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Clinical and Experimental Obstetrics & Gynecology  2020, Vol. 47 Issue (2): 277-286    DOI: 10.31083/j.ceog.2020.02.5299
Original Research Previous articles | Next articles
Human placental suppressors of cytokine signalling (SOCS) and inflammatory cytokines are dysregulated in assisted reproduction, advanced maternal age and pre-term birth
S. J. Knight1, A. D. Smith1, H. Kim2, 3, 4, A. C. Collier1, *()
1Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada
2Centre for Blood Research, University of British Columbia, University of British Columbia, Vancouver, Canada
3Faculty of Dentistry, University of British Columbia, Vancouver, Canada
4Department of Biochemistry and Molecular Biology, University of British Columbia, University of British Columbia, Vancouver, Canada
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Summary of Investigation: Assisted reproduction technologies (ART) are now commonly used to conceive. ART is associated with higher incidence of negative birth outcomes which may be due to altered cytokine signaling. Materials and Methods: This pilot study evaluated the suppressors of cytokine signaling SOCS and levels of proinflammatory cytokines ART and non-ART placentas (n=14 each) matched for maternal and gestational age, delivery method, pregnancy weight gain, and body mass index. Comparisons of advanced maternal age (AMA), with or without pre-term birth (PTB) were included. SOCS1, 2, and 3 levels were evaluated with immunohistochemistry and IFN-γ, IL1-β, IL-6, IL-8, IL-10, and TNF-α with ELISA. Results: ART was associated with significantly lower SOCS3. Although SOCS1/IL-10 and SOCS2 and 3/IFN-γ significantly associated in normal conception, associations were lost in ART. In AMA, placental SOCS1 and 2 were associated with IFN-γ, and SOCS3 with IL-6, but under 35 these associations were lost. Term birth was associated with placental SOCS1 inhibition of IL-8 and SOCS2 induction of IL-10, but PTB was not. Conclusion: Cytokine signaling is dysregulated in human placentas by ART which might be a cause of negative reproductive outcomes in ART.

Key words:  Advanced maternal age      Advanced maternal age      In vitro fertilization      Infertility      Inflammation      Parturition      Pre-term birth     
Published:  15 April 2020     
Fund: RMATRIX - 3U54MD007584-03S1/National Institutes of Health;MC2-127872/Canadian Institutes of Health Research (CIHR) Clinician-Scientist Salary Award Faculties of Dentistry and Pharmaceutical Sciences, UBC
*Corresponding Author(s):  A. C. Collier     E-mail:

Cite this article: 

S. J. Knight, A. D. Smith, H. Kim, A. C. Collier. Human placental suppressors of cytokine signalling (SOCS) and inflammatory cytokines are dysregulated in assisted reproduction, advanced maternal age and pre-term birth. Clinical and Experimental Obstetrics & Gynecology, 2020, 47(2): 277-286.

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Table 1  — Demographics of the cohort.
Normal conception (n = 14) Assisted reproductive technology (n = 14) p value
Maternal age (years) 33.77 ± 2.02 34.85 ± 1.24 0.55
Gestational age (days) 248.7 ± 30.9 248.2 ± 26.0 0.95
Delivery method
Caesarian 64 % (n = 9) 64 % (n = 9) 1
Vaginal 36 % (n = 5) 36 % (n = 5)
Pregnancy weight gain (kg) 11.2 ± 8.7 9.4 ± 3.9 0.57
Asian 61 % 48 % 0.12
Caucasian 28 % 48 % 0.008
Native Hawaiian/Pacific Islander 10 % 4 % 1
Nested study
n = 3
n = 3
n = 5
n = 3
n = 3
n = 3
n = 5
n = 3
Maternal age (years) 38.0 ± 2.0 42.3 ± 4.0 26.5 ± 4.9 30.7 ± 2.1 40.6 ± 3.1 37.0 ± 2.7 31.8 ± 1.7 31.0 ± 1.0
Gestational age (weeks) 33.5 ± 1.1 38.9 ± 0.7 30.4 ± 5 39.4 ± 0.9 34.2 ± 1.7 38.1 ± 1.2 32.3 ± 4.7 38.3 ± 0.9
Figure 1.  — Representative immunohistochemistry micrographs for SOCS 1, 2, and 3. Left column is negative control, right column is the ART slide (positive). Black arrows indicate positive DAB staining (brown) localized to the syncytium. Endothelial staining is not apparent. Counterstaining of nuclei (blue) is with Gill’s Hematoxylin. Despite quenching, slight non-specific staining of erythrocytes is noticeable.

Figure 2.  — SOCS expression levels in human placenta. A-C: Normal conception vs. assisted reproduction (ART); D-F: Term vs. preterm birth (PTB) regardless of conception method. G-I Advanced maternal age (AMA ≥ 35 years) vs. normal maternal age (< 35 years), regardless of conception method. Bars are means ± SEM. N values for each bar are listed underneath.

Figure 3.  — Correlations between SOCS and cytokines in placentas from normally conceived and ART pregnancies. A and B: SOCS1 correlates strongly with IL-10 in normally conceived placentas (p = 0.002, r = 0.77) but not in ART (p = 0.52, r = 0.19). C and D: SOCS2 correlates well with IFN-γ in normally conceived placentas (p = 0.02, r = 0.60) but not in ART (p = 0.80, r = 0.08), and E and F: SOCS3 correlates strongly with IFN-γ in normally conceived placentas (p = 0.02, r = 0.48) but not in ART (p = 0.56, r = 0.17). Solid line is the correlation fit, dashed line is the 95% confidence interval.

Figure 4.  — Significant associations between SOCS and cytokines in placental tissue from AMA pregnancies ñ these associations did not occur placentas from mothers under 35. A and B: SOCS1 is positively correlated with TNF-α (p = 0.04, r = 0.60) in placentas from AMA mothers, but the correlation does not occur in normal maternal age (p = 0.38, r = 0.28). B: SOCS2 is strongly correlated with TNF-α (p = 0.003, r = 0.80) in AMA, but not in normal maternal age (p = 0.93, r = -0.03). C: SOCS3 is strongly correlated with IL6 (p = 0.009, r = 0.73), but this is not observed in placentas from normal maternal aged women (p = 0.89, r = -0.04). Solid line is correlation fit, dashed line is 95% confidence interval.

Figure 5.  — Significant associations between SOCS and cytokines in term placental tissue, that were lost in pre-term birth. A and B: SOCS2 is correlated with placental IL-10 at term (p = 0.03, r = 0.62), but not in pre-term placentas (p = 0.01, r = 0.95). C and D: SOCS3 is negatively correlated with IL-8 (p = 0.03, r = -0.59) at term, but not in pre-term placentas (p = 0.59, r = -0.17). Solid line is correlation fit, dashed line is 95% confidence interval.

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