1073 Pregnancy is an immunologic paradox: the semialloge- netic blastocyst is not rejected by the immune system of the mother. 1 To solve this paradigm, research has focused on the specific immune response during pregnancy. It has been suggested that type 1 cytokines are harmful for maintenance of pregnancy, whereas type 2 cytokines ap- pear to be protective for the fetus. 2-5 Therefore, during pregnancy the immune response is shifted from a T H 1 type response (cellular immune response) to a T H 2 type immune response (humoral immune response). 6 In- deed, we have shown that lymphocytes from pregnant women show a decreased production of T H 1 cytokines compared with nonpregnant women. This results in a de- creased T H 1/T H 2 ratio during pregnancy. 7 Little is known about the innate immunity (ie, inflam- matory responses) during pregnancy. Previous research from our laboratory has shown that endotoxin-induced inflammatory responses are much more intense and per- sistent in pregnant rats compared with nonpregnant rats. 8 This suggests that pregnancy is a proinflammatory condition, which is in line with other data demonstrating that circulating monocytes and granulocytes are activated during pregnancy in humans 9 and in rats. 10 Sacks et al 11 hypothesized that particulate or soluble placental prod- ucts may have modulating effects on the maternal im- mune response during human pregnancy. Monocytes could possibly be target cells and could be activated. 11 Monocytes are the first cells to be activated in nonspe- cific immune responses. On activation (eg, by endo- From the Department of Obstetrics and Gynecology, University Hospital Groningen, a Reproductive Immunology, Division of Medical Biology, Department of Pathology and Laboratory Medicine, University of Groningen, b and the Department of Obstetrics and Gynecology, Medical Center Leeuwarden. c Supported by the the “J.C. de Cock Stichting” grant No. 00-12. Received for publication June 6, 2002; revised October 28, 2002; ac- cepted January 8, 2003. Reprint requests: A. L. Veenstra van Nieuwenhoven, MD, Department of Obstetrics and Gynecology, CMC5, 4th Floor, Room Y4218, University Hospital Groningen, Hanzeplein 1, 9700 RB Groningen. E-mail: veenstravannieuwenhoven@freeler.nl © 2003, Mosby, Inc. All rights reserved. 0002-9378/2003 $30.00 + 0 doi:10.1067/mob.2003.263 Endotoxin-induced cytokine production of monocytes of third-trimester pregnant women compared with women in the follicular phase of the menstrual cycle Angelique L. Veenstra van Nieuwenhoven, MD, a Annechien Bouman, MD, a Henk Moes, b Maas Jan Heineman, MD, PhD, a Loe F. M. H. de Leij, PhD, c Job Santema, MD, PhD, c and Marijke M. Faas, PhD b Groningen, The Netherlands OBJECTIVE: Little is known about the function of the innate immune response during pregnancy.We there- fore investigated monocyte cytokine production, as a measure of monocyte function, in pregnant women compared with nonpregnant women. STUDY DESIGN: Whole blood of women in the follicular phase (day 5-6) and of healthy pregnant women (30 weeks) was collected and stimulated with endotoxin (2 μg/mL). After incubation for 4 hours (37°C, 5% carbon dioxide), red blood cells were lysed and white blood cells were permeabilized, followed by staining with anti- CD14 (fluorescein isothiocyanate labeled) and with phycoerythrin-labeled tumor necrosis factor-α, inter- leukin-1β, or interleukin-12. The cells were analyzed by flow cytometry after fixation. Results are expressed as a percentage cytokine producing cells after endotoxin stimulation. Statistical analysis was performed with the Mann-Whitney U test (P < .05). RESULTS: Compared with the percentage endotoxin-induced cytokine producing peripheral monocytes in women in the follicular phase, this percentage in pregnancy was decreased for interleukin-12 (mean 6.63 ± 1.34 vs 3.34 ± 0.87, P < .05) and tumor necrosis factor-α (mean 50.20 ± 5.80 vs 31.29 ± 5.57, P > .05). No significant difference was seen in the production of interleukin-1β (mean 58.22 ± 11.09 vs 47.18 ± 7.88, P > .05). CONCLUSION: The percentage of interleukin-12 and tumor necrosis factor-α producing monocytes is de- creased in pregnant women compared with nonpregnant women, suggesting that pregnancy is a proinflam- matory state. (Am J Obstet Gynecol 2003;188:1073-7.) Key words: Cytokine production, interleukin-12, tumor necrosis factor-α, monocytes, pregnancy, interleukin-1β, endotoxin