The Impact of Female Fetal Sex on Preeclampsia and the Maternal Immune Milieu

Overview

Journal Pregnancy Hypertens

Publisher Elsevier

Date 2018 Apr 21

PMID 29674199

Citations 27

Authors

Brandie D Taylor

Roberta B Ness

Mark A Klebanoff

Gong Tang

James M Roberts

David M Hougaard

Kristin Skogstrand

Catherine L Haggerty

Affiliations

Soon will be listed here.

Abstract

Objective: Small studies suggest that fetal sex alters maternal inflammation. We examined the association between fetal sex, preeclampsia and circulating maternal immune markers.

Methods: This was a secondary data analysis within a nested case-control study of 216 preeclamptic women and 432 randomly selected normotensive controls from the Collaborative Perinatal Project. All women had singleton, primiparous pregnancies without chronic health conditions. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) for associations between female fetal sex and preeclampsia. Outcomes included preeclampsia, preterm preeclampsia (<37 and <34 weeks), and normotensive preterm birth <37 weeks. Associations between female fetal sex and immune markers [interleukin (IL)-6, IL4, IL5, IL12, IL10, IL8, IL1-beta, interferon (IFN)-gamma, tumor necrosis factor (TNF)-beta, and transforming growth factor-beta] were examined using a statistical method developed for large proportions of censored biomarker data. Models were adjusted for maternal age, race, body mass index, and smoking.

Results: Women with early preterm preeclampsia (<34 weeks) had higher odds of having a female fetus (OR 3.2, 95% CI 1.1-9.6) and women with normotensive preterm birth had lower odds (OR 0.5, 95% CI 0.3-0.9). Female fetal sex was associated with lower first trimester pro-inflammatory IFNγ and IL-12 but higher second trimester pro-inflammatory IL1β and TNFβ, anti-inflammatory IL4r, and regulatory cytokines IL5 and IL10. Female fetal sex was associated with higher postpartum IL10 in preeclamptic women only.

Conclusions: We identified sexual dimorphism in maternal inflammation. Longitudinal studies are needed to determine if fetal sex impacts the maternal immune milieu across pregnancy.

Citing Articles

Higher prevalence of gestational diabetes in euthyroid women with thyroid autoimmunity who were expecting a female fetus.

Prasai M, Lomre M, Jelloul E, Kleynen P, Veltri F, Sitoris G Eur Thyroid J. 2025; 14(1).

PMID: 39888679 PMC: 11850046. DOI: 10.1530/ETJ-24-0339.

Maternal lipids in overweight and obesity: implications for pregnancy outcomes and offspring's body composition.

Albrecht M, Worthmann A, Heeren J, Diemert A, Arck P Semin Immunopathol. 2025; 47(1):10.

PMID: 39841244 PMC: 11754334. DOI: 10.1007/s00281-024-01033-6.

Sex-specific phenotypical, functional and metabolic profiles of human term placenta macrophages.

Paparini D, Grasso E, Aguilera F, Arslanian M, Lella V, Lara B Biol Sex Differ. 2024; 15(1):80.

PMID: 39420346 PMC: 11484421. DOI: 10.1186/s13293-024-00652-w.

Understanding preeclampsia from cutting edge knowledge-protecting maternal and fetal health.

Bokuda K Hypertens Res. 2024; 47(12):3367-3371.

PMID: 39375510 DOI: 10.1038/s41440-024-01932-z.

Placental Origins of Preeclampsia: Insights from Multi-Omic Studies.

Cao C, Saxena R, Gray K Int J Mol Sci. 2024; 25(17).

PMID: 39273292 PMC: 11395466. DOI: 10.3390/ijms25179343.

References

Staff A, Benton S, von Dadelszen P, Roberts J, Taylor R, Powers R . Redefining preeclampsia using placenta-derived biomarkers. Hypertension. 2013; 61(5):932-42. DOI: 10.1161/HYPERTENSIONAHA.111.00250. View

Dinse G, Jusko T, Ho L, Annam K, Graubard B, Hertz-Picciotto I . Accommodating measurements below a limit of detection: a novel application of Cox regression. Am J Epidemiol. 2014; 179(8):1018-24. PMC: 3966718. DOI: 10.1093/aje/kwu017. View

Skjaerven R, Wilcox A, Klungsoyr K, Irgens L, Vikse B, Vatten L . Cardiovascular mortality after pre-eclampsia in one child mothers: prospective, population based cohort study. BMJ. 2012; 345:e7677. PMC: 3508198. DOI: 10.1136/bmj.e7677. View

Redman C, Sargent I . Immunology of pre-eclampsia. Am J Reprod Immunol. 2010; 63(6):534-43. DOI: 10.1111/j.1600-0897.2010.00831.x. View

