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\begin{document}

\title{Is endothelial function impaired among women with placenta-mediated
fetal growth restriction? Evidence from a prospective cohort study using
peripheral artery tonometry}



\author[1]{Michal Kirshenbaum}%
\author[1]{Lior Topaz}%
\author[1]{Micha Baum}%
\author[2]{Shali Mazaki-Tovi}%
\author[3]{Yoav Yinon}%
\affil[1]{Sheba Medical Center}%
\affil[2]{Sheba Medical Center, Tel-Hashomer, Israel 52621; Sackler School of Medicine, Tel Aviv University, Tel Aviv Israel 69978}%
\affil[3]{Chaim Sheba Medical Center}%


\vspace{-1em}



  
  \date{June 15, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Objective- To assess maternal endothelial function in singleton
pregnancies complicated by intrauterine growth restriction (IUGR) due to
placental dysfunction. Design- Prospective cohort study. Setting- 37
pregnant women who underwent endothelial function assessment using
EndoPATTM device. Population or Sample- Study population included two
groups: 1. Pregnancies with estimated fetal weight below 10th percentile
and abnormal umbilical artery flow (n=15); 2. Pregnancies with normal
fetal growth without placental complications matched by gestational age
(n=22). Exclusion criteria included diseases with potential vascular
dysfunction or smoking. Methods- EndoPAT device evaluates changes in
peripheral vascular flow and tone in reaction to temporal ischemia.
Normal post-ischemic endothelial reaction is an increase in vascular
flow. A ratio of the readings before and after ischemia is used to
calculate the score for endothelial function, called reactive hyperemic
index (RHI). Low RHI value indicates endothelial dysfunction. Main
outcome measures- RHI values. Results- Mean gestational age at endoPAT
examination was comparable between the IUGR and control group (32.5 \selectlanguage{ngerman}±
2.2 vs, 31.6 ± 3.2, respectively; p=0.21). Mean RHI was significantly
lower in the IUGR group compared to the control group (1.32 ± 0.16 vs
1.51 ± 0.31, p= 0.02, respectively). As expected, mean gestational age
at delivery and neonatal birth weight were lower in the IUGR group
compared to the control group (35.4 ± 2.3 vs 37.3 ± 2.6 p=0.04; 1640 ±
414 grams vs 2785 ± 587 grams, p\textless{}0.001 respectively).
Conclusions- Pregnant women with isolated IUGR due to placental
dysfunction had impaired endothelial function.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\emph{Tweetable abstract:}

Pregnant women with isolated IUGR due to placental dysfunction were
found to have impaired systemic endothelial function.

\emph{Funding statement:}

The authors have no funding sources to declare.

\emph{Introduction:}

Normal placental angiogenesis is a crucial process that establishes
feto-maternal circulation. Inadequate placental angiogenesis, defined as
defective remodeling of the uteroplacental arteries, can lead to
placental complications such as early pregnancy loss, preeclampsia and
intra-uterine growth restriction (IUGR) \textsuperscript{1}.

The physiological vascular changes observed in pregnancy, including an
increase in cardiac output and reduction in peripheral resistance and
blood pressure, are largely governed by alteration in endothelial
function mediated via nitric oxide and vascular endothelial growth
factor \textsuperscript{2,3}. Moreover, normal pregnancy is associated
with a reduction in central blood pressure, arterial stiffness and wave
reflection \textsuperscript{4}. There is a large body of evidence
indicating that endothelial dysfunction is involved in the
pathophysiology of preeclampsia. Studies, which have investigated
endothelial function by measuring flow mediated dilatation (FMD),
demonstrated decreased vasodilatation response in preeclamptic women
compared to normal pregnant women \textsuperscript{56}. Moreover,
augmentation index, a measure of systemic arterial stiffness, is
elevated in pregnancies complicated with hypertensive disease and
particularly preeclampsia \textsuperscript{78}. In addition, maternal
vascular function might help in defining a subset of patients who will
develop severe preeclampsia characteristics \textsuperscript{9}. These
findings supports the perception that vascular dysfunction is the
underlying pathophysiology of preeclampsia. In line with this
hypothesis, several studies have shown that endothelial dysfunction is
more common in women with a history of preeclampsia many years after the
affected pregnancy, compared to women with previous normal pregnancy.
These findings might explain their increased risk of future
cardiovascular disease \textsuperscript{10--12}. Similar to
preeclampsia, isolated intra-uterine growth restriction (IUGR) is also
associated with future maternal increased risk of ischemic heart
disease\textsuperscript{13}. Moreover, endothelial function, measured by
FMD, was significantly reduced in women with previous isolated
placenta-mediated IUGR 6-24 months after delivery \textsuperscript{14}.
Nevertheless, maternal endothelial function has never been evaluated
during pregnancies complicated by isolated placenta-mediated IUGR.

