Date post: | 07-May-2015 |
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Health & Medicine |
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Functional adaptation during pregnancy: a meta-analysis
of animal studies
J. van Drongelen
Insight in:
1. Cellular pathways involved in pregnancy-induced
vasodilation
2. Systematic overview of literature (mesenteric arteries)
3. Advantages of systematic review of animal studies
During pregnancy
Chamberlain and Broughton (1998); Slangen et al. (1996); Danielson et al. (1995)
Human Weeks of gestation
Rat Days of gestation NP 5 11 16 21
Vasodilation
Mesenteric vascular bed important!
Local vascular tone
EC
M
Local vascular tone
EC
M
Local vascular tone
Pressure
EC
M
Local vascular tone
EC
M
Pressure
Measuring vasomotion
SMC
Resp
on
se
EC
Measuring vasomotion
EC50%
Emax
Effect
Stimulus
50%
Summary
• Pregnancy induces vasodilation
• Two types of stimuli (pharmacological / mechanical)
• G-protein coupled receptors are important
• Theories mainly based on rats
Mesenteric system is important
Conflicting results in literature
Idea
• Systematic review
Effect of first pregnancy on vascular responses in mesenteric arteries
Goal
Selection of studies concerning
• Healthy subjects in their first pregnancy
• Healthy nulliparous subjects
• Comparable age
• Vasodilator and vasoconstrictor mesenteric responses
Pubmed and Embase search
Three components
1. Pregnancy
2. Mesenteric arteries
3. Vasodilator and vasoconstrictor responses
Component Description
Pregnancy "pregnancy"[MeSH Terms] OR "pregnancy"[tiab] OR "pregnancies"[tiab] OR
"gestation"[tiab] OR "pregnant"[tiab] OR "maternal-fetal relations"[tiab]
Mesenteric arteries "mesenteric arteries"[MeSH Terms] OR "Mesentery/blood supply"[Mesh] OR
"mesenteric"[tiab] OR "mesentery artery"[tiab] OR "mesentery arteries"[tiab] OR
"mesenterial artery"[tiab] OR "mesenterial arteries"[tiab] OR "arteria
mesenterica"[tiab] OR "omental microvessels"[tiab] OR "omental arteries"[tiab] OR
"omental artery"[tiab]
Vasoconstrictor and
vasodilator responses
"vasoconstriction"[MeSH Terms] OR "vasoconstriction"[tiab] OR
"vasoconstrictions"[tiab] OR "vasoconstrictor agents"[MeSH Terms] OR
"vasoconstrictor agents"[Pharmacological Action] OR "vascular resistance"[MeSH
Terms] OR "vascular resistance"[tiab] OR "vascular capacitance"[MeSH Terms] OR
("vascular"[tiab] AND "capacitance"[tiab]) OR "vasoconstrictor"[tiab] OR
"vasoconstrictors"[tiab] OR "vasopressor"[tiab] OR "vasoactive agonist"[tiab] OR
"vasoactive agonists"[tiab] OR "vasopressors"[tiab] OR "vasomotor system"[MeSH
Terms] OR "vasomotor system"[tiab] OR "peripheral resistance"[tiab] OR "artery
constriction"[tiab] OR "vessel constriction"[tiab] OR "vasoconstrictive"[tiab] OR
"vasoconstricting"[tiab] OR "vasoconstricted"[tiab] OR "vasodilation"[MeSH Terms]
OR "vasodilation"[tiab] OR "vasodilatation"[tiab] OR "vasodilatating"[tiab] OR
"vasodilating"[tiab] OR "vasodilative"[tiab] OR "vasodilatative"[tiab] OR "artery
dilation"[tiab] OR "vessel dilation"[tiab] OR "artery dilatation"[tiab] OR "vessel
dilatation"[tiab] OR "vasodilator agents"[MeSH Terms] OR "vasodilator
agents"[Pharmacological Action] OR "vasodilator"[tiab] OR "vasodilators"[tiab] OR
"vasorelaxation"[tiab] OR "Vascular Endothelium Dependent Relaxation"[tiab] OR
"Endothelium Dependent Relaxation"[tiab] OR "Vascular Endothelium-Dependent
Relaxation"[tiab] OR "Endothelium-Dependent-Relaxation"[tiab] OR
"hemodynamics"[MeSH Terms] OR "hemodynamics"[tiab]OR "hemodynamic"[tiab]
OR "vasodilated"[tiab] OR "vasoactive agent"[tiab] OR "vasoactive drug"[tiab] OR
"vasoactive drugs"[tiab] OR "dilation"[tiab] OR "dilatation"[tiab] OR
"contraction"[tiab] OR "relaxation"[tiab]
Identified studies (n=398)
Subtracted studies (n=96)
Title and abstract (n=302)- No healthy first pregnancy versus virgin control (n=258)- No mesenteric artery vasoconstrictor/vasodilator response (n=19)- No standard medium (n=5)- No original data; review (n=20)
Included studies (n=55)
Full article (n=43)- No healthy first pregnancy versus virgin control (n=12)- No mesenteric artery vasoconstrictor/vasodilator response (n=26)- No age-matching (n=5)
Included responses (r=188)- Pharmacological /
Electrical (r=160)* EC50 described (r=83)* Emax described (r=63)* Graph present (r=130)
- Mechanical (r=28)* Graph present (r=27)
Responses (r=78)- Response <5 measurements (r=38)- Other blockade than NO, PGI2, endothelium (r=40)
Inclusion and exclusion
Study characteristics
Species (55 studies)
• Rodents: - rat (n=46)
SDR (n=27)
WR (n=15)
unknown (n=1)
- mouse (n=5)
- guinea pig (n=2)
• Rabbit (n=1)
• Pigs (n=1)
Gestational period (188 responses)
• Early (r=3)
• Mid (r=23)
• Late (r=161)
• Unknown (r=1)
Quality
Randomization 4%
Blinding 0%
Pharmacological stimuli
• EC50% 52%
• Emax 39%
• Graph 81%
• Clear number 74%
Mechanical stimuli
• Effect size 7%
• Graph 96%
• Clear number 92%
Meta-analysis
x3
Results
= =
=
EC
M
Pressure
In summary
SDR WR Mice Guinea pigs
Vasodilation
- flow-mediated vasodilation
.
.
- compliance = . .
- vasodilator agents (EC) =
- vasodilator agents (SMC) . . .
Vasoconstriction
- myogenic reactivity
?
=
.
.
- vasoconstrictor agents (SMC) = =
Conclusion
1. Most studies concern late pregnancy
2. Quality is limited
3. Flow-mediated vasodilation is uniformly upregulated
4. Heterogeneity amongst species
5. Importance of systematic reviews for animal data
6. Difficulty in extrapolation to vasodilator pathways
involved in human pregnancy
Take home message
Systematic reviews of animal studies
• Give new insight
• Identify lacunas in knowledge
• Lead to new original research
• Increase efficancy of animal use
• Reduce unnecessary use of animals
Take home message
Systematic review of animal studies
There is no excuse
Acknowledgements
Dr. CR Hooijmans
Dr. RBM de Vries
Drs. L. ten Bos
Prof. Dr. PABM Smits
Prof. Dr. FK Lotgering
Prof. Dr. MJ Ritskens
Prof. Dr. MEA Spaanderman