is specu- lated that errors in immune-led placen- tation could be responsible for implan- tation disorders of pregnancy such as SGA (including intrauterine growth re- striction) and preeclampsia. 9 Although genotype combinations of uterine-spe- ciﬁc natural killer cell receptors and pla- cental human leukocyte antigen sub- types correlate with preeclampsia risk, 10 more direct clinical observations are lacking. Speciﬁcally, there is no direct clinical evidence temporally linking im- mune system differences around the time of implantation with the develop- ment of later gestational diseases. The purpose of this prospective study was to investigate whether there was ev- idence of differential immune system proﬁles at early pregnancy in association with SGA (birthweight, 10th percen- tile), when compared with babies who were born of average weight. MATERIALS AND METHODS Study cohort Ethics approval was obtained before commencement of the study (Mercy Health Human Research Ethics Com- mittee, study number R03/23), and From the Department of Obstetrics and Gynecology, University of Melbourne, Parkville (Drs Georgiou, Thio, Permezel, Heng, and Tong); Mercy Perinatal Research Center, Mercy Hospital for Women, Heidelberg (Drs Georgiou, Russell, Permezel, and Lee); and the Department of Obstetrics and Gynecology, Monash University, Clayton (Dr Tong), VIC, Australia. Presented in part at the 56th Annual Scientiﬁc Meeting of the Society for Gynecologic Investigation, Glasgow, Scotland, March 18-21, 2009, and at the Annual Meeting of the International Federation of Placenta Associations, Adelaide, South Australia, Oct. 6-9, 2009. Received May 18, 2010; revised Sept. 8, 2010; accepted Dec. 2, 2010. Reprints not available from the authors. Supported by the Medical Research Foundation for Women and Babies and The National Health and Medical Research Council of Australia, Grant nos. 509127 (H.M.G., S.T.), 490970 (S.T.), and 454880 (Y.J.H.). 0002-9378/$36.00 • © 2011 Mosby, Inc. All rights reserved. • doi: 10.1016/j.ajog.2010.12.005 Research www. AJOG.org MAY 2011 American Journal of Obstetrics & Gynecology 415.e1