There are several noninvasive methods for endothelial function
assessment, all of which are based on the change in diameter and flow in
arteries in response to post ischemic reactive
hyperemia\textsuperscript{15}. A widely used method for assessing
endothelial function is flow mediated dilation (FMD). Nonetheless, the
clinical application of FMD is limited due to its dependence on the
operator's skills , its technical difficulties and problems with
calibration between laboratories, which may preclude its use in
widespread clinical practice \textsuperscript{16}. Therefore, new
noninvasive techniques have been developed in-order to make endothelial
function assessment more accessible in general medical practice.
Reactive hyperemia-peripheral artery tonometry (RH-PAT,
EndoPAT\textsuperscript{TM}-2000, Itamar Ltd., Caesarea, Israel) has
been recently developed as a simple and potentially more reproducible
method. Previous studies validated the use of
EndoPAT\textsuperscript{TM} and found a reliable correlation with
conventional FMD \textsuperscript{1718}.

Therefore, our aim was to compare endothelial function of healthy women
during pregnancy complicated with IUGR to those with normal pregnancies
using the EndoPAT\textsuperscript{TM} method.

\emph{Methods:}

\textbf{Subjects-}

This was a prospective observational cohort study, in which women who
attended the MFM clinics at a single tertiary center, were enrolled
during an 18 months period. The study group included women with
pregnancies complicated by isolated placenta-mediated IUGR. IUGR was
defined as estimated fetal weight below the
10\textsuperscript{th}percentile using population-based growth curves
for singletons accompanied by an abnormal umbilical artery Doppler flow,
defined as pulsatility index above the 95\textsuperscript{th} percentile
or absence/ reverse of end- diastolic velocity \textsuperscript{19}. The
control group included women with uncomplicated pregnancies with
appropriate for gestational age (AGA) fetus matched to the study group
by gestational age at testing. Exclusion criteria for both groups
included hypertensive diseases of pregnancy, chronic hypertension, renal
disease, diabetes mellitus, smoking, body mass index \textgreater{}30
kg/m\textsuperscript{2} , aspirin treatment and betamethasone
administration within a week prior to the EndoPAT test. Patients with
fetal anomalies or genetic abnormalities were also excluded. The
abnormal umbilical artery Doppler flow and lack of fetal anomalies and
genetic abnormalities indicated that placental insufficiency was most
likely the underlying cause of IUGR.

The study was approved by the institutional review board of Sheba
medical center. All women gave informed written consent before entering
the study.

\textbf{Endothelial function assessment-}

Maternal endothelial function was assessed using the
Endo-PAT\textsuperscript{TM} 2000 device. Unlike previously used
techniques of duplex ultra-sonography to assess flow-mediated
vasodilation, the Endo-PAT\textsuperscript{TM} is totally
non-operator-dependent method, which assesses digital flow mediated
dilatation during reactive hyperemia, as a measure of endothelial
function. The device records endothelium-mediated changes in the digital
pulse waveform known as the PAT ( Peripheral Arterial Tone) signal,
measured with a pair of novel modified plethysmographic probes, situated
on the index finger of each hand. Endothelium-mediated changes in the
PAT signal are elicited by creating a downstream hyperemic response.
Hyperemia is induced by occluding blood flow through the brachial artery
for 5 minutes using an inflatable cuff on one hand. The response to
reactive hyperemia is calculated automatically by the system. Reactive
Hyperemia Index (RHI) is the post to pre occlusion PAT signal ratio in
the occluded side. These values are normalized to measurements from the
contra-lateral arm, which serves as control for non-endothelial
dependent systemic effects. Higher RHI values represent adequate
endothelial cell hyperemic response and well endothelial function. Based
on previous validation studies, RHI \textgreater{}1.67 was considered as
normal \textsuperscript{1820}.

All examinations were performed in the same temperature controlled room,
during the morning, after a night fasting. Figure 1 shows examples of
normal and abnormal EndoPAT tests.