Velez D, Fortunato S, Morgan N, Edwards T, Lombardi S, Williams S . Patterns of cytokine profiles differ with pregnancy outcome and ethnicity. Hum Reprod. 2008; 23(8):1902-9. PMC: 6457081. DOI: 10.1093/humrep/den170. View

Vatten L, Skjaerven R . Offspring sex and pregnancy outcome by length of gestation. Early Hum Dev. 2004; 76(1):47-54. DOI: 10.1016/j.earlhumdev.2003.10.006. View

Malarstig A, Eriksson P, Hamsten A, Lindahl B, Wallentin L, Siegbahn A . Raised interleukin-10 is an indicator of poor outcome and enhanced systemic inflammation in patients with acute coronary syndrome. Heart. 2007; 94(6):724-9. PMC: 2564840. DOI: 10.1136/hrt.2007.119271. View

Muralimanoharan S, Maloyan A, Myatt L . Evidence of sexual dimorphism in the placental function with severe preeclampsia. Placenta. 2013; 34(12):1183-9. PMC: 3868439. DOI: 10.1016/j.placenta.2013.09.015. View

Yeganegi M, Leung C, Martins A, Kim S, Reid G, Challis J . Lactobacillus rhamnosus GR-1 stimulates colony-stimulating factor 3 (granulocyte) (CSF3) output in placental trophoblast cells in a fetal sex-dependent manner. Biol Reprod. 2010; 84(1):18-25. PMC: 4480822. DOI: 10.1095/biolreprod.110.085167. View

10.

Myatt L, Redman C, Staff A, Hansson S, Wilson M, Laivuori H . Strategy for standardization of preeclampsia research study design. Hypertension. 2014; 63(6):1293-301. DOI: 10.1161/HYPERTENSIONAHA.113.02664. View

11.

Shiozaki A, Matsuda Y, Satoh S, Saito S . Impact of fetal sex in pregnancy-induced hypertension and preeclampsia in Japan. J Reprod Immunol. 2011; 89(2):133-9. DOI: 10.1016/j.jri.2010.12.011. View

12.

Taylor B, Tang G, Ness R, Olsen J, Hougaard D, Skogstrand K . Mid-pregnancy circulating immune biomarkers in women with preeclampsia and normotensive controls. Pregnancy Hypertens. 2016; 6(1):72-8. PMC: 4785833. DOI: 10.1016/j.preghy.2015.11.002. View

13.

Andersen L, Jorgensen J, Herse F, Andersen M, Christesen H, Dechend R . The association between angiogenic markers and fetal sex: Implications for preeclampsia research. J Reprod Immunol. 2016; 117:24-9. DOI: 10.1016/j.jri.2016.05.005. View

14.

Enninga E, Nevala W, Creedon D, Markovic S, Holtan S . Fetal sex-based differences in maternal hormones, angiogenic factors, and immune mediators during pregnancy and the postpartum period. Am J Reprod Immunol. 2014; 73(3):251-62. PMC: 4317383. DOI: 10.1111/aji.12303. View

15.

Peelen M, Kazemier B, Ravelli A, de Groot C, van der Post J, Mol B . Impact of fetal gender on the risk of preterm birth, a national cohort study. Acta Obstet Gynecol Scand. 2016; 95(9):1034-41. DOI: 10.1111/aogs.12929. View

16.

Stumpf C, Lehner C, Yilmaz A, Daniel W, Garlichs C . Decrease of serum levels of the anti-inflammatory cytokine interleukin-10 in patients with advanced chronic heart failure. Clin Sci (Lond). 2003; 105(1):45-50. DOI: 10.1042/CS20020359. View

17.

Welsh P, Murray H, Ford I, Trompet S, de Craen A, Jukema J . Circulating interleukin-10 and risk of cardiovascular events: a prospective study in the elderly at risk. Arterioscler Thromb Vasc Biol. 2011; 31(10):2338-44. DOI: 10.1161/ATVBAHA.111.231795. View

18.

Elsmen E, Kallen K, Marsal K, Hellstrom-Westas L . Fetal gender and gestational-age-related incidence of pre-eclampsia. Acta Obstet Gynecol Scand. 2006; 85(11):1285-91. DOI: 10.1080/00016340600578274. View

19.

Clifton V, Murphy V . Maternal asthma as a model for examining fetal sex-specific effects on maternal physiology and placental mechanisms that regulate human fetal growth. Placenta. 2004; 25 Suppl A:S45-52. DOI: 10.1016/j.placenta.2004.01.004. View

20.

Nie L, Chu H, Liu C, Cole S, Vexler A, Schisterman E . Linear regression with an independent variable subject to a detection limit. Epidemiology. 2011; 21 Suppl 4:S17-24. PMC: 3265361. DOI: 10.1097/EDE.0b013e3181ce97d8. View