Physiological adaptation of endothelial function to pregnancy: systematic review and meta-analysis.
OBJECTIVE
To establish reference values for flow-mediated dilatation (FMD) and brachial artery diameter (BAD) in pregnancy and to provide insight into the physiological and pathological course of endothelial adaptation throughout human singleton pregnancy.


METHODS
A meta-analysis was performed following a systematic review of current literature on FMD, as a derivative for endothelial function, and BAD, throughout uncomplicated and complicated pregnancy. PubMed (NCBI) and EMBASE (Ovid) electronic databases were used for the literature search, which was performed from inception to 9 June 2016. To allow judgment of changes in comparison with the non-pregnant state, studies were required to report both non-pregnant mean reference of FMD (matched control group, prepregnancy or postpartum measurement) and mean FMD at a predetermined and reported gestational age. Pooled mean differences between the reference and pregnant FMD values were calculated for predefined intervals of gestational age.


RESULTS
Fourteen studies that enrolled 1231 participants met the inclusion criteria. Publication dates ranged from 1999 to 2014. In uncomplicated pregnancy, FMD was increased in the second and third trimesters. Between 15 and 21 weeks of gestation, absolute FMD increased the most, by a mean (95% CI) of 1.89% (0.25-3.53%). This was a relative increase of 22.5% (3.0-42.0%) compared with the non-pregnant reference. BAD increased progressively, in a steady manner, by the second trimester but not significantly in the first half of the second trimester. We could not discern differences in FMD and BAD between complicated and uncomplicated pregnancies at 29-35 weeks' gestation, reported in the three studies that met our inclusion criteria. Despite the increase in FMD and BAD throughout gestation, both reference curves were characterized by wide 95% CIs.


CONCLUSIONS
During healthy pregnancy, endothelium-dependent vasodilatation and BAD increase. Women with a complicated pregnancy had FMD values within the lower range when compared with those with uncomplicated pregnancy but, as a group, did not differ from each other. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.
Department of Obstetrics and Gynaecology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.
V A
http://orcid.org/0000-0002-8323-8596
VA
Lopes van Balen
Department of Obstetrics and Gynaecology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.
T A G
TAG
van Gansewinkel
Department of Obstetrics and Gynaecology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.
S
S
de Haas
Department of Clinical Epidemiology and Medical Technology Assessment, Maastricht University Medical Center, Maastricht, The Netherlands.
S M J
http://orcid.org/0000-0003-2796-729X
SMJ
van Kuijk
Department of Obstetrics and Gynaecology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
J
http://orcid.org/0000-0002-4592-4288
J
van Drongelen
Department of Obstetrics and Gynaecology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.
C
C
Ghossein-Doha
Department of Obstetrics and Gynaecology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.
M E A
http://orcid.org/0000-0002-7837-5019
MEA
Spaanderman
D000222:Adaptation, Physiological / Q000502:physiology*; D001916:Brachial Artery / Q000502:physiology*; D004730:Endothelium, Vascular / Q000502:physiology*; D005260:Female; D006801:Humans; D046110:Hypertension, Pregnancy-Induced / Q000503:physiopathology*; D011247:Pregnancy; D011262:Pregnancy Trimester, Second / Q000502:physiology; D011263:Pregnancy Trimester, Third / Q000502:physiology; D012039:Regional Blood Flow; D014664:Vasodilation / Q000502:physiology*
FMD; endothelial function; fetal growth restriction; gestational hypertensive disease; physiology; placenta syndrome; pre-eclampsia; pregnancy