\textbf{Statistical analysis-}

On the basis of previous validation studies, which defined normal
endothelial function as RHI \textgreater{}1.67 and revealed a variance
of \textasciitilde{} 15\% in RHI measurement, 11 subjects in each group
were required to detect a difference between groups of at least 15\%
(corresponding to absolute difference in RHI of 0.25 units) with 80\%
power and 5\% type 1 error \textsuperscript{21,22}. Normally distributed
data were described as mean \selectlanguage{ngerman}± standard deviation (SD), and non-normally
distributed data were described as median and intra-quartile range
(IQR). Univariate analyses were performed by t-test or Mann-Whitney test
as appropriate for continuous variables and by Chi-square or Fisher's
exact test for categorical variables. Significant difference was defined
as p\textless{}0.05. All analyses were conducted using SPSS 24 (SPSS
Inc., Chicago, IL).

\emph{Results:}

A total of 37 patients were enrolled and included in the study: 15
patients with IUGR consisted the study group and 22 patients with AGA
fetus consisted the control group. Maternal characteristics and
obstetric outcomes of the study groups are resented in table 1. Maternal
age, parity and BMI were comparable between the groups (table 1). As
expected, patients in the IUGR group were delivered earlier compared to
the controls (36.7 vs 37.7 weeks, p=0.04) and the mean neonatal birth
weight was significantly lower among the IUGR group compared with the
normal controls (1634 ± 428 grams vs 2785 ± 587 grams respectively,
p\textless{}0.01).

The results of endothelial function assessment are described in table 2.
The median gestational age at EndoPAT test was 32 weeks in both groups
(table 2). Systolic and diastolic blood pressure did not differ between
the two groups at the time of endothelial function assessment (113 vs
110 mmHg, p= 0.08; 74 vs 67 mmHg, p=0.06, respectively). The median RHI
value was significantly lower in the IUGR group compared with the normal
control group (1.31 vs 1.47 respectively, p=0.04). All women in the IUGR
group had an abnormal RHI value (\textless{}1.67), compared with 68\% of
the control group (p=0.056).

\emph{Disscusion:}

In the current study, we found that RHI values of women with pregnancies
complicated with placenta-mediated IUGR were significantly lower
compared with RHI values of pregnant women with normal intra-uterine
growth. The lower RHI values indicate systemic vascular dysregulation
and endothelial dysfunction.

Of note, although the median RHI value was significantly lower among
women in the IUGR group, the median RHI value in women with normal fetal
growth was also below the level defined as normal in the general
population. This finding is in correlation with previous studies that
assessed endothelial function in different stages during normal
pregnancy, and found that from the third trimester onward, there is a
gradually deterioration in endothelial function \textsuperscript{2324}.
Therefore, it is possible that there is a physiological decrease in
endothelial function during normal pregnancies. This finding may account
for the lack of significant difference in the rate of endothelial
dysfunction between the two groups, according to the definition used in
the non-pregnant population. Of note is the fact that despite the
physiologic endothelial dysfunction demonstrated in the control group,
the absolute lower RHI levels among women with IUGR pregnancies
indicates that endothelial function is impaired in women with
normotensive IUGR.

It is well established that women with preeclampsia exhibit endothelial
dysfunction both during pregnancy and years after
delivery\textsuperscript{11,25,26}. However, the data regarding IUGR
pregnancies without hypertension or preeclampsia are limited.
Endothelial cell activation markers were reported to be higher only in
preeclamptic but not in IUGR pregnancies, supporting the hypothesis that
endothelial dysfunction in IUGR pregnancies is confined to the
uteroplacental circulation and is not systemic as in preeclampsia
\textsuperscript{27}. On the other hand, Yinon et al. have showed that
patients with previous early onset placenta-mediated IUGR without
preeclampsia had endothelial dysfunction years after delivery similar to
patients with previous early-onset preeclampsia. Moreover, patients with
previous IUGR had the most severe degree of endothelial dysfunction even
in comparison to patients with previous preeclampsia
\textsuperscript{14}. These findings correlate with epidemiological data
indicating increased risk for cardiovascular disease in women who had
pregnancies complicated by IUGR\textsuperscript{13}. The findings of our
study support the aforementioned studies and show that endothelial
function in women with pregnancies complicated by IUGR is already
impaired during pregnancy. It is well known that multiple key angiogenic
factors play a crucial role in placental angiogenesis, amongst them are
sFLT-1, sEng, VEGF and PlGF, which coordinate to generate the placental
villous tree, and abnormal expression of these angiogenic factors will
result in endothelial dysfunction \textsuperscript{2829}. However, it is
still unknown whether maternal exposure to these angiogenic factors
released from the ischemic placenta during pregnancy result in
endothelial damage and future maternal vascular disease or whether
endothelial dysfunction is a preexisting condition leading to both
placental dysfunction in pregnancy resulting in preeclampsia and IUGR
and to increased risk of future cardiovascular disease later in life. We
believe that our data support the later theory in which maternal
vascular dysfunction is a predisposing factor leading to both abnormal
placental development and future cardiovascular disease. However, in
order to prove this hypothesis, it would be preferable to assess
endothelial function prior to conception.

Our finding of impaired endothelial function in women with pregnancies
complicated with IUGR may explain the increased risk of these women for
future cardiovascular disease. Therefore, intervention such as lifestyle
modification or prophylactic treatment may prove beneficial in reducing
long- term morbidity and mortality among these women.

The strength of this study lies in its prospective nature and the well
characterization of the study groups including patients with isolated
IUGR without hypertensive diseases. Only cases of IUGR that were
accompanied with abnormal umbilical artery Doppler flow were included,
thus ensuring that all cases of IUGR were due to placental
insufficiency. Moreover, to best of our knowledge, this is the first
study investigating endothelial function in IUGR pregnancies using the
EndoPAT\textsuperscript{TM} method. The main limitation of this study is
the small number of patients studied, which may limit our ability to
detect differences between the groups. However, despite the small sample
size, significant difference in RHI was found between the two groups.

\textbf{Conclusion:}

Our study found that endothelial function among women with pregnancies
complicated with IUGR due to placental insufficiency was significantly
impaired compared to women with normal pregnancies. More studies are
needed in order to assess the effectiveness of endothelial function test
using EndoPAT device early in gestation to predict IUGR and the
implication of endothelial dysfunction during pregnancies complicated
with IUGR on these women's future health.

\emph{Disclosure of interests:} The authors have no financial, personal,
political, intellectual or religious interests to declare.

\emph{Contribution to authorship:}

Michal Kirshenbaum- Conceived and planned the experiment, performed the
endothelial function assessment using the EndoPAT device and wrote the
manuscript.

Lior Topaz- Performed the endothelial function assessment using the
EndoPAT device.

Micha Baum- Helped in planning the experiment and recruiting the
patients.

Shali Mazaki-Tovi- Helped in planning the experiment, recruiting the
patients and interpreting the final results.

Yoav Yinon- Conceived and planned the experiment, contributed to the
interpretation of the results and consulted in writing the manuscript.

\emph{Ethic approval:}

The study was approves by Sheba Medical Center IRB

protocol number: 2624-15-SMC

\emph{Funding statement:} We have no funding source to declare.

\emph{References:}

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Table 1. Maternal characteristics and obstetric outcomes\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
& \textbf{IUGR} & \textbf{Control} & \textbf{P}\tabularnewline
\midrule
\endhead
\textbf{Maternal age, mean SD} & 30.8 & 31.6 & 0.3\tabularnewline
\textbf{G median (IQR)} & 2 (1,3) & 2 (1,3) & 0.4\tabularnewline
\textbf{BMI} & 26.2 \selectlanguage{ngerman}± 5.3 & 26.8 \selectlanguage{ngerman}± 4.2 & 0.35\tabularnewline
\textbf{Gestational age at delivery, median (IQR)} & 36.7 (35.6, 37.2) &
37.7 (35.3, 39.3) & 0.04\tabularnewline
\textbf{Neonatal weight, mean SD} & 1634 \selectlanguage{ngerman}± 428 & 2785 \selectlanguage{ngerman}± 587 &
\textless{}0.001\tabularnewline
\bottomrule
\end{longtable}

BMI- body mass index

Table 2. Endothelial function assessment\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
& \emph{IUGR} & \emph{Control} & \emph{P}\tabularnewline
\midrule
\endhead
\emph{Gestational age at EndoPAT, median (IQR)} & \emph{32.(31,33)} &
\emph{32 (31,33)} & \emph{0.18}\tabularnewline
\emph{Systolic BP prior to EndoPAT, median (IQR)} & \emph{113 (110,118)}
& \emph{110 (100,114)} & \emph{0.08}\tabularnewline
\emph{Diastolic BP prior to EndoPAT, median (IQR)} & \emph{74 (67, 78)}
& \emph{67 (60, 76)} & \emph{0.07}\tabularnewline
\emph{RHI, median (IQR)} & \emph{1.31 (1.215,1.345)} & \emph{1.47
(1.29,1.57)} & \emph{0.02}\tabularnewline
\emph{RHI \textless{} 1.67 n (\%)} & \emph{15 (100)} & \emph{15 (68)} &
\emph{0.05}\tabularnewline
\bottomrule
\end{longtable}

BP- blood pressure